133. Case Report: Ventricular Arrhythmias & Heart Failure – A Shocking Diagnosis – University of Chicago

CardioNerds (Amit Goyal and Daniel Ambinder), join cardiology fellows from the University of Chicago, (Dr. Mark Belkin, Dr. Ian Hackett, and Dr. Shirlene Obuobi) for an important discussion about case of a woman presenting with implantable cardioverter-defibrillator (ICD) discharges found to be in ventricular tachycardia (VT) storm and work through the differential of ventricular arrhythmias, etiologies of heart failure, and indications for permanent pacemaker and ICD placement. Advanced imaging modalities that aid in the diagnosis of cardiac sarcoidosis, manifestations and management of cardiac sarcoidosis are also discussed. Dr. Nitasha Sarswat and Dr. Amit Patel provide the E-CPR for this episode. Audio editing by CardioNerds Academy InternLeticia Helms.

Claim free CME just for enjoying this episode! Disclosures: Dr. Amit Patel disclosed ownership of small stocks in GE Healthcare Bio-Sciences.

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Case Media


Episode Teaching

Pearls

  1. The etiology of wide-complex tachycardias (WCT) of ventricular origin can be broken down by structurally normal versus structurally abnormal hearts. WCT in structurally normal hearts can be further broken down into idiopathic or primary arrhythmia syndromes. WCT in structurally abnormal hearts can be broken down into ischemic and non-ischemic etiologies.
  2. In patients with an unexplained non-ischemic cardiomyopathy, conduction abnormalities and/or ventricular arrhythmias should raise suspicion for cardiac sarcoidosis. Additional manifestations include atrial arrhythmias and  pulmonary hypertension.
  3. Accurate diagnosis and treatment of cardiac sarcoidosis often requires multimodality cardiovascular imaging. Check out these terrific videos from Cardiac Imaging Agora: 1) PET for inflammation/sarcoidosis and 2) Echo and CMR for sarcoidosis.
  4. While a pathological tissue diagnosis is the gold-standard, endomyocardial biopsy has a low sensitivity, weven when paired with image guidance. Remember to consider extra-cardiac sites for biopsy.
  5. Decisions regarding ablation of ventricular arrhythmia or ICD placement should be done individually with careful assessment of active inflammation secondary to cardiac sarcoidosis and possible response to immunosuppressive medications.
  6. Management of cardiac sarcoidosis has two basic principles: 1) Treat the underlying process with immunosuppression and 2) Treat the cardiac sequelae: heart failure, conduction abnormalities, ventricular arrhythmias, atrial arrhythmias, and pulmonary hypertension.

Notes

1. The patient in this case was found to be in VT storm. Taking a step back, when we suspect a wide complex tachycardia (WCT) is VT, what are some etiologies we should keep in mind?

  • Differentiating between a supraventricular vs. ventricular origin of a WCT will be a topic for a future episode! But after you have determined that the origin of WCT is ventricular, considerations for the underlying etiology should include ischemia-related, non-ischemic cardiomyopathy-associated, primary arrhythmia syndromes and idiopathic (in addition to common considerations such as medications and electrolyte abnormalities)
  • Chronic ischemia-related WCT is typically scar-mediated, a result of re-entrant mechanism and more commonly presenting as monomorphic VT. WCT in the setting of acute ischemia is likely a result of combination increased automaticity and re-entry, typically manifesting as polymorphic VT.  In fact, acute ischemia is the most common cause of polymorphic VT, not Torsades de Pointes, and should be our first consideration. Torsades de Pointes specifically occurs due to an early afterdepolarization in a patient with an acquired or congenital prolonged QT interval.
  • Non-ischemic related WCT etiologies in structurally abnormal hearts include (but not limited to) cardiac sarcoidosis, myocarditis (specifically giant-cell myocarditis), hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left dominant arrhythmogenic cardiomyopathy and Chagas disease. Especially in patients with dilated CM, if your initial evaluation does not reveal an etiology, then genetic testing should be considered to identify genetic sources of arrhythmogenic cardiomyopathies, such as laminin and desmoplakin mutations (See Episode 56: CNCR with Northwestern University!)
  • Primary arrhythmia syndromes include, but are not limited to, Brugada, Long QT, Short QT, and catecholaminergic polymorphic VT (CPVT).
  •  Idiopathic WCT includes outflow tract, fascicular, or papillary muscle ventricular tachycardias (VT).


2. What is the underlying pathophysiology for the cardiac manifestations of sarcoidosis?

  • Typically, the clinical manifestations of cardiac sarcoidosis depend on the extent and location of the inflammatory process and subsequent fibrosis. Granulomas can be found anywhere in the heart, though more commonly involve the interventricular septum and left ventricle.
  • The most common presentations include conduction abnormalities (e.g., atrioventricular block, right bundle branch block), atrial and ventricular arrhythmias, and less commonly clinical heart failure. Of note, AV blocks and ventricular arrhythmia increase the risk of sudden cardiac death, which may be the first manifestation of cardiac sarcoid.
  • Furthermore, RV involvement is common in cardiac sarcoid – whether it be from the hemodynamic consequences of extensive LV involvement, pulmonary hypertension (pre- and post-capillary mechanisms) or direct RV involvement. However, isolated RV involvement is rare.
  • Sarcoidosis-associated pulmonary hypertension may be present in 5-20% of patients with sarcoidosis and is multifactorial with FIVE major etiologic categories:
    1. Cardiac: Group 2 (post-capillary) PH from elevated left-sided filling pressures related to heart failure.
    2. Parenchymal: Group 3 PH related to pulmonary parenchymal fibrosis.
    3. Vascular: vasculitis, arteritis, pulmonary embolism, pulmonary venoocclusive disease
    4. Anatomic: adenopathy compressing arteries, vascular distortion from pulmonary fibrosis, fibrosing mediastinitis
    5. Comorbidities: portopulmonary hypertension (if there is hepatic involvement), anemia, OSA.

3. How do we utilize multi-modality imaging in the diagnosis of cardiac sarcoidosis?

  • Multi-modality imaging aids in the diagnosis of cardiac sarcoidosis in two primary ways: (1) evaluating the extent and pattern of myocardial scar/fibrosis and (2) assessing for active inflammation.
  • Cardiac magnetic resonance imaging (CMR) is utilized to delineate the pattern of scar if present. As discussed in EP #33, CMR is a powerful tool in the evaluation of cardiomyopathy, allowing quantification of RV/LV size, mass, global/regional function, and identification of myocardial scar by late gadolinium enhancement (LGE). Characteristic scar patterns of cardiac sarcoid include patchy, multifocal LGE typically in the mid-myocardium and sub-epicardium. While a positive CMR scan in the setting of biopsy-proven extracardiac sarcoid is indicative of probable cardiac sarcoid, a negative CMR scan does not exclude subclinical disease.
  • PET/CT is also used for the evaluation of cardiac sarcoid, typically to identify the extent of active inflammation, guide immunosuppression therapy and/or if CMR is not available. 18-fluorodeoxyglucose (FDG)-PET/CT requires proper dietary preparation. Macrophages present in inflamed tissues will avidly take up 18F-FDG. But to avoid a false positive we need to suppress physiologic myocardial uptake of glucose to identify only pathologic WBC uptake. One way to suppress physiologic 18F-FDG is to give patients a high fat, ultra-low carb diet (instead of a prolonged fasting state alone), so myocytes preferentially rely on free fatty acids for fuel. PET imaging should be accompanied by an evaluation of myocardial perfusion, similar to the resting portion of a nuclear stress test, to evaluate for defects corresponding to areas of inflammation.
  • Note, if 18F-FDG-PET scan reveals diffuse FDG uptake with no perfusion defect this can commonly indicate a false positive result from inadequate suppression of physiologic FDG uptake, as extensively inflamed myocardial should also lead to decreased perfusion in the involved region. See our upcoming Nuclear and Multi-Modality Imaging Series for more on imaging in Cardiac Sarcoid!

4. What is the role of endomyocardial biopsy in the diagnosis of cardiac sarcoidosis?

  • Endomyocardial biopsy (EMB) historically has only a 25% success rate due to the patchiness of cardiac sarcoidosis. There are improved chances of success if EMB is done via an image-guided or electro-anatomical guided method, but sensitivity remains insufficient to rule out cardiac sarcoidosis even with guided biopsies.
  • Importantly, to confirm the diagnosis of cardiac sarcoidosis, per the 2014 Heart Rhythm Society (HRS) Expert Consensus Recommendation, pathological tissue of non-caseating granulomas is needed. This can either be directly from the myocardium, via EMB, or from an extra-cardiac source when  paired with at least one cardiac manifestation. Common places to biopsy include mediastinal lymph nodes via bronchoscopy or lymph nodes near the skin surface. Extra-cardiac sites can be identified on whole-body PET scans by FDG-uptake, as described above.

5. What is the role of VT ablation and ICD placement in cardiac sarcoid?

Ventricular arrhythmia ablation is considered on an individual patient basis in cardiac sarcoidosis. Patients should be assessed for active inflammation, and if present, they should typically first be treated with immunosuppression as this may suppress the arrhythmias without ablation. Antiarrhythmic medications may be added to help prevent additional VT episodes. If ventricular arrhythmias persist despite adequate immunosuppressive and anti-arrhythmic treatment, then ablation may be considered.

According to the HRS guidelines, ICD implantation in cardiac sarcoid is given a Class I indication if the patient has sustained VT (including prior cardiac arrest) and/or LVEF <35% despite optimizing immunosuppression. EP study, CMR and/or PET can be used to guide ICD implantation on an individual basis in patients not meeting a Class I indication. ICD implantation is not recommended (Class III) in patients with no history of syncope, normal LVEF/RVEF, no LGE on CMR, negative EP study, no indication for permanent pacing, incessant VT, or severe NYHA Class IV heart failure.

6. What are common immunosuppressive regimens in cardiac sarcoid?

  • Immunosuppression regimens vary institution to institution, and often physician to physician. Prednisone is the most common first line agent. It has been shown to improve atrioventricular conduction, mild-moderate left ventricular dysfunction, and burden of ventricular arrhythmias. Most often patients are started on higher doses of prednisone, and then subsequently weaned off with the goal of fully stopping, or reducing to as low a dose as possible, so as to avoid the chronic side effects of prednisone. Common steroid-sparing agent include methotrexate, azathioprine, and mycophenolate. In refractory cases, biologic therapies such as infliximab or rituximab can be used.
  • Repeat cardiac PET scans can be done to assess for improvement in inflammation, often two to three months after starting treatment. The timing and frequency of this repeat imaging is not well delineated and may vary between institutions and physicians. Finally, aside from immunosuppression, there are limited data on use of standard heart failure guideline-directed medical therapy (GDMT) in these patients. Overall, it is recommended that patients with reduced ejection fraction (EF) are put on the same GDMT as the standard patient with a reduced EF, as they may have beneficial effects in regard to EF improvement and heart failure-related outcomes.

References

  1. Birnie DH, Sauer WH, Bogun F et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305-23.
  2. Birnie DH, Nery PB, Ha AC, Beanlands RS. Cardiac Sarcoidosis. J Am Coll Cardiol 2016;68:411-21.
  3. Trivieri MG, Spagnolo P, Birnie D,  et al. Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Oct 20;76(16):1878-1901. doi: 10.1016/j.jacc.2020.08.042.
  4. Shlobin OA, Baughman RP. Sarcoidosis-Associated Pulmonary Hypertension. Semin Respir Crit Care Med. 2017. doi:10.1055/s-0037-1603767

CardioNerds Case Report Production Team

130. Case Report: A Nagging Cough Post PCI – Indiana University

CardioNerds (Amit Goyal and Daniel Ambinder), join cardiology fellows from Indiana University cardiology fellows (Dr. Asad Torabi, Dr. Michelle Morris, and Dr. Sujoy Phookan) to discuss a case of a patient who developed a nagging cough post PCI and is ultimately diagnosed with Dressler Syndrome. This case describes the work up and management of post infarct pericarditis and briefly reviews the dilemma of utilizing triple anti-thrombotic therapy with high dose aspirin in the post myocardial infarction period. Indiana University faculty and expert, Dr. Julie Clary provides the E-CPR for this episode.

With this episode, the CardioNerds family warmly welcomes Indiana University to the CardioNerds Healy Honor Roll. CardioNerds Healy Honor Roll programs are a collection of cardiology fellowship programs across the United States that support and foster the CardioNerds spirit and mission of democratizing cardiovascular education. Honor roll programs nominate fellows who are highly motivated and are passionate about medical education. Indiana University’s fellowship program director, Dr. Deepak Bhakta has nominated Dr. Asad Torabi for this position.

Claim free CME just for enjoying this episode! Disclosures: None

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Patient Summary

A 56-year-old man with recent anterior STEMI and new heart failure with reduced ejection fraction presented with fevers, persistent cough, and pleuritic chest pain following percutaneous coronary intervention for the past two weeks. He was ultimately found to have post cardiac injury syndrome – post infarct pericarditis (formerly known as Dressler syndrome) with elevated inflammatory markers, a small pericardial effusion, and incidentally noted to have an apical left ventricular thrombus. This case describes the work up and management of post infarct pericarditis and briefly reviews the dilemma of utilizing triple anti-thrombotic therapy with high dose aspirin in the post myocardial infarction period.  


Case Media


Episode Teaching

Pearls

1. Post cardiac injury syndrome (PCIS) following myocardial infarction can be very debilitating and recurrence is the concern when treatment is not pursued. 

2. Acute pericarditis is a clinical diagnosis which does not require imaging and can have a wide spectrum on presentation ranging from fever/cough to the classic positional chest pain.

3. PCIS following myocardial infarction is less common in the post PCI era but we are starting to see more cases in late presenters.

4. We have good level of evidence to suggest the use of colchicine to reduce the recurrence of PCIS. COPPS and COPPS-2, are two such randomized placebo control trials, which show benefit in the cardiac surgical patient.

5. While triple therapy on high dose aspirin is not discussed in the 2013 ACCF/AHA STEMI guidelines, carefully assess your patient’s bleeding risk and invoke patient shared decision making whenever possible.

Notes

1. What is Post-Cardiac Injury Syndrome (PCIS) and what are the clinical manifestations?

  • PCIS is an umbrella term for specific clinical scenarios which may result in symptomatic acute pericarditis.
  • PCIS encompasses:
    • Post-myocardial infarction pericarditis which may be early or late (Dressler syndrome – the focus of this case)
    • Post-pericardiotomy syndrome (PPS)
    • Post-traumatic pericarditis including traumatic and iatrogenic (following most percutaneous procedures such as ablations, PCI, lead placement, etc).

2. How is PCIS (or post infarct pericarditis) diagnosed?

  • This is a clinical diagnosis, made when ≥ 2 of the following are present:
    • Fever without alternative cause
    • Pericarditic or pleuritic chest pain
    • Friction rub
    • Pericardial effusion
    • Pleural effusion with elevated CRP
  • Note this is different from the diagnostic criteria for other causes of acute pericarditis which requires 2 of the 4 following features:
    • Pericarditic chest pain
    • Friction rub
    • New widespread ST-elevations or PR depressions on ECG
    • Pericardial effusion (new or worsening)
  • Supporting findings for pericarditis include:
    • Elevation of inflammatory markers (CRP, ESR, WBC)
    • Pericardial inflammation on cross sectional cardiac imaging (CT, CMR)

3. What are the complications of not treating Dressler syndrome?

  • Imazio et al published an excellent case series in 2009 which answers this question. Overall the prevalence of complications for early and late post-infarct pericarditis was low. No cases of constrictive pericarditis were observed but the incidence of recurrent pericarditis was observed at 3.2%.
  • The 2015 ESC pericardial guidelines recommend considering careful follow-up after PCIS to exclude possible evolution towards constrictive pericarditis with echocardiography every 6-12 months according to clinical features and symptoms (Class IIa).

4. What is the evidence for high dose Aspirin in Dressler syndrome?

  • This is a class 1b evidence in the 2013 ACCF/AHA STEMI guidelines. This evidence comes from data from a small case series of 24 patients which compared aspirin to indomethacin head-to-head. Overall aspirin was non-inferior with similar bleeding risk. The guidelines recommend the use of high dose aspirin because of NSAIDS may interfere with DAPT and there is also concern regarding scar thinning and infarct expansion. 
  • The 2015 ESC pericardial guidelines recommend aspirin as a first choice for anti-inflammatory therapy of post-myocardial infarction pericarditis and those who are already on antiplatelet therapies (Class I).

5. What is the role of colchicine for MI, for chronic coronary disease, for pericarditis, and for PCIS?

  • Following MI (without pericarditis): the COLCOT trial showed that colchicine is effective at preventing major adverse cardiac events after MI. In this randomized, double-blind, placebo-controlled trial, a total of 4,745 patients (within 30 days of MI and following intended coronary revascularization) were randomized to colchicine 0.5mg daily or to placebo. After a median follow-up of 22.6 months, there was a significant reduction in the primary efficacy outcome (cardiovascular death, MI, CVA, resuscitated cardiac arrest, or urgent hospitalization for UA leading to revascularization) (HR 0.77, 95% CI 0.61-0.96, p = 0.02).
  • Chronic coronary disease (without pericarditis): the LoDoCo2 trial showed that colchicine is effective in reducing major adverse cardiac events in patients with chronic coronary disease. In this randomized, double-blind, placebo-controlled trial, a total of 5,522 patients were randomized to colchicine 0.5mg daily or to placebo. After a median follow-up of 28.6 months, there was a significant reduction in CV mortality, MI, ischemic stroke, or coronary revascularization driven by ischemia events in the treatment arm (HR 0.69, 95% CI 0.57-0.83, p < 0.001).
  • Acute pericarditis: the unblinded COPE trial and blinded randomized placebo-controlled ICAP trial demonstrated benefit of colchicine in the first episode of pericarditis, added to NSAID therapy. The CORP trial (blinded RCT) demonstrated benefit of colchicine in recurrent pericarditis.
  • Post-pericardiotomy syndrome: the COPPS and COPPS-2 trials showed efficacy of colchicine when initiated 3 days following or 2-3 days preceding surgery respectively, at the cost of increased gastrointestinal side effects.  The 2015 ESC pericardial guidelines recommend:
    • Class IIA: Colchicine added to aspirin or NSAIDs should be considered for the therapy of PCIS, as in acute pericarditis.
    • Class IIA: Colchicine should be considered after cardiac surgery using weight-adjusted doses (i.e. 0.5 mg once for patients ≤70 kg and 0.5 mg twice daily for patients .70 kg) and without a loading dose for the prevention of PPS if there are no contraindications and it is tolerated. Preventive administration of colchicine is recommended for 1 month.

6. What is the recommended approach to triple anti-thrombotic therapy in patient with MI s/p PCI and an indication for anticoagulation?

  • The duration for triple therapy should be limited to the shortest duration possible/needed (the duration of aspirin in this regimen remains controversial. In the 2020 ACC expert consensus pathway, a short duration of no more than 30 days is   recommended. Clopidogrel is the P2Y12 inhibitor of choice in this regimen to minimize the risk of bleeding and aspirin should be limited to <100 mg.
  • However, the guidelines do not specifically address approach to Dressler syndrome in a post-MI patient treated with PCI who has an indication for anticoagulation (as with apical thrombus in this case) where high dose aspirin would be recommended for pericarditis, DAPT for stent, and warfarin for the thrombus. As with all cases, shared decision making with careful weighing of risks and benefits is advised, in concert with an experienced heart team.

References

Berman J, Haffajee CI, Alpert JS. Therapy of symptomatic pericarditis after myocardial infarction: retrospective and prospective studies of aspirin, indomethacin, prednisone, and spontaneous resolution. Am Heart J. 1981 Jun;101(6):750-3. doi: 10.1016/0002-8703(81)90610-4. PMID: 7234652. https://pubmed.ncbi.nlm.nih.gov/7234652/

Imazio M, Negro A, Belli R, Beqaraj F, Forno D, Giammaria M, Trinchero R, Adler Y, Spodick D. Frequency and prognostic significance of pericarditis following acute myocardial infarction treated by primary percutaneous coronary intervention. Am J Cardiol. 2009 Jun 1;103(11):1525-9. doi: 10.1016/j.amjcard.2009.01.366. Epub 2009 Apr 8. PMID: 19463510. https://pubmed.ncbi.nlm.nih.gov/19463510/

Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, López-Sendón J, Ostadal P, Koenig W, Angoulvant D, Grégoire JC, Lavoie MA, Dubé MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16. PMID: 31733140. https://pubmed.ncbi.nlm.nih.gov/31733140/

Imazio M, Trinchero R, Brucato A, Rovere ME, Gandino A, Cemin R, Ferrua S, Maestroni S, Zingarelli E, Barosi A, Simon C, Sansone F, Patrini D, Vitali E, Ferrazzi P, Spodick DH, Adler Y; COPPS Investigators. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J. 2010 Nov;31(22):2749-54. doi: 10.1093/eurheartj/ehq319. Epub 2010 Aug 30. PMID: 20805112. https://pubmed.ncbi.nlm.nih.gov/20805112/

Imazio M, Belli R, Brucato A, Ferrazzi P, Patrini D, Martinelli L, Polizzi V, Cemin R, Leggieri A, Caforio AL, Finkelstein Y, Hoit B, Maisch B, Mayosi BM, Oh JK, Ristic AD, Seferovic P, Spodick DH, Adler Y. Rationale and design of the COlchicine for Prevention of the Post-pericardiotomy Syndrome and Post-operative Atrial Fibrillation (COPPS-2 trial): a randomized, placebo-controlled, multicenter study on the use of colchicine for the primary prevention of the postpericardiotomy syndrome, postoperative effusions, and postoperative atrial fibrillation. Am Heart J. 2013 Jul;166(1):13-9. doi: 10.1016/j.ahj.2013.03.025. Epub 2013 May 6. PMID: 23816016.
https://pubmed.ncbi.nlm.nih.gov/23816016/

Kumbhani DJ, Cannon CP, Beavers CJ, Bhatt DL, Cuker A, Gluckman TJ, Marine JE, Mehran R, Messe SR, Patel NS, Peterson BE, Rosenfield K, Spinler SA, Thourani VH. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021 Feb 9;77(5):629-658. doi: 10.1016/j.jacc.2020.09.011. Epub 2020 Nov 26. PMID: 33250267. https://pubmed.ncbi.nlm.nih.gov/33250267/

Klein AL, Abbara S, Agler DA, Appleton CP, Asher CR, Hoit B, Hung J, Garcia MJ, Kronzon I, Oh JK, Rodriguez ER, Schaff HV, Schoenhagen P, Tan CD, White RD. American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography. J Am Soc Echocardiogr. 2013 Sep;26(9):965-1012.e15. doi: 10.1016/j.echo.2013.06.023. PMID: 23998693. https://pubmed.ncbi.nlm.nih.gov/23998693/


CardioNerds Case Report Production Team

125. Case Report: Pressured to Diagnose A Young Woman with Syncope – University of Minnesota

CardioNerds (Amit Goyal & Karan Desai) join University of Minnesota fellows, Dr. Julie Power, Dr. Sasha Prisco, and Dr. Abdisamad Ibrahim for a riveting discussion in which they were pressured to diagnose a young woman with syncope. The fellows expertly take us through the next steps in the differential diagnosis, and management of pulmonary hypertension in this young patient! University of Minnesota faculty and expert in right ventricular (RV) failure in pulmonary arterial hypertension (PAH) Dr. Kurt Prins provides the E-CPR for this episode.

With this episode, the CardioNerds family warmly welcomes The University of Minnesota to the CardioNerds Healy Honor Roll. The CardioNerds Healy Honor Roll programs support and foster the the CardioNerds spirit and mission of democratizing cardiovascular education. Healy Honor Roll programs nominate fellows from their program who are highly motivated and are passionate about medical education. The University of Minnesota fellowship program director, Dr. Jane Chen has nominated Dr. Julie Power for this position. In addition to being a CardioNerds Ambassador, Julie has already done amazing CardioNerds work as part of the CardioNerds Academy fellowship.

Claim free CME just for enjoying this episode! Disclosures: None

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Patient Summary- Syncope and Pulmonary Hypertension

A Somali woman in her mid-30s with no significant past medical history presented with shortness of breath and exertional syncope. EKG revealed evidence of RV strain. CTA-PE protocol did not show PE. However, there was RV dilation and subsequent echocardiogram demonstrated normal LV, but moderately reduced RV function with evidence of RV pressure and volume overload. RVSP was estimated to be 188 mmHg!


Case Media

A. CXR, B. ECG, C. PA measurements: Main PA measures 2.4 cm, right PA measures 2.3 cm, left PA measures 1.9 cm, D. Tricuspid valve Doppler, E. RA tracing, F. RV tracing, G. PA tracing, H. Wedge tracing

CTA PE: No PE, markedly dilated pulmonary trunk at 4.7 cm. Right main pulmonary artery measures 3.1 cm.
TTE: Parasternal long axis: Moderate right ventricular dilation compressing left ventricle. Global right ventricular function is moderately reduced.
TTE: Parasternal long axis- RV view: Right ventricular dilation with mild pulmonary regurgitation
TTE: Mild pulmonary regurgitation with dilation of main PA
TTE: Paradoxical septal motion consistent with right ventricular pressure and volume overload.
TTE: Apical 4 chamber
Paradoxical septal motion consistent with right ventricular pressure and volume overload. Moderate right ventricular dilation.
Global right ventricular function is moderately reduced.
Severe right atrial enlargement.
Paradoxical septal motion consistent with right ventricular pressure and volume overload.
Moderate right ventricular dilation.
Global right ventricular function is moderately reduced.
Severe right atrial enlargement.
Moderate to severe tricuspid regurgitation.
TTE: Positive bubble study

Episode Teaching

Pearls

  1. Pulmonary hypertension (PH) can generally be categorized as pre-, post-, or combined pre- and post-capillary PH. Isolated pre-capillary pulmonary hypertension is characterized by: mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Woods units (WU). Pulmonary arterial hypertension (PAH) (WHO Group 1) falls under pre-capillary pulmonary hypertension.
  2. Schistosomiasis is the most common cause of PAH (WHO Group I) worldwide. Approximately 7% of patient with hepatosplenic schistosomiasis have PAH. Some studies suggest that treatment of with praziquantel reverses vascular remodeling; however, there is point of no return, beyond which, anthelmintic therapies are ineffective to prevent progression.
  3. Exertional syncope and pericardial effusion are both risk factors for higher mortality in PAH.
  4. Women with severe PAH have extremely high risk of maternal morbidity and mortality. Endothelin receptor antagonists are contraindicated in pregnancy due to teratogenicity. Therefore, a pregnancy test must be obtained monthly while on this therapy.
  5. Patients with a lower socioeconomic status, based on median household income, have more advanced PAH at the time of diagnosis.

Notes

1. How do you approach syncope?

Syncope is a sudden transient loss of consciousness associated with absence of postural tone followed by complete and usually rapid recovery. There should be not be clinical evidence of “non-syncope” conditions including seizures, hypoglycemia, drug or alcohol intoxication, concussion due to head trauma and so forth.

  • One approach to determining the etiology of the syncope is to consider 4 major categories: orthostatic, reflex-mediated, cardiac-obstructive, or cardiac-electrical.
  • Reflex-mediated (neurocardiogenic) syncope typically has a prodrome and encompasses vasovagal syncope, situational syncope, and carotid hypersensitivity.
  • Orthostatic syncope is syncope occurring when rising from recumbency. It is generally associated with an orthostatic SBP drop by more than 20 mmHg or DBP drop by more than 10 mmHg with a compensatory rise in heart rate. We most commonly think of dehydration or hypovolemia causing orthostasis. Being post prandial can cause orthostasis as well. Neurogenic orthostatic hypotension (OH) involves excessive pooling of blood volume in the splanchnic and/or leg circulation. Upon standing, there is decreased venous return to the heart with a subsequent decrease in cardiac output and cerebral perfusion. The autonomic nervous system can typically increase vascular tone, inotropy and chronotropy; however, in neurogenic OH these mechanisms are inadequate. Conditions where neurogenic OH is relatively common include multiple system atrophy, Parkinson’s disease, Huntington’s disease, peripheral neuropathies (e.g., diabetes, amyloidosis), and spinal cord injury, amongst other etiologies. Finally, common medications associated with orthostatic syncope include diuretics, alpha blockers, and tricyclic antidepressants.
  • Cardiac-obstructive syncope may occur from structural obstruction (i.e., aortic stenosis, HCM, mitral stenosis, pulmonary embolism) or other lesions which limit the stroke volume (i.e., pericardial tamponade, pulmonary hypertension.
  • Cardiac-electrical syncope include both tachyarrhythmias and bradyarrhythmias, often without a prodrome.


2. What are the different types of pulmonary hypertension (PH)? What are the hemodynamic definitions of pulmonary hypertension?

  • The WHO separates PH into 5 groups:
    • Group 1: Pulmonary arterial hypertension (e.g., idiopathic, heritable [BMPR2], anorexigen associated, drug or toxin-associated, HIV, connective tissue disease associated, schistosomiasis, portal hypertension, congenital heart disease, amongst other causes)
    • Group 2: Pulmonary hypertension due to left sided heart disease (e.g., HFrEF, HFpEF, left-side valvular heart disease)
    • Group 3: Pulmonary hypertension due to lung disease or hypoxia: (e.g.,COPD, ILD, OSA, hypoxia without lung disease such as high altitude, developmental lung disorders)
    • Group 4: PH due to pulmonary artery obstructions most commonly Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
    • Group 5: Multifactorial causes such as hematologic disorders (chronic hemolytic anemia, as with myeloproliferative disorders), metabolic disorders (e.g., Gaucher disease, glycogen storage diseases, CKD), and systemic disorders (e.g., pulmonary Langerhans cell histiocytosis, neurofibromatosis, sarcoidosis)

When we consider the hemodynamics of pulmonary hypertension, we break down PH into isolated pre-capillary, isolated post-capillary, or combined pre-and post-capillary pulmonary hypertension.



Mean Pulmonary Artery Pressure (mmHg)Wedge Pressure (mmHg)Pulmonary Vascular Resistance (Woods Units)WHO Groups
Pre-capillary> 20≤ 15≥ 31, 3, 4, 5
Post-capillary> 20> 15< 32, 5
Combined pre- and post-capillary> 20> 15≥ 32, 5, multifactorial

PAH falls under pre-capillary pulmonary hypertension, which is defined as mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) ≥ 3 Woods units (WU).

3. How do you work up suspected PAH?

  • To start investigating for PAH, as always, we start with a thorough history and physical. The most common presenting symptom of pulmonary hypertension in general is exertional dyspnea/reduced exercise tolerance. Symptoms of PH can be nonspecific, especially early in its course, and thus there can be a delay in diagnosis. Remember, some patients have increased risk of developing PH and should be screened. These are patients with known risk factors for developing PAH, including relatives of patients with BMPR2 mutations, HIV, connective tissue disease (especially systemic sclerosis), portal hypertension, etc.
  • Other accompanying symptoms may include chest pain, fatigue, and lightheadedness. Manifestations of more advanced disease include syncope, abdominal distension, and significant lower extremity edema attributable to right ventricular (RV) failure.
  • Physical exam may reveal a loud P2, murmur of tricuspid regurgitation, an RV S3, jugular venous distension with or without Kussmaul’s sign, liver pulsatility, ascites, and/or peripheral edema.
  • Review the CXR and EKG for findings consistent with pulmonary hypertension. Common EKG findings include right atrial enlargement, right axis deviation, RBBB, and an RV strain pattern in the right precordial leads. Findings on chest X-ray may include enlarged main and hilar pulmonary arteries (with loss of the peripheral blood vessels) and RV enlargement.
  • Basic lab work should include a CBC with differential, biochemistry, TFTs, and HIV. The patient’s clinical presentation could lead you to screen for serologic evidence of connective tissue disorders or hepatitis. Cardiac biomarkers, including NT-proBNP, may have a role in prognosis and treatment response.
  • Echocardiogram is essential in the evaluation of PH. In addition to estimating the pulmonary artery systolic pressure (PASP) by measuring the tricuspid regurgitant jet, we can characterize RV and RA size, RV function, and RV wall thickness, which may help both support the diagnosis and gauge prognosis for PH. Further, we can evaluate for left-sided heart disease contributing to PH. The presence of a pericardial effusion is a poor prognostic sign. 
  • PFTs, overnight oximetry with blood gases, and CT chest can help delineate the relative contribution of pulmonary disease to the patient’s PH disease (WHO Group 3). VQ scan can rule out a diagnosis of CTEPH with high sensitivity (WHO Group 4).
  • Right heart catheterization is necessary to confirm the diagnosis of PH. Furthermore, we can determine if a patient is “vasodilator responsive.” In the catheterization lab, a positive vasodilator response is defined as a decrease in mPAP ≥ 10 mmHg to an absolute value of ≤ 40 mmHg (without a decrease in cardiac output) with the use of inhaled nitric oxide or IV epoprostenol. If a patient has positive vasodilator test, calcium channel blockers can be initiated, however not all patients will be long term responders. We tend to do vasoreactivity testing in patients with PAH and not for other forms of PH (e.g., Pulmonary Veno-Occlusive Disease or Groups 2, 3, 4, or 5).

4. What are PAH specific pharmacologic treatments?

  • Remember that PAH is fundamentally a disease of increased pulmonary vascular resistance (PVR) causing elevated pulmonary pressures. The consequence of increased PVR includes increased RV afterload and hypoxemia and the subsequent clinical manifestations of PAH. Normally, the pulmonary vascular bed has a balance between vasodilators and vasoconstrictors that can maintain a low-resistance, high-compliance state. This balance is disturbed in PAH and the goal of therapy is to “restore” balance between vasodilation and vasoconstriction.
  • The management of PAH has 3 medication groups:
    • Nitric oxide pathway:
      • PDE5 inhibitors: Sildenafil and tadalafil. These medications prevent the breakdown of cGMP which mediates the potent vasodilator and inhibitor of platelet aggregation, nitric oxide. The most common side effect for these medications is headache. Remember these medications should not be taken with nitrates!
      • Soluble guanylate cyclase (sGC) stimulators: riociguat. These medications stimulate sGC and thus increase sensitivity to NO. Riociguat is primarily used in CTEPH, but can also be used in PAH (PATENT-1 and -2 Trials) including PAH associated with sickle cell disease
    • Endothelin-1 (ET-1) pathway:
      • Endothelin receptor antagonists (ERAs): macitentan, bosentan, ambrisentan. Endothelin-1 is produced by endothelial cells and acts on two receptors, endothelin receptor A (ET-A) and endothelin receptor B (ET-B). ET-A is expressed on vascular smooth muscle cells and ET-B on both smooth muscle cells and endothelial cells. Stimulation of both receptors tends to lead to vasoconstriction, while stimulation of ET-B leads to vasodilation. ERAs antagonize these receptors to shift the balance towards vasodilation (e.g., bosentan is a dual ET-A/ET-B antagonist and ambrisentan is a more selective ET-A antagonist). Common side effects are lower extremity edema and hepatotoxicity. NOTE: patient should not get pregnant on ERAs because of teratogenicity!
    • Prostacyclin Pathway
      • Prostacyclin analogs: epoprostenol, iloprost, treprostinil. Prostacyclin is a potent endogenous vasodilator and inhibits platelet aggregation. This class of medications have PO, SQ, IV, and inhaled formulations. Common side effects include headache, diarrhea, nausea, and jaw pain.
      • PCA-receptor agonist: selexipag (oral).

Also remember CCB in vasodilator responsive patients with PAH!

Other aspects of pharmacologic PAH treatment not discussed here include diuretics, digoxin, and oral anticoagulation, especially for patients with more advanced disease and on continuous parenteral prostacyclin therapy due to microthrombi in pulmonary arterioles.

5.How do we risk stratify PAH patients and response to treatment?

  • The REVEAL 2.0 risk score helps determine 1 year mortality based on WHO group, renal function, functional class, age, heart rate, 6 minute walk test, BNP, presence of pericardial effusion of echocardiogram, PFTs, and RHC values.
  • Patients should also undergo routine 6 minute walk test and/or cardiopulmonary exercise test to assess their functional status and response to medications. Biomarkers may be helpful to assess treatment response. Echocardiography and RHC may be used every 6 to 12 months in patients with unstable or deteriorating symptoms to guide therapy and then considered on a case-by-case basis in stable patients.

References

  1. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S55-S66.
  2. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S78-S84.
  3. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012; 141(2):354-362.
  4. Delcroix M. and Naeije R.: “Optimising the management of pulmonary arterial hypertension patients: emergency treatments”. Eur Respir Rev. 2010; 19: 204.
  5. Knafl D, Gerges D, King CH, Humbert M, Bustinduy AL. Schistosomiasis-associated pulmonary arterial hypertension: a systematic review. European Respiratory Review. 2020; 29 (155).
  6. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009; 119:2250-2294.
  7. Nazzareno G, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(sup 25):D60-D72.
  8. Sherman, Stephanie (Host). (2019, January 31). Syncope (Episode 12) [Audio podcast episode]. In The Clinical Problem Solvers. https://clinicalproblemsolving.com/2019/01/31/episode-12-syncope-with-dr-stephanie-sherman/.
  9. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019: 53(1).
  10. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009; 54(suppl 1):S43-S54.
  11. Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. European Respiratory Review. 2016; 25 (142) 408-417.
  12. Talwar A, Sahni S, Talwar A, Kohn N, Klinger JR. Socioeconomic status affects pulmonary hypertension disease severity at time of first evaluation. Pulm Circ. 2016; 6(2):191-195. doi:10.1086/686489.

CardioNerds Case Report Production Team

121. Case Report: Complex Shock in Shone Complex – University of Wisconsin-Madison

CardioNerds (Amit Goyal & Daniel Ambinder) join Dr. Rayan Jo Rachwan, Dr. Anupama Joseph, and Dr. Mohammed Merchant from the University of Wisconsin-Madison for a classic Madison dinner cruise! They discuss the following case: Mixed shock secondary to severe right ventricular outflow tract obstruction with Gemella Haemolysans prosthetic pulmonary valve endocarditis in a young patient with Shone Complex (syndrome). Dr. Ford Ballantyne III provides the E-CPR segment for this episode. Special introductory music composed by Dr. Rayan Jo Rachwan. We are excited to welcome University of Wisconsin- Madison to the CardioNerds Healy Honor Roll and Dr. Rayan Jo Rachwan as the CardioNerds Ambassador.

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Patient Summary

A 26-year-old male with history of bicuspid aortic valve and Shone Complex (syndrome)—status post coarctation repair, subaortic resection and Ross-Konno operation—presenting with 3 months of constitutional and respiratory symptoms. Initial evaluation demonstrated that patient was in a state of mixed shock due to a large pulmonary Melody valve thrombus with superimposed Gemella Haemolysans prosthetic valve endocarditis. He required treatment with inotropes, pressors, followed by intubation and extracorporeal membrane oxygenation (ECMO). Patient was treated initially via right heart catheterization with balloon dilation and stent placement to his right ventricle-to-pulmonary artery conduit, which lead to significant improvement in his hemodynamics. Patient was then decannulated from ECMO, extubated, weaned off pressor support and later underwent a successful surgical resection of the infected pulmonary homograft and Melody valve/stents and replacement with pulmonary-valved conduit. He was also discharged on a prolonged course of antibiotics.


Case Media – Shone Complex

A. CXR, B. ECG, C. TV Doppler, D. PV Doppler

CTA Chest

•Melody pulmonic valve repair with large thrombus arising from the mid-distal valve extending into the main pulmonary artery and proximal left pulmonary artery. Evaluation for distal subsegmental pulmonary emboli is limited. •Tiny focus of air in the thrombus may be related to contrast injection. Infection is less likely. •Enlarged right heart chambers, may be in part chronic right heart enlargement and/or new right heart strain. No pulmonary infarct.

CT chest abdomen and pelvis with contrast

•Findings suggestive of acute hepatitis and acute pancreatitis. No pancreatic hypoenhancement or peripancreatic fluid collection. •No abscess within the abdomen or pelvis. •Small caliber of the infrarenal abdominal aorta and bilateral iliac arteries, probably congenital. 

TTE 1
TTE 2
TTE 3
TTE 4
TTE 5
TTE 6
RHC with balloon dilation of the RV-PA conduit and evidence of multiple levels of stent fracture.
Pulmonary angiogram showing no evidence of distal embolization or significant pulmonary embolism and no evidence of perforation. There is evidence of moderate pulmonary insufficiency into a dilated right ventricle.

Episode Teaching – Shone Complex

Pearls

1. Patients with congenital heart disease are more predisposed to infective endocarditis (IE). Therefore, there should be a low-threshold for infectious workup in the case of unexplained fever or malaise without associated symptoms for >72 hours. Every routine visit should screen for symptoms and signs of IE.

2. Treatment of right ventricular (RV) outflow tract obstruction with balloon dilation +/- stenting can be considered as a bridge to valve replacement in the case of severe hemodynamic compromise; thus, restoring RV and pulmonary artery coupling. As with many complex decisions this should be made in consultation with an experience heart team and shared decision making with the patient or proxy.

3. Patients with RV volume and/or pressure overload from right-sided valve etiology should be assessed serially (i.e., yearly) with transthoracic echocardiography.

4. When precise quantitative data about the RV is required to make important clinical decisions (e.g., when to recommend pulmonary valve replacement), cardiac magnetic resonance imaging (CMR) remains the diagnostic modality of choice.

5. Repairing or replacing the pulmonary valve should be considered when RV end-diastolic volume >160 mL/m2 and/or RV end-systolic volume >80 mL/m2 on CMR.

Notes

  1. What is Shone syndrome?
  • Shone syndrome (a.k.a. Shone anomaly, Shone complex) is a rare congenital abnormality that accounts for 0.6% of all congenital abnormalities.
  • It is characterized by a series of left-sided obstructive lesions. The diagnosis is made with the presence of at least 3 of 8 described lesions.
  • The 8 described lesions are:
    1. Cor Triatriatum
    2. Supramitral ring
    3. Parachute mitral valve
    4. Subaortic stenosis
    5. Bicuspid aortic valve and small aortic valve annulus
    6. Coarctation of the aorta
    7. Hypoplastic (stiff) left ventricle.
    8. Small aortic arch
  • Supravalvular mitral ring, parachute mitral valve, subaortic stenosis, and coarctation of the aorta were the first four described lesions and constitute the classic constellation of Shone complex.
  • Incomplete forms involve an LV inflow lesion plus at least one LV outflow lesion.
  • Frequently, coarctation of the aorta is recognized before the other defects are detected. The coarctation may mask the effects of the other lesions and some patients with Shone syndrome are only diagnosed when symptoms persist after coarctation repair.
  1. How does Shone syndrome manifest?
  • The symptoms associated with Shone syndrome are mostly symptoms of congestive heart failure (which can occur in the first week of life), potentially presenting in early childhood as fatigue, rapid breathing and wheezing, faster than normal heart rate, poor oral intake, poor weight gain, fluid retention (edema) in the legs, pallor (anemia), and frequent pneumonias.
  • In a series of 28 adult patients with Shone syndrome followed for a median of 8 years (Aslam et al., CJC 2016), nearly half had cardiovascular hospitalizations during adulthood, mostly for arrhythmias or heart failure.
  • The severity and prognosis depend on the individual lesions involved and the degree of obstruction to flow they cause.
  1. How is Shone syndrome diagnosed?
  • Diagnosis involved multimodality imaging predominantly with TTE, as well as TEE, CMR, and/or cardiac CTA as useful adjuncts depending on the lesions and patient age.
  • Invasive hemodynamics and angiography are important adjuncts, particularly while planning repair.
  1. How is Shone syndrome treated?
  • It is treated by addressing each of the constituent defects. For example:
    • Coarctation of the aorta:
      Treated surgically with excision with end-to-end anastomosis or subclavian flap angioplasty. Alternatively, it can be treated with transcatheter balloon angioplasty, particularly in the case of re-coarctation after surgical repair.
    • Subaortic stenosis:
      Treated surgically by excising the excess tissue below the aortic valve. If other forms of aortic stenosis are present, surgical repair may involve the replacement of the aortic valve.
    • Mitral stenosis (caused by “parachute” mitral valve and by supravalvular mitral membrane):
      Treated by surgery (valve replacement vs. valve repair).
  1. What is the prognosis of patients with Shone syndrome?
  • The long-term prognosis for patients with Shone syndrome is difficult to predict and is extremely variable depending on the lesions involved and degree of obstruction.
  • It depends on the extent of mitral valve disease, the degree to which the left ventricle is hypoplastic, and the cumulative effects of surgical treatments.
  • Moreover, patients who develop pulmonary arterial hypertension (PAH) have a poorer prognosis. Early surgical intervention is important to prevent the adverse consequences of long-standing obstruction and ensuing PAH.
  1. How are patients with Shone syndrome followed-up?
  • With regard to right ventricular (RV) assessment, echocardiography (more widely available) provides useful diagnostic information in many clinical circumstances that affect the right heart.
  • However, when precise quantitative data is required to make important clinical decisions (e.g., when to recommend pulmonary valve replacement), cardiac magnetic resonance imaging (CMR) remains the diagnostic modality of choice.
  • Repairing or replacing a dysfunctional pulmonary valve should be considered when RV end-diastolic volume (RVEDV) >160 mL/m2 and/or RV end-systolic volume (RVESV) >80 mL/m2 on CMR.
  • RV normalization could be achieved with pulmonary valve replacement when preoperative RVEDV is ≤160 mL/m2 or RVESV is ≤80 mL/m2 on CMR.
  1. What is the Melody valve and what is it used for?
  • The Melody valve consists of bovine jugular vein sewn within a platinum-iridium stent.
  • Transcatheter pulmonary valve placement with the Melody valve is effective in the short term for relief of right ventricular outflow tract (RVOT) obstruction and pulmonary regurgitation in patients with surgically implanted right ventricle–to–pulmonary artery conduits.
  • Melody stent fracture (MSF) with valve dysfunction is the most common indication for reintervention after Melody valve placement.
  • MSF is more likely in patients with severely obstructed RVOT conduits and when the Melody valve is directly behind the anterior chest wall and/or clearly compressed.
  • Pre-stenting of the conduit before valve implantation improves the durability of the implanted valve.
  1. Congenital heart disease (CHD) and infective endocarditis (IE)?
  • The risk of infective endocarditis (IE) remains a major concern in patients with congenital heart disease (CHD), whether unrepaired, palliated, or corrected. The overall incidence of endocarditis in adults with CHD is 11 per 100 000 person-years (vs. 1.5 to 6.0 per 100 000 patient-years in the general population).
  • The increased survival of children with CHD and the use of conduits and prostheses in corrective surgery may have contributed to an increasing incidence of IE.
  1. What is Gemella haemolysans bacteria?
  • Gemella haemolysans is a Gram-positive coccoid, catalase-negative, facultative anaerobic microorganism of the mucus membranes in humans.
  • It is able to cause severe and generalized infection as opportunistic pathogens, and it has become an emerging bacterial etiology in IE.
  • Generally, Gemella endocarditis is associated with previous valvular damage or a poor dental state.

References

Nicholson, George T., et al. “Late outcomes in children with Shone’s complex: a single-centre, 20-year experience.” Cardiology in the Young 27.4 (2017): 697.

Delaney, Jeffrey W., et al. “Covered CP stent for treatment of right ventricular conduit injury during melody transcatheter pulmonary valve replacement: results from the PARCS study.” Circulation: Cardiovascular Interventions 11.10 (2018): e006598.

McElhinney, Doff B., et al. “Stent fracture, valve dysfunction, and right ventricular outflow tract reintervention after transcatheter pulmonary valve implantation: patient-related and procedural risk factors in the US Melody Valve Trial.” Circulation: Cardiovascular Interventions 4.6 (2011): 602-614.

Schneider, Adriaan W., et al. “Twenty-year experience with the Ross–Konno procedure.” European Journal of Cardio-Thoracic Surgery 49.6 (2016): 1564-1570.

Brown, John W., et al. “The Ross-Konno procedure in children: outcomes, autograft and allograft function, and reoperations.” The Annals of thoracic surgery 82.4 (2006): 1301-1306.

Mulder, Barbara JM. “Endocarditis in congenital heart disease: who is at highest risk?.” (2013): 1396-1397.

Bokma, Jouke P., et al. “Preoperative thresholds for mid-to-late haemodynamic and clinical outcomes after pulmonary valve replacement in tetralogy of Fallot.” European heart journal 37.10 (2016): 829-835.

Aslam S, Khairy P, Shohoudi A, Mercier LA, Dore A, Marcotte F, Miró J, Avila-Alonso P, Ibrahim R, Asgar A, Poirier N, Mongeon FP. Shone Complex: An Under-recognized Congenital Heart Disease With Substantial Morbidity in Adulthood. Can J Cardiol. 2017 Feb;33(2):253-259. doi: 10.1016/j.cjca.2016.09.005. Epub 2016 Sep 29. PMID: 27956040.


CardioNerds Case Report Production Team

110. Case Report: Feeling Dyspneic & Rejected – University of Maryland

CardioNerds (Amit Goyal and Karan Desai) enjoy a picnic at Charm City’s Inner Harbor with Dr. Manu Mysore, Dr. Shawn Samanta, and Dr. Rawan Amir from the University of Maryland division of Cardiology as they dive into important case discussion about a patient with of non-ischemic cardiomyopathy s/p orthotopic heart transplantation who presents with dyspnea due to cell mediated rejection. Dr. Gautam Ramani Medical Director of Clinical Advanced Heart Failure at the University of Maryland, provides the e-CPR segment.

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Patient Summary

A 58 year old woman with a history of non-ischemic cardiomyopathy s/p orthotopic heart transplantation in 2015 presented with worsening dyspnea upon exertion. Dyspnea in a post cardiac transplant brings forth a wide differential diagnosis spanning all the typical causes of dyspnea as well as causes more specific or common to the patient with a heart transplant. In this particular case, TTE showed newly reduced ejection fraction and valvular disease. Cell mediated rejection was considered highest on the differential and confirmed on endomyocardial biopsy. Given hemodynamic compromise with multiple foci of myocyte damage on biopsy, she was started on high dose steroids and anti-thymocyte globulin for treatment of rejection.  Early identification and management of cell mediated rejection is crucial to the survival of patients like ours. Final diagnosis: orthotopic heart transplantation rejection.


Case Media – Orthotopic heart transplant rejection

TTE: Short axis
TTE: Long axis
TTE: Apical 4 Chamber
Coronary angiography: RCA
Coronary angiography: LAD/LCx

Episode Education

Pearls

  1. New onset heart failure in a post cardiac transplant patient should raise concern for acute cardiac allograft rejection, as well as all the usual culprits in nontransplant patients.
  2. Younger African American women and those with elevated HLA mismatches are key risk factors for cell mediated rejection.
  3. Treatment for cell-mediated (i.e., T-Cell mediated) rejection includes steroids and antithymocyte immunoglobulin and regimens are based on the severity ofclinical and histologic features.
  4. Though infrequent as an initial presentation of acute cellular rejection, new onset arrhythmias in a post cardiac transplant patient should raise concern for rejection as a possible etiology. 
  5. Reversal of rejection should be verified with endomyocardial biopsy following treatment for rejection. The timing and frequency of biopsy will likely depend upon whether corticosteroids and/or antithymocyte therapy was utilized.

Notes – Cell mediated rejection and more!

1) What are some common complications of cardiac transplantation?

Common complications following cardiac transplantation can be divided into two major categories: graft-related complications and non-graft-related complications.

  • Graft-related complications include:
    • Early graft dysfunction (EGD) – reversible and irreversible injury related to organ procurement and reperfusion. Remember it is common for transplant patients to require inotropic and vasopressor support coming off cardiopulmonary bypass. Furthermore, LV diastolic dysfunction is also common after transplantation usually reflecting reversible ischemia or reperfusion injury and normally resolves over days to weeks, depending on the severity of reperfusion.
      • Primary graft dysfunction (PGD) is a severe form of EGD that presents as a left, right or biventricular dysfunction occurring within the first 24 hours of transplantation for which there is no identifiable secondary cause (e.g. hyperacute rejection, prolonged ischemic time from massive intra-operative bleeding. The etiology is likely multifactorial including but not limited to reperfusion injury, the effect of donor brain death, and pre-existing donor heart disease.
    • Early RV dysfunction related to pulmonary vascular resistance and fluid shifts early post-transplant may be particularly challenging. The RV is exposed to similar reperfusion injury or ischemic insults as the LV and typically RV dysfunction post-transplant includes RV dilation, subsequent poor coaptation of the tricuspid valve and tricuspid regurgitation. The “untrained” donor RV has to overcome potentially increased afterload (due to increased pulmonary vascular resistance) in the recipient, and as has been covered in previous Cardionerds episodes, the RV systolic function is highly sensitive to changes in afterload.
    • Acute allograft rejection – either cellular-mediated rejection or antibody-mediated rejection, occurring due to the recipient’s immune system reacting against graft antigens (e.g., mainly, but not only, the human leukocyte antigen (HLA) mismatches). Hyperacute rejection is rare and commonly fatal complication of cardiac transplantation. It is mediated by preformed anti-donor antibodies and can lead to diffuse hemorrhage and thrombosis in the allograft. In the current era of panel-reactive antibody screening (PRA) where we screen for preformed anti-HLA recipient antibodies to donor lymphocytes, hyperacute rejection is rare but remains a possibility (especially in highly sensitized patients and/or depending on the technique of obtaining PRAs). See more below on antibody- and cell-mediated rejection.
    • Cardiac Allograft Vasculopathy – an important cause of morbidity and mortality late following heart transplant related to both immune- and nonimmune-mediated coronary injury causing accelerated atherosclerosis and fibroproliferation with diffuse intimal hyperplasia resulting in allograft ischemia. For a detailed discussion on CAV, enjoy Ep #69.
  • Non-Graft-Related Complications
    • Infections – related both to nosocomial exposures and immunosuppression, the typical infectious agents and syndromes predictably vary according to time from transplant. Early following transplant, the recipient is particularly susceptible due to post-operative nosocomial exposures (e.g., surgical wound, vascular access, urinary catheter, etc) and high dose peri-transplant immunosuppression. As such, wound/line/urinary infections and infections involving fungal and multidrug resistant bacterial organisms are common in the early phase (<1 month). In the mid-term (1-6 months), pneumonia, UTIs, and viral infections (CMV, HSV, VZV) are common. In the late-term, after the first post-transplant year, opportunistic infections become less common, and the typical community-based pathogens predominate.
    • Acute and chronic renal injury – renal dysfunction is a common and important complication post-cardiac transplantation. Etiologies are varied and interrelated and include pre-transplant renal dysfunction, acute injury pre-operatively, calcineurin inhibitor toxicity, cardiorenal syndromes related to graft dysfunction, and chronic injury due to long-term metabolic complications (diabetes, hypertension).
    • Malignancies – major problem in transplant recipients with rising cumulative risk over time. Post-transplant cancer risk is related to both immunosuppression dulling the normal immune system’s cancer surveillance and viral triggers for carcinogenesis. Common malignancies include lung cancer (especially as a significant proportion of patients with ischemic cardiomyopathy have a history of tobacco use), skin cancer, lymphomas, and breast and colon cancer. Post-transplant lymphoproliferative disorder (PTLD) is an EBV-associated proliferation of B-lymphocytes that is typically related to the degree of immunosuppression.

2) What are acute cell mediated rejection and antibody mediated rejection?

  • Acute cell mediated rejection (ACR) is a host T cell lymphocyte response directed towards allograft tissue, leading to T-cell mediated cytotoxicity of myocardial tissue. It can be seen anywhere from weeks to months after transplantation. Risk factors include younger donor and/or recipient age, African American ethnicity, and history of significant HLA mismatches.  
  • Acute antibody mediated rejection (AMR) constitutes graft injury by circulating antibodies (immunoglobulin M or G) targeting antigens expressed by graft endothelial cells. Injury may be complement mediated or complement independent (e.g., by other inflammatory pathways within endothelial cells and/or by natural killer cells).

3) What are clinical manifestations of acute cell mediated rejection?

  • Ideally, ACR is diagnosed prior to overt clinical manifestations from surveillance endomyocardial biopsies or Allomap testing (a blood test of gene-expression profiling of peripheral blood mononuclear cells used in select patients).
  • Clinical manifestations of acute cell mediated rejection typically include symptoms of LV dysfunction including dyspnea, PND, orthopnea, palpitations, syncope or near-syncope. Signs of RV dysfunction causing right-sided congestion may include gastrointestinal symptoms such as nausea which could be a marker of hepatic congestion! Occasionally, patients can present with new onset atrial arrhythmias including atrial fibrillation or atrial flutter.
  • Ultimately, cardiac transplant rejection is a form of myocarditis and so progressively severe forms may result in any of the manifestations of fulminant myocarditis including cardiogenic shock, atrial and ventricular arrhythmias, and conduction abnormalities. Thankfully, this is rare with modern immunosuppression and with routine rejection surveillance.

4) How is acute cell mediated rejection diagnosed and what are the histologic classifications?

  • ACR is diagnosed via endomyocardial biopsy.
  • Notably, there is wide interobserver variability in severity grading between pathologists and centers.
  • Biopsy samples are graded histologically as follows:
Histological GradeInterpretation
Grade 0RIndicates no sign of cell mediated rejection.
Grade 1RRepresents mild cell mediated rejection with interstitial and/or perivascular infiltrate with up to one focus of myocyte damage.
Grade 2RRepresents moderate cell mediated rejection involving ≥2 foci of infiltrate with associated myocyte damage.
Grade 3RRepresents severe cell mediated rejection with diffuse infiltrate and multifocal myocytic damage, with or without edema, hemorrhage, or vasculitis.
Biopsy samples are graded histologically

5) How is acute cell mediated rejection treated?

  • Treatment of ACR depends on the severity of rejection, as deemed both clinically and histologically.
  • Clinical severity is determined by presence of hemodynamic instability (i.e., decrease in cardiac output, decrease in pulmonary artery oxygen saturation, elevated pulmonary capillary wedge pressure, symptoms of heart failure)
  • Histologic severity is determined by the histologic grade as above.
  • If there is ACR warranting immunosuppression escalation, serial endomyocardial biopsies are typically performed to verify resolution and guide further management.
  • Anti-rejection therapy should typically be adjusted or discontinued if there is a documented infection with resolution of histologic rejection on subsequent biopsy.
  • Antibiotic and antiviral prophylaxis is given with anti-rejection treatment (high-dose steroids +/- anti-thymocyte globulin)
  • Treatment is (generally) as follows:
    • Grade 1R without hemodynamic compromise – generally does not warrant specific treatment.
    • Grade 1R w/ hemodynamic compromise – generally treated with high-dose corticosteroids or antibody therapy depending on the severity of hemodynamic compromise. If there is severe hemodynamic compromise, some centers will pursue more aggressive therapy with Grade 1R rejection including considering plasmapharesis.
    • Grade 2R without hemodynamic compromise – generally treated with a transient increase in the corticosteroid dose with subsequent return to the prior oral steroid dose. Select patients may even be treated as an outpatient if there is no hemodynamic compromise.
    • Severe or refractory rejection (Grade 2R w/ hemodynamic compromise, Grade 3R, or rejection unresponsive to corticosteroid therapy) – generally treated with pulse dose steroids with a slow taper as well as anti-thymocyte globulin (ATG). ATG is an infusion of horse or rabbit antibodies against human T cells to deflect a high immunologic burden. Other treatment options depending on the clinical situation include plasmapheresis, extracorpeal photopheresis (an apheresis and photodyamic therapy technique that uses 8-methoxy-psolaren and UV light to modulate T-cell therapy), and total lymphoid irradiation.

6) What is the surveillance schedule post cardiac transplantation for acute cell mediated rejection?

  • Acute cell mediated rejection as mentioned above happens most frequently during the first three to six months after cardiac transplantation.
  • A typical transplant center will perform endomyocardial biopsies weekly for the first four weeks after cardiac transplantation followed by biweekly for the next six weeks or so.
  • Schedule switches slightly in that biopsies are then pursued monthly for the next three to four months before being switched to every three months until it has been a year since cardiac transplantation.
  • This schedule does vary between transplant centers and it is common practice to pursue less invasive monitoring beyond the first few years after transplantation such as through peripheral blood gene expression profiling.

References – Cell mediated rejection

  1. Hamon D, Taleski J, Vaseghi M, Shivkumar K, Boyle NG. Arrhythmias in the Heart Transplant Patient. Arrhythm Electrophysiol Rev. 2014;3(3):149-155. doi:10.15420/aer.2014.3.3.149
  1. Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48(4):319-327.
  1. Ludhwani, Dipesh. “Heart Transplantation Rejection – StatPearls – NCBI Bookshelf.” National Center for Biotechnology Information, https://www.ncbi.nlm.nih.gov/books/NBK537057/. Accessed 26 Jan. 2021.
  1. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010;25(1):61-74.
  1. Potena, Luciano et al. “Complications of Cardiac Transplantation.” Current cardiology reports vol. 20,9 73. 10 Jul. 2018

CardioNerds Case Report Production Team

107. Case Report: A Rare Cause of Cardiogenic Shock – More than Meets the Eye – Thomas Jefferson University Hospital

With this episode, the CardioNerds family warmly welcomes Indiana University to the CardioNerds Healy Honor Roll. CardioNerds Healy Honor Roll programs are a collection of cardiology fellowship programs across the United States that support and foster the CardioNerds spirit and mission of democratizing cardiovascular education. Honor roll programs nominate fellows who are highly motivated and are passionate about medical education. Indiana University’s fellowship program director, Dr. Deepak Bhakta has nominated Dr. Asad Torabi for this position.

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Patient Summary

A 35 year old healthy male presents with cardiogenic shock and new heart failure with reduced ejection fraction. He has ventricular instability and is diagnosed with giant cell myocarditis by endomyocardial biopsy. His course over several years includes LVAD bridge to heart transplantation. He then has a recurrence of giant cell myocarditis in the transplanted heart which is successfully treated with high dose immunosuppression. 


Case Media

A. ECG, B. CXR


Episode Schematics & Teaching

Giant Cell Myocarditis Pearls

  1. Giant cell myocarditis (GCM is a rare – and often fatal – cause of acute myocarditis. A hallmark of GCM is the presence of multinucleated giant cells; however, these may take 1-2 weeks to appear and can also be seen in sarcoidosis.
  2. Most etiologies of fulminant myocarditis do not have bradyarrhythmias as a prominent feature, and their presence should increase the suspicion for sarcoidosis, Chagas disease, or GCM.
  3. While non-specific, a clue to the diagnosis of GCM amongst other causes of myocarditis could be rapid clinical deterioration with minimal response to guideline directed therapy, including a lack of spontaneous recovery on mechanical support which more commonly occurs in fulminant lymphocytic myocarditis.
  4. Mechanical support is typically needed in the management of GCM, either as a bridge to transplantation or recovery.
  5. GCM can recur in the transplanted heart. This happens in up to 25% of transplant patients and warrants aggressive immunosuppression which usually is sufficient to ensure disease remission.

Notes – Giant Cell Myocarditis

  1. What is Giant Cell myocarditis (GCM)?
    • Giant cell myocarditis (GCM) is an extremely rare – and often fatal – cause of acute non-infectious myocarditis. The pathophysiology of GCM is poorly understood, but thought to be a T-cell mediated autoimmune process leading to diffuse or multifocal inflammatory infiltrate, including lymphocytes with multinucleated giant cells (note multinucleated giant cells are not exclusive to GCM and can be seen in sarcoidosis as well). It has been estimated to occur at a rate of 0.13 cases per 100,000 people (one in a million).
    • It typically affects the myocardium in isolation and may not have any extracardiac manifestations, presenting with rapid hemodynamic deterioration, ventricular arrhythmias, and at times bradyarrhythmias.  The rate of death or cardiac transplantation has been estimated at 89%, with a median survival of 5.5 months from the onset of symptoms to the time of death or transplantation.
  2. When should you be suspicious of GCM?
    • The classic presentation is in a middle-aged Caucasian male who develops acute or subacute nonischemic cardiomyopathy (NICM) with clinical heart failure that progressively worsens. These patients often develop cardiogenic shock or arrhythmic instability – including both ventricular arrhythmia and conduction delays/heart block. See our prior episodes on the basics of building a clinical suspicion for myocarditis and the differential diagnosis (Episodes 29-33).
    • While non-specific, a clue to the diagnosis of GCM amongst other causes of myocarditis should be rapid clinical deterioration with minimal response to guideline directed therapy, including a lack of spontaneous recovery on mechanical support which more commonly occurs in fulminant lymphocytic myocarditis. Furthermore, bradyarrhythmias are less common in myocarditis and should raise the suspicion for GCM, sarcoidosis or Chagas disease.
  3. How is GCM diagnosed?
    • Definitive diagnosis of GCM requires endomyocardial biopsy (EMB). Similar to other rare forms of myocarditis like sarcoidosis or eosinophilic myocarditis, GCM requires pathology for diagnosis. Typically, a Class I indication (based on a joint statement 2007 statement from the AHA/ACC/ESC) for performing an EMB are (1) unexplained acute cardiomyopathywith < 2 weeks duration that is associated with hemodynamic compromise or  (2) unexplained cardiomyopathy between 2 weeks’ to 3 months’ duration associated with a dilated LV and new bradyarrhythmia, new ventricular arrhythmias or lack of response to GDMT within 1 to 2 weeks of initial diagnosis. 
    • The specific pathology will naturally include multinucleated Giant cells, but it will also include a high count of CD3 cells and usually a higher CD8 to CD4 ratio. The characteristic giant cells make typically take 1-2 weeks to appear and thus EMB in the first few days of the illness may render a false negative. Furthermore, because myocardial involvement in GCM can be patchy, repeat biopsy may be needed if the clinical suspicion remains high. Finally, multinucleated cells can also be seen in sarcoidosis; however, granulomas and fibrosis tend to be more striking features in cardiac sarcoid.
    • MRI can aid the diagnosis of GCM, however, many of these patients are too unstable to undergo MRI. When an MRI is able to be obtained, it will generally show diffuse abnormalities in T1 and T2 imaging and mapping.
  4. How is GCM treated?
    • In addition to GDMT as tolerated, treatment includes multi-drug immunosuppression that typically involve some combination of cyclosporine, azathioprine, and high dose steroids. Antithymocyte immunoglobulin and the T-cell specific monoclonal antibody, muromonab, have been used as well. Even after treating the underlying myocarditis with aggressive immunosuppression, ventricular arrhythmias may persist.
    • Mechanical circulatory support (MCS) is often needed as a bridge to heart transplantation or recovery. Options typically include intra-aortic balloon pump (IABP), IMPELLA (both RV and/or LV support devices), LVAD, RVAD, and ECMO. In patients with fulminant myocarditis, our goal is to maintain tissue perfusion while ensuring that we reduce LV workload and LVEDP. For this reason, peripheral VA ECMO alone is generally not used as it can increase afterload.
    • IABP is typically not useful in a patient with a rapid and severe decrease in cardiac output, as it offers an additional 0.5L to 1 L/min of support. In this patient, LVAD and RVAD support were pursued. Surgical RVAD implantation involves cannulation of the right atrium or RV as well as pulmonary artery and is connected to an extracorporeal centrifugal flow pump. Another option for percutaneous RV support is a novel axial-flow pump. This device utilizes a catheter-mounted microaxial flow pump with the inflow just below the right atrium-inferior vena cava junction and the outflow into the pulmonary artery after insertion via the femoral vein due to the design of the system, internal jugular placement and ambulation are not possible.
  5. What are the expected outcomes in patients with GCM?
    • Outcomes are generally poor without a heart transplant. With transplantation, however, 5-year survival is estimated at around 71%, which is similar to transplant survival rates in patients of other disease. Of note, GCM can recur in the transplanted heart. This happens in up to 25% of transplant patients. Recurrence warrants aggressive immunosuppression which is typically sufficient for disease remission.

References

1. Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, Mafrici A, Grosu A, Briguglia D, Guglielmetto S, Perego GB, Colombo S, Caico SI, Giannattasio C, Maestroni A, Carubelli V, Metra M, Lombardi C, Campodonico J, Agostoni P, Peretto G, Scelsi L, Turco A, Di Tano G, Campana C, Belloni A, Morandi F, Mortara A, Cirò A, Senni M, Gavazzi A, Frigerio M, Oliva F, Camici PG; Registro Lombardo delle Miocarditi. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation. 2018 Sep 11;138(11):1088-1099. doi: 10.1161/CIRCULATIONAHA.118.035319. PMID: 29764898.

2. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr. The quest for new approaches in myocarditis and inflammatory cardiomyopathy. J Am Coll Cardiol. 2016;68:2348-2364.

3. Rosenstein ED, Zucker MJ, Kramer N. Giant cell myocarditis: most fatal of autoimmune diseases. Semin Arthritis Rheum. 2000 Aug;30(1):1-16.

4. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis–natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med. 1997 Jun 26;336(26):1860-6.

5. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R; American Heart Association; American College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation. 2007 Nov 6;116(19):2216-33.

6. Kociol, R. D. et al. (2020). Recognition and Initial Management of Fulminant Myocarditis. Circulation, 141, E69-E92.

7. Kandolin R, Lehtonen J, Salmenkivi K, Räisänen-Sokolowski A, Lommi J, Kupari M. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013 Jan;6(1):15-22.

8. Tschöpe C, Van Linthout S, Klein O, et al. Mechanical Unloading by Fulminant Myocarditis: LV-IMPELLA, ECMELLA, BI-PELLA, and PROPELLA Concepts. J Cardiovasc Transl Res. 2019;12(2):116-123.

9. Kirklin JK, Naftel DC. Mechanical circulatory support: registering a therapy in evolution. Circ Heart Fail. 2008;1(3):200-205.

10. Kapur NK, Esposito ML, Bader Y, et al. Mechanical Circulatory Support Devices for Acute Right Ventricular Failure. Circulation. 2017 Jul;136(3):314-326.

11. Toennes, B; Garan, A. Percutaneous Right Ventricular Support Devices for Right Ventricular Failure Mar 01, 2016. ACC journal expert analysis. 

12. Patil NP, Mohite PN, Sabashnikov A, et al. Preoperative predictors and outcomes of right ventricular assist device implantation after continuous-flow left ventricular assist device implantation. J Thorac Cardiovasc Surg. 2015;150(6):1651-1658.

13. Cooper LT Jr, ElAmm C. Giant cell myocarditis: diagnosis and treatment. Herz. 2012;37:632-636

14. Scott RL, Ratliff NB, Starling RC, Young JB. Recurrence of giant cell myocarditis in cardiac allograft. J Heart Lung Transplant. 2001;20:375-380

15. Patel PM, Saxena A, Wood CT, O’Malley TJ, Maynes EJ, Entwistle JWC, Massey HT, Pirlamarla PR, Alvarez RJ, Cooper LT, Rame JE, Tchantchaleishvili V. Outcomes of Mechanical Circulatory Support for Giant Cell Myocarditis: A Systematic Review. J Clin Med. 2020 Dec 1;9(12):3905.


CardioNerds Case Report Production Team

106. Case Report: A Hole in the HFpEF Diagnosis – Boston University, Massachusetts General Hospital, and Brigham and Women’s Hospital

CardioNerds (Amit Goyal & Karan Desai) join Dr. Alex Pipilas (FIT, Boston University) and Dr. Danny Pipilas (FIT, MGH) for in Boston, MA. Adult congenital heart disease expert Dr. Keri Shafer (Brigham and Women’s Hospital) provides the E-CPR expert segment. They discuss a case of heart failure secondary to sinus venosus defect with partial anomalous pulmonary venous return.

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Patient Summary

A 78-year-old woman with atrial fibrillation and heart failure with preserved ejection fraction presented with recurrent dyspnea and volume overload. A transthoracic echocardiogram demonstrated severe right ventricular enlargement and dysfunction. A CT pulmonary angiogram demonstrated partial anomalous pulmonary venous return and a transesophageal echocardiogram revealed a sinus venosus defect with left to right shunting. A right heart catheterization with oximetry saturation (“shunt run”) demonstrated pulmonary hypertension and a large left to right shunt (Qp/Qs ~ 3). She was referred for cardiac surgery and underwent repair of the sinus venosus defect and baffling of the anomalous pulmonary venous flow to the left atrium.


Case Media

A. CXR, B. ECG, C. TR Velocity

TTE: PLAX
TTE: RV Outflow
TTE: AP4
TEE: Sinus Venosus ASD
TEE: Sinus Venosus ASD 2

Episode Schematics & Teaching

Pearls

  1. It is critical to determine whether there is more to a diagnosis of heart failure with a preserved ejection fraction. Utilize all available clinical data and risk calculators to determine if there are more appropriate diagnoses causing the patients symptoms, especially when certain aspects of the presentation does not add up.
  2. Right ventricular failure may be related to pressure overload (i.e., pulmonary hypertension, PV stenosis), volume overload (i.e., tricuspid regurgitation, left to right shunt lesions), or primary myocardial process (i.e., ischemia, infiltration, ARVC). In cases of severe right ventricular enlargement and dysfunction without apparent cause, look for a left to right shunt lesion (i.e., VSD, ASD, PAPVR). Sometimes further imaging (TEE, cardiac CT, cardiac MRI) is necessary to detect these lesions if not visualized on TTE.
  3. Left to right shunts can be quantified in the cardiac catheterization laboratory by measuring oxygen saturation in each chamber and detecting an O2 “step up” (increase in oxygen saturation from one chamber to the next). Large left to right shunts are quantified using the Fick principle and comparing the ratio of pulmonary blood flow (Qp) to systemic blood flow (Qs).
  4. Large left-to-right shunts can cause right ventricular volume overload and pulmonary hypertension. Patients often present with signs and symptoms of right ventricular failure including shortness of breath, exercise intolerance, volume overload, atrial arrhythmias, and recurrent heart failure. Some may develop right-to-left shunting and possible paradoxical embolism.
  5. ACC/AHA guidelines recommend closure of a sinus venosus defect if the PA systolic pressure is < 50% systemic pressures AND PVR is <1/3 of SVR. It is a Class III recommendation (potentially harmful) to close a defect if PA systolic pressure is >2/3 of systemic systolic pressure and/or PVR >2/3 SVR.

Quotable:

About ACHD – “As we go through this physiology, I just want to remind all of the listeners out there that you have the opportunity to apply the knowledge you have from medical school about physiology to the adult human heart. You can’t make assumptions as we sometimes do in the setting of normal cardiac anatomy. We really need to think about the compliances of the downstream structures and where is the blood flow.” – Keri Shafer, MD

Notes

  1. What are features and causes of RV failure?
  • The clinical symptoms of right ventricular failure include fatigue, dyspnea, lower extremity edema, elevated JVP, early satiety, and abdominal swelling. Although there is overlap between the symptoms of right ventricular failure and left ventricular failure, in isolated right ventricular failure orthopnea, paroxysmal nocturnal dyspnea, and pulmonary edema are typically absent.
  • It is convenient to break down the etiologies of right heart failure into “buckets”. Specifically, volume overload, pressure overload, and primary cardiomyopathic processes. Causes of right ventricular volume overload include valvular disease (tricuspid regurgitation, pulmonic insufficiency) and left-to-right shunts (ASD, VSD, sinus venosus defect, coronary sinus defect, PAPVR). Causes of right ventricular pressure overload, or excessive afterload, include pulmonary arterial hypertension, pulmonary embolism and chronic thromboembolic pulmonary hypertension, pulmonic stenosis, chronic hypoxemia, and longstanding elevated left atrial pressure causing group 2 PH (mitral regurgitation/stenosis, HFrEF, HFpEF). Cardiomyopathic processes include cardiac amyloidosis, right ventricular myocardial infarction, post-transplant right ventricular dysfunction, and arrhythmogenic right ventricular cardiomyopathy. Also, keep in mind that these disease processes often overlap.

2. What is partial anomalous pulmonary venous return (PAPVR)?

  • Normally, the four pulmonary veins return oxygenated blood to the left atrium.
  • Partial anomalous pulmonary venous return is a spectrum of congenital heart defects when one or more (but not all) of the pulmonary veins return oxygenated blood from the lungs to the systemic venous system (typically the SVC, IVC, or RA).
  • The most common PAPVRs are LUPV (left upper pulmonary vein) à ascending vertical vein à innominate vein or RUPV à SVC. The latter is often associated with a concurrent sinus venosus defect connecting the RA and LA.
  • Scimitar syndrome is a subtype of PAPVR in which part or all of the blood from the right lung is returned into the IVC. On chest X-ray, the outline of the anomalous drainage and associated congestion gives the appearance of a scimitar.

3. What is a sinus venosus defect? What is the sinus venosus?

  • Early in development, the atria are one single chamber. The sinus venosus is the posterior entryway for blood returning to this primitive atrium.
  • Eventually, the sinus venosus closes and moves rightward due to hemodynamic shifts during development.
  • In adults, the sinus venous becomes the smooth posterior wall of the adult right atrium called the sinus venarum and is separated from the anterior wall of the RA by the cristae terminalis.
  • If a persistent channel through the sinus venosus remains into adulthood, it can result in an intra-cardiac shunt. This is termed a sinus venosus defect and accounts for 10-15% of all inter-atrial shunts.
  • Typically, this shunt is left-to-right and may lead to right ventricular volume overload, dysfunction and pulmonary hypertension. Some patients may develop right-to-left shunting or paradoxical embolism. Arrhythmias are an important complication.
  • As above, sinus venosus defects are associated with PAPVR with RUPV à SVC.
  • NOTE: a sinus venosus defect is NOT a defect in the atrial septum and so is not an “ASD”. Rather it is a defect connecting either the SVC-RA junction (more common) or the IVC-RA junction to the LA. The former is associated with a RUPV PAPVR and the latter is associated with a RLPV PAPVR.

4. What are the imaging modalities that are used to identify sinus venosus defects?

  • Sinus venosus defects are poorly visualized on transthoracic echocardiography (TTE).
  • If there is clinical suspicion for an inter-atrial shunt not visualized on TTE, then a transesophageal echocardiogram (TTE) should be performed. Additional imaging modalities include cross-sectional imaging with cardiac CT or cardiac MRI, which may also identify the presence of concomitant PAPVR.
  • In cases of RV dilation and dysfunction without know etiology, evaluation for sinus venosus defect +/- PAPVR should be pursued.

5. What is the role for right heart catheterization in characterizing shunt defects?

  • A right heart catheterization is useful for multiple reasons.
  • Intracardiac pressure measurements serve as a surrogate for volume status.
  • One can also obtain oxygen saturation in each cardiac chamber to identify the presence of a “step up”, or unexpected increase in oxygen saturation, which signifies a left-to-right shunt. To simplify, a left-to-right shunt is when oxygenated blood from the systemic circulation (left) inappropriately mixes with the pulmonary circulation (right), increasing the oxygen concentration. This can occur via anomalous pulmonary veins, defects at the atrial or ventricular level, or sometimes systemic arterio-venous fistulas.
  • To obtain pressure measurements, a balloon-tipped catheter (Swann-Ganz catheter, PA catheter) is inserted through a vein and advanced through the heart and “wedged” in the pulmonary artery to estimate left atrial pressure. Normal pressure measurements are as follows (in mmHg): Right atrium < 8, right ventricle 25/5 (systolic/end diastolic pressure), pulmonary artery 25/15 (systolic/diastolic), and pulmonary capillary wedge pressure 8-12. Cardiac output can also be measured by thermodilution and via the Fick principle.
  • In our case, the patient’s pressure measurements were: RA 20, RV 72/24, PA 68/36 (47), PCWP 26.
  • As the catheter is passed through the great vessels and cardiac chambers and into the pulmonary artery, small amounts of blood can be sent for oximetry. Blood can be taken from the proximal and distal SVC, proximal and distal IVC, right atrium (low, mid, high), RV, PA and aorta. Taking multiple samples in each chamber are only necessary when the level of a suspected shunt is unknown. A left to right shunt is detected by an oximetry “step up” where oxygenated blood from the systemic circulation blood mixes with deoxygenated blood from the venous circulation.
  • An oxygen saturation step up of >7% is considered significant at the level of the great veins and RA while a step up of >5% is considered significant at levels distal to the RA.
  • For intra-cardiac shunts, the degree of left to right shunting can be quantified by calculating the ratio of pulmonary blood flow (Qp; oxygen consumption divided by the difference in AV oxygen content across the lungs) to systemic blood flow (Qs; oxygen consumption divided by the difference in the arteriovenous oxygen content across the systemic circulation). This ratio is calculated using the Fick principle for cardiac output, and by making a few assumptions.
  • Because intra-cardiac shunts will affect the mixed venous (pulmonary artery oxygen saturation), a systemic mixed venous saturation needs to be calculated to estimate “pre-shunt” mixed venous O2. This is defined by Flamm’s formula: (3*SVC +IVC)/4
    • We also assume that oxygen consumption, hemoglobin concentration and atmospheric pressure are constant. This allows for many of the terms in the complex calculation to cancel out, leaving only the oximetry saturations.
    • Ultimately, the simplified equation for Qp/Qs becomes the difference in saturation across the systemic circulation (Ao – calculated mixed venous) divided by the difference across the pulmonic circulation (PV sat – PA sat).
    • Practically, the pulmonary venous saturation cannot be obtained without transeptal puncture or retrograde catheterization through the left sided valves. In the absence of a significant R to L shunt, we expect systemic arterial saturation and pulmonary venous saturation to be the same, and thus the pulmonary venous saturation is often replaced by systemic arterial saturation in this equation.
  • Small shunts are defined by Qp/Qs <1.5. These are often asymptomatic and generally do not need to be treated. Large shunts are defined by Qp/Qs >2 and often require closure.
  • Our patient’s saturations were as follows: SVC 50%, IVC 43%, RA 77%, PA 79%, Ao 94%.
    • The calculated mixed venous saturation is then 48.25% ((3*50% + 1*43%) / 4 = 48.25%).
    • Finally, her Qp/Qs = (94 – 48.25)/(94-79) = 3.1.
  • When we walk through this equation with our patient’s data, her Qp/Qs is 3.1, meaning that for every 1 L of cardiac output through the systemic circulation, 3.1 L are going through the pulmonary circulation.

6. What are the indications and contraindications to correction of sinus venosus defects and PAPVR?

  • According to the 2018 ACC/AHA guidelines, in adults with a primum ASD, sinus venous defect or coronary sinus defect causing impaired functional capacity, right atrial and/or right ventricular enlargement and net left to right shunt sufficiently large to cause physiological sequelae (Qp/Qs >1.5:1) – without cyanosis at rest or during exercise – should be referred for surgical repair unless precluded by comorbidities.
  •  It is important to evaluate for pulmonary hypertension, as the recommendations differ based on the degree of concomitant pHTN.
  • Surgical correction is:
    • Class I (B-NR) if the systolic PA pressure is less than 50% of the systemic pressure and the PVR is less than one third of the SVR.
    • Class III, or potentially harmful, (C-LD) if the PA systolic pressure is greater than 2/3 of the systemic systolic pressure or if the PVR is greater than 2/3 of the SVR and/or if there exists a right to left shunt.
  • Those with PA systolic pressures between 50% and 2/3 systemic pressures and PVRs between 1/3 and 2/3 should be considered for repair on a case-by-case basis (Class IIb, our patient in this case).

References

Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(14). doi:10.1161/cir.0000000000000603. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000603

De Faria Yeh D, Bhatt AB, Gaggin HK, Januzzi JL. Adult Congenital Heart Disease. In: MGH Cardiology Board Review. 2nd ed. Cham: Springer International Publishing; 2021:387-420. https://www.springer.com/gp/book/9783030457914

Askari AT, Messerli AW. In: Cardiovascular Hemodynamics An Introductory Guide. Cham: Springer International Publishing; 2019. https://www.springer.com/gp/book/9783030191306


CardioNerds Case Report Production Team

103. Case Report: A Rare Cause of Postpartum Angina and Arrest – University of Maryland

CardioNerds (Amit Goyal & Daniel Ambinder) join University of Maryland cardiology fellows (Manu Mysore, Adam Zviman, and Scott Butler) for some cardiology and an Orioles game in Baltimore! They discuss a rare cause of postpartum angina and cardiac arrest due to coronary vasculitis. Program director Dr. Mukta Srivastava provides the E-CPR expert segment and a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Rick Ferraro with mentorship from University of Maryland cardiology fellow Karan Desai.

This case has been published in JACC Case Reports!

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Ep 103 Coronary Vasculitis University of Maryland
Episode graphic by Dr. Carine Hamo



Patient Summary

A woman in her early 30s with a past medical history of Hashimoto’s thyroiditis and one prior miscarriage at <8 weeks presented with chest pain about 6 weeks postpartum from the birth of her third child. In the ED, she continued to report intermittent sharp chest discomfort and found to have a diastolic decrescendo murmur at the left upper sternal border and labs demonstrating a troponin-I of 0.07 ng/dL. Join the UMD Cardionerds for the incredible course and story of this young patient as we go through the differentia and approach to postpartum chest pain and ultimately arrive in a very rare diagnosis!   For a detailed course, enjoy the JACC case report.


Case Media

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Episode Schematics & Teaching


The CardioNerds 5! – 5 major takeaways from the #CNCR case

1. How Do We Evaluate Chest Pain in Younger Patients 

  • Start with the same things as everyone else!  Think broadly about the big three concerning etiologies of chest pain: Cardiac, Gastric, and Pulmonary (The excellent Clinical Problems Solvers 4+2+2 construct here is always a great resource. Find them at: https://clinicalproblemsolving.com/dx-schema-chest-pain/).   
  • Of course it is important to think about non-life threatening etiologies as well – esophageal spasm, gastric ulcer, rib fracture, skin lesion, among many others – given that high-risk chest pain is less likely in younger adults.  
  • While less common, acute coronary syndrome is not uncommon in young patients, as 23% of patients with MI present at age <55 years.  

2. What About Chest Pain in Women?  

  • As has been discussed on the Cardionerds podcast (Listen to episodes with Dr. Nanette Wenger, Dr Martha Gulati, and Dr. Leslie Cho), women generally present with acute coronary syndrome at a later age, with a higher burden of risk factors than men, and with greater symptom burden but are less likely to be treated with guideline-directed medical therapies, undergo cardiac catheterization and receive timely reperfusion. In one study of young patients with acute MI, women – 19% of cases overall – were less likely to undergo revascularization or receive guideline-directed therapy 
  • The construct of classifying chest pain as “typical” and “atypical” likely leads to misdiagnosis or delayed diagnosis of acute myocardial infarction in women. Rather, it is important to recognize that while symptoms may not be “typical” for angina, coronary disease can manifest in many different ways.  
  • While many women will presents with chest pain suggestive of angina, women are more likely than men to present with dyspnea, indigestion, weakness, nausea/vomiting and/or fatigue. Note, shoulder pain and arm pain are twice as predictive of an acute myocardial infarction diagnosis in women compared with men.  
  • Furthermore, while obstructive epicardial disease remains the primary cause of acute MI in young women, it is also important to keep other causes of chest pain such as MINOCA, SCAD (see the UCLA episode), peripartum cardiomyopathy (see the Penn and MCW episodes), or coronary vasculitis on the differential. While these etiologies are rare, they are disproportionately represented in young women.  

3. How do we think about categorizing vasculitis? 

  • Vasculitis is a broad term encompassing many forms of vessel wall (including arteries, veins or capillaries) inflammation.  This can be secondary to autoimmunity, infection, drug reaction, and malignancy to name a few underlying causes.  
  • Generally vasculitis is divided by large vessel (e.g., Takayasu, Giant Cell), medium vessel (e.g., Polyarteritis Nodosa), and small vessel etiologies (e.g., Granulomatosis with Polyangitis, Eosinophilic Granulomatosis with Polyangiitis, Microscopic Polyangitis, Immune-mediated Vasculitis, amongst others). This characterization follows the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitis.  
  • Other important categories includes variable vessel vasculitis (e.g., Behcet’s Disease, Cogan’s Syndrome) and vasculitis associated with systemic disease (e.g., Lupus vasculitis, Rheumatoid vasculitis, Sarcoid vasculitis).  

4. What Does Vasculitis Look Like in the Heart? 

  • While inflammation can occur throughout the heart – e.g., pericarditis or myocarditis – vasculitis in the heart refers specifically to inflammation of the coronary arteries. This is a relatively rare process, with <10% of vasculitis patients exhibiting cardiac involvement.  
  • Patients with coronary vasculitis rarely present with isolated coronary involvement and typically have systemic manifestations, such as constitutional symptoms in addition to cardiac symptoms (e.g., angina, heart failure, arrhythmia). Examination may reveal asymmetric pulses or BP readings between limbs and arterial bruits, with imaging revealing multi-organ infarcts without a clear embolic origin. Amongst the vasculitides, Takayasu Arteritis (TA) is one of the more frequent etiologies of coronary arteritis.  
  • In Takayasu Arteritis (TA), the affected arteries are typically the aorta and its major branches. In contrast to giant cell arteritis (GCA), TA is quite rare and tends to have onset <40 years age; however, for both diagnoses coronary involvement is rare. TA patients will typically have constitutional symptoms and may have diminished/absent arterial pulses often accompanied by bruits. Weakness of the arterial walls may lead to aneurysms and specifically aortic root aneurysm may result in aortic valve insufficiency. When involving the coronaries, there are three main type of TA lesions: stenosis or occlusion of the ostia/proximal segments (Type 1); diffuse or focal coronary vasculitis involving all the epicardial branches or focal areas (Type 2); coronary aneurysms (Type 3). 

5. What Are the Complications of Coronary Vasculitis?  

  • The consequences of coronary vasculitis are variable and much of the data we have comes from case reports. As in the case presented, severe coronary ischemia and its complications, including arrhythmia and cardiac arrest, are a major concern. However, cardiac arrest is rarely the first presentation of coronary vasculitis, especially if it is detected early. The manifestations of coronary vasculitis are also going to be dependent on the specific etiology of the arteritis.  
  • Amongst the medium vessel vasculitis and specifically polyarteritis nodosa, 15-20% of patients will have cardiac involvement, with major complications including heart failure, myocardial infarction, or arrhythmia.  
  • Amongst the small vessel vasculitis, eosinophilic granulomatosis with polyangiitis is the most common culprit for cardiac involvement, primarily secondary to eosinophilic toxicity. Cardiac involvement is a major cause of mortality and poor prognostic sign in EGPA. 

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

Cardionerds Cardiology Podcast Presents CardioNerds Case Report Series

References

  1. Kostner, M. J., & Warrington, K. J. (2019, March 13). Vasculitis of the Coronary Arteries. ACC.org. 
  2. Ward, E. V., Nazari, J., & Edelman, R. R. (2012). Coronary artery vasculitis as a presentation of cardiac sarcoidosis. Circulation125(6), e344-e346. 
  3. Awad, H. H., McManus, D. D., Anderson Jr, F. A., Gore, J. M., & Goldberg, R. J. (2013). Young patients hospitalized with an acute coronary syndrome. Coronary Artery Disease24(1), 54-60. 
  4. Bugiardini, R., Cenko, E. (2020). Sex differences in myocardial infarction deaths. Lancet, 396:72–73 
  5. DeFilippis, E.M., Collins, B.L., Singh A., et. al Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Mass General Brigham YOUNG-MI registry, European Heart Journal, ehaa662 
  6. Miloslavsky, E., & Unizony, S. (2014). The heart in vasculitis. Rheumatic Disease Clinics40(1), 11-26. 
  7. Mehta LS, Beckie TM, DeVon HA et al; American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. (2016) Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation. Mar 1;133(9):916-47. doi: 10.1161/CIR.0000000000000351.  

CardioNerds Case Reports: Recruitment Edition Series Production Team

94. Case Report: Altered Mental Status & Electrical Instability: DIGging through the Differential – University of Illinois at Chicago

CardioNerds (Amit Goyal & Karan Desai) join University of Illinois at Chicago cardiology fellows (Brody Slostad, Kavin Arasar, and Mary Rodriguez-Ziccardi) for a cup of tea from atop Hancock Tower! They discuss an illuminating case of altered mental status & electrical instability due to digitalis poisoning. Program director Dr. Alex Auseon and APD Dr. Mayank Kansal provide the E-CPR and a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Tommy Das with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summaryCase mediaCase teachingReferences

CardioNerds (Amit Goyal & Karan Desai) join University of Illinois at Chicago cardiology fellows (Brody Slostad, Kavin Arasar, and Mary Rodriguez-Ziccardi) for a cup of tea from atop Hancock Tower! They discuss an illuminating case of altered mental status & electrical instability due to digitalis poisoning. Program director Dr. Alex Auseon and APD Dr. Mayank Kansal provide the E-CPR and a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Tommy Das with mentorship from University of Maryland cardiology fellow Karan Desai.
Episode graphic by Dr. Carine Hamo

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Patient Summary

A woman in her late 80s with history of systemic arterial hypertension and dementia presented with 2 weeks of nausea, vomiting, confusion, and yellow-tinted vision. When she presented to the hospital, initial history was limited as her caregiver was unaware of her medications and medical history. An initial ECG showed isorhythmic A-V dissociation and scooping ST segments laterally. Given her clinical history, this raised the suspicion for Digoxin toxicity, and a serum digoxin level was significantly elevated. However, this was not a home medication for the patient, nor did she have access to it! Listen to the episode now as the UIC Cardionerds masterfully take us through this case that would surely stump Dr. House!  


Case Media

through the Differential

A. Initial ECG
B. CXR- Patchy opacities of the left lower lobe consistent with pulmonary edema and/or aspiration​ pneumonia.
C. Repeat ECG: AF with AV block, persistent scooped T waves​
D. Post arrest ECG: Flutter/fib with AV block, VERY LONG PAUSES up to 6 seconds
E. ECG post TVP: A flutter, slow V response (pacing picking up), intrinsic ventricular rate 20-40, PM set to 50 bpm
F. Most recent ECG: Normal sinus rhythm

TTE

Episode Schematics & Teaching

The CardioNerds 5! – 5 major takeaways from the #CNCR case

1) This episode featured a challenging case of digitalis toxicity. Cardionerds, what is the mechanism of action of cardiac glycosides?  

  • Cardiac Glycosides (such as digoxin, digitalis, and oubain), inhibit the myocardial Na/K ATPase pump. This leads to an increased concentration of intracellular sodium, which then drives the influx of calcium into cardiac myocytes via the Na/Ca exchanger. This increase in intracellular calcium leads to further calcium release from the sarcoplasmic reticulum making even more calcium available to bind to troponin, increasing contractility. 
  • In addition to their effect on inotropy, cardiac glycosides increase vagal tone, reducing SA node activity and slowing conduction through the AV node by increasing the refractory period 

2) The first published account of digitalis to treat heart failure dates back to the 18th century, when botanist and physician William Withering published “An account of the Foxglove and some of its medical uses with practical remarks on dropsy, and other diseases”. A lot has changed over the years; what are some of the uses of digoxin in the modern day?  

  • The DIG trial (1997) demonstrated a reduction in hospitalizations in patients with HFrEF treated with digoxin. However, no impact on mortality was shown. A major limitation from randomized trials of digoxin is the lack of contemporary background HF treatment (e.g., ARNI, SGLT2i, MRA, Device Therapy). Thus, its role in modern HFrEF management is typically limited to reducing hospitalizations in patients with persistent NYHA Class III or IV symptoms despite maximally tolerated guideline-directed medical therapy 
  • Digoxin can also be used for acute or chronic rate control in atrial fibrillation, and may be particularly useful in patients with RVR refractory to beta blockers/calcium channel blockers or in those patients who cannot tolerate these agents due to hypotension. Notably, data from the ARISTOTLE trial (2018) showed a significant mortality increase was seen in patients with a digoxin level ≥1.2 ng/ml, while no increase in mortality was seen with levels <0.9 ng/ml.  
  • Recent data from the small, randomized RATE-AF trial showed no difference in quality of life and similar heart rate control in older patients with permanent atrial fibrillation and heart failure symptoms. Thus, while the therapeutic window may be limited, there remains a role for digoxin in the treatment of HFrEF, Afib, or both. 

3) While digoxin can be given in HFrEF and/or AF, its use is limited by its side-effects and potential toxicity. What are the clinical manifestations of digitalis toxicity?  

  • Arrhythmia: Digitalis toxicity can cause virtually any atrial or ventricular arrhythmia. More to come in take-away #4! 
  • GI: Acute toxicity is associated with nausea, vomiting, abdominal pain. Meanwhile, chronic toxicity can be more subtle with less pronounced nausea, anorexia and weight loss developing over weeks to months.  
  • Neuro: Alterations in color vision (chromatopsia), particularly seeing a yellow hue, can be specific for digitalis poisoning. Headache, fatigue, lethargy and altered mental status can also occur.  

4) Lets dig a little deeper into digoxin induced arrhythmias; why is digoxin so arrhythmogenic, and what are the most common electrical manifestations?  

  • By inhibiting the  Na/K ATPase pump, digoxin increases intracellular sodium and calcium levels, as well as extracellular potassium. These electrolytes shifts, in addition to the increased parasympathetic activity, lead to Digoxin’s arrhythmogenicity.  
  • Generally, younger patients develop bradyarrythmias due to increased vagal tone, while older patients who may have pre-existing cardiac disease are more likely to develop tachyarrythmias.  
  • Influx of calcium into the cardiac myocyte leads to delayed afterdepolarizations in phase 4 of the ventricular action potential, which can trigger ventricular tachycardia.  
  • Digoxin also increases atrial pacemaker cell automaticity, leading to an increase in atrial arrythmias. This occurs via an increase in the slope of phase 4 of the pacemaker action potential (decreasing the time to depolarization), lowering the depolarization threshold, and increasing the resting potential. 
  • While ectopic atrial tachycardia with AV block and bidirectional VT are associated with digoxin toxicity, virtually any arrhythmia can be seen in digitalis toxicity. However, atrial fibrillation and flutter are less likely to be induced by digoxin toxicity.  

5) Now that we’ve established all the effects and side-effects of digoxin, lets wrap up with some points on treating cardiac glycoside toxicity! 

  • The mainstay of therapy for acute and/or severe digoxin toxicity is digoxin-specific antibody (Fab) fragments. Empiric treatment for adults with imminent cardiac arrest or ingestion of an unknown amount of digoxin consists of 10 vials, with each vial binding approximately 0.5mg of digoxin.  
  • Indications for Fab fragments aside from acute overdose include: 
    • Hemodynamically unstable arrythmias 
    • Hyperkalemia 
    • Evidence of end-organ damage from hypoperfusion 
  • Notably, the serum digoxin concentration alone does not dictate Fab fragment treatment. Additionally, in patients with severe renal impairment, Fab fragments may be ineffective and may provide a false sense of benefit. The manifestations of digoxin toxicity may improve initially in these patients given Fab; however, recurrent toxicity can occur weeks later as digoxin moves from peripheral tissues.  
  • While other cardiac glycosides have cross-reactivity with digoxin and can be treated with Fab fragments, dosing can be challenging due to lack of correlation between serum digoxin level and cardiac glycoside activity. 
  • Potassium homeostasis in digoxin toxicity is nuanced. Hyperkalemia, as a result of Na-K ATPase inhibition, is a predictor of mortality in acute toxicity. After Fab fragments are given, hyperkalemia is often rapidly corrected, and over-aggressive treatment of hyperkalemia in the setting of acute toxicity may ultimately lead to hypokalemia once Fab fragments are given.  

References

  1. Digitalis Investigation Group (1997). The effect of digoxin on mortality and morbidity in patients with heart failure. The New England journal of medicine, 336(8), 525–533. 
  2. Lopes, R. D., Rordorf, R., De Ferrari, G. M., et al. (2018). Digoxin and Mortality in Patients With Atrial Fibrillation. Journal of the American College of Cardiology, 71(10), 1063–1074.  
  3. Chen, J. Y., Liu, P. Y., Chen, J. H., & Lin, L. J. (2004). Safety of transvenous temporary cardiac pacing in patients with accidental digoxin overdose and symptomatic bradycardia. Cardiology, 102(3), 152–155. 
  4. Taboulet, P., Baud, F. J., Bismuth, C., & Vicaut, E. (1993). Acute digitalis intoxication–is pacing still appropriate?. Journal of toxicology. Clinical toxicology, 31(2), 261–273.  

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

Cardionerds Cardiology Podcast Presents CardioNerds Case Report Series

CardioNerds Case Reports: Recruitment Edition Series Production Team

90. Case Report: Atrioesophageal Fistula (AEF) Formation after Pulmonary Vein Isolation – Thomas Jefferson University Hospital

CardioNerds (Amit Goyal) joins Thomas Jefferson cardiology fellows (Jay Kloo, Preya Simlote and Sean Dikdan – host of the Med Lit Review podcast) for some amazing craft beer from Independence Beer Garden in Philadelphia! They discuss a fascinating case of atrioesophageal fistula (AEF) formation after pulmonary vein isolation (PVI). Dr. Daniel Frisch provides the E-CPR and program director Dr. Gregary Marhefka provides a message for applicants. Johns Hopkins internal medicine resident Colin Blumenthal with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summaryCase mediaCase teachingReferences

CardioNerds (Amit Goyal) joins Thomas Jefferson cardiology fellows (Jay Kloo, Preya Simlote and Sean Dikdan - host of the Med Lit Review podcast) for some amazing craft beer from Independence Beer Garden in Philadelphia! They discuss a fascinating case of atrioesophageal fistula (AEF) formation after pulmonary vein isolation (PVI). Dr. Daniel Frisch provides the E-CPR and program director Dr. Gregary Marhefka provides a message for applicants. Johns Hopkins internal medicine resident Colin Blumenthal with mentorship from University of Maryland cardiology fellow Karan Desai.
Episode graphic by Dr. Carine Hamo

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

CardioNerds Case Reports Page
CardioNerds Episode Page
CardioNerds Academy
Subscribe to our newsletter- The Heartbeat
Support our educational mission by becoming a Patron!
Cardiology Programs Twitter Group created by Dr. Nosheen Reza

Cardionerds Cardiology Podcast Presents CardioNerds Case Report Series

Patient Summary

A man in his mid-60s with a history of paroxysmal Afib presented to the ED after one week of chest pain and altered mental status. His afib had been difficult to rate and rhythm control, and thus he had undergone catheter ablation with pulmonary vein isolation 3 weeks prior to presentation. In the ED he was found to be febrile and had a witnessed seizure. Blood cultures returned positive for Strep agalactiae and his CT head showed multiple areas of intravascular air. Join the Thomas Jefferson University Cardionerds as they take us through an expert discussion on the differential of post-catheter complications, the diagnosis of atrial-esophageal fistula and ultimately management of this potentially fatal complication!


Case Media

A. ECG: Normal sinus rhythm HR 105 bpm
B. CXR
C. CT head: Multiple tiny foci of air throughout bilateral cerebral hemispheres. Appearance is most suggestive of intravascular air, although it is unclear if it is venous, arterial or both.
D. MRI: 1. Restricted diffusion in bilateral cortical watershed zones, as well as in the posterior medial left cerebellar hemisphere, most consistent with recent infarctions.
E. CT Chest: A small focus of air tracking along the left mainstem bronchus anterior to the esophagus, may represent a small amount of pneumomediastinum versus air in an outpouching of the esophagus. No air tracking more cranially along the mediastinal soft tissues. No definite soft tissue defect in the esophagus.
F. Surgical repair of LA & Esophagus


Episode Teaching

The CardioNerds 5! – 5 major takeaways from the #CNCR case

  1. What is a pulmonary vein isolation? What are the most common complications? When is catheter ablation indicated?
    1. The majority of Afib triggers come from areas where the pulmonary veins attach to the left atrium. Approximately 15-20% of patients undergoing ablation will have non-pulmonary vein triggers. Guided by this anatomic and pathophysiologic underpinning, electrical isolation and ablation of these areas helps prevent propagation of the Afib impulses. The most effective method for pulmonary vein isolation (PVI) is ablation of the PV antrum, areas located near the PV ostia, using an oval mapping catheter to confirm ablation of electrical activity from the PV ostia.
    2. Vascular access complications (e.g. hematoma, pseudoaneurysm) are the most common complications following PVI and occur in approximately 1-4% (KD: I think complication rate is lower in studies I’ve reviewed) cases. Most other complications occur in less than 1% of cases and include cardiac tamponade/perforation, TIA/stroke, PV stenosis, pneumonia, phrenic nerve palsy, gastric motility disorders, atrial-esophageal fistula, and death.
    3. There is some growing evidence that catheter ablation may be superior to medical management alone in certain symptomatic populations (e.g., HFrEF). However, in the recent CABANA trial, catheter ablation did not significantly reduce death, disabling stroke, or serious bleeding compared to medical management in all comers with new-onset or untreated symptomatic Afib.
    4. The 2020 ESC guidelines on AFib give a Class I recommendation to Afib ablation for (1) symptom control in patients with paroxysmal or persistent AFib who have failed or are intolerant of at least one Class I or III antiarrhythmic drug (AAD); or (2) to reverse LV dysfunction in AFib patients when tachycardia-induced cardiomyopathy is highly probable regardless of their symptom status.
  2. What is an atrial esophageal fistula (AEF) and how does it form after a PVI?
    1. Esophageal perforation is a rare complication of PVI and occurs in 0.1-0.25% of procedures. If it goes undetected, an AEF can form, which is an abnormal connection between the esophagus and the left atrium. Overall it is the 2nd most common cause of death after PVI, with acute cardiac tamponade being the most common.
    2. In normal human anatomy, the esophagus runs just posterior to the LA, often coming within a few millimeters at its closest point. Regardless of modality (e.g. cryoablation, radiofrequency ablation), this close proximity can lead to damage of the esophagus via multiple mechanisms.  First, all current ablation techniques use thermal injury, which can lead to direct mucosal damage the esophagus. Additionally, damage to the anterior esophageal plexus can impact gastric motility and emptying, which can increase reflux and lead to esophageal ulceration. Finally, thermal damage to the end arterioles can cause ischemic injury to the esophagus, which weakens the esophagus and predisposes it to ulcer and fistula formation.
    3. Though data is limited, ulceration of the esophagus appears to be the primary defect in AEF with the ulcer slowly propagating from the esophagus through the pericardium to the LA, forming a one way connection from the esophagus to the LA.
  3. What can be done to help avoid AEF formation during a PVI? What risk factors put patients at high risk for AEF formation?
    1. Esophageal temperature monitoring is frequently implemented to help reduce the risk of esophageal damage. In the 2017 HRS-led expert consensus statement on ablation of AFib, three-quarters of the writing group members terminate ablation if they observe a 1 C or 2 C rise in temperature from baseline, or a recorded temperature of 39C-40C in their practice. Temperatures above 41C increase the risk of AEF formation. Many providers also prescribe a PPI to reduce gastric acid secretion, a possible contributor to esophageal damage, but this data is not based clinical trial data.
    2. Multiple systems including esophageal cooling devices and methods to move the esophagus away from the LA are under development, but none have substantial clinical data to warrant widespread use.
    3. Risk factors for AEF formation include RF ablation (though can be seen with all ablation energy sources), higher esophageal temperature, and higher energy delivery (longer contact time, higher power, increased contact force, larger catheter tip, and  higher irrigation flow).
  4. What are the most common signs and symptoms of an AEF and how is it diagnosed?
    1. Since AEFs start as an esophageal ulcer that progresses to a fistula, AEF formation typically takes 1-6 weeks (mean 20 days) from the time of ablation. Many of the common signs and symptoms are nonspecific and include fever, fatigue, AMS, chest pain, nausea, vomiting, dysphagia, hematemesis, melena, and dyspnea. Common complications include sepsis from bacteria (generally gram-positive organisms) entering the blood stream from the esophagus and stroke from air emboli.
    2. CT with oral and IV contrast or MRI imaging of the esophagus are the most useful diagnostic modalities. Occasionally this can show contrast extravasation from the LA to the esophagus, but more commonly it will show air from the esophagus into the pericardial space. Barium swallow can also be helpful as it has a very high specificity, but unfortunately a low sensitivity. Blood cultures and head CT are often obtained given the symptoms that patients present with and increase clinical suspicion if they demonstrate bacteremia or air emboli. Importantly, once AEF is suspected, EGD is contraindicated as insufflation of the esophagus can lead to a large air embolus and stroke.
  5. How are AEFs treated? What is the prognosis?
    1. Early diagnosis and treatment of AEFs is crucial as mortality is 100% without treatment. Esophageal ulceration or even pericardial esophageal fistulas have significantly better prognosis, highlighting the necessity for early identification. Esophageal stenting has not shown to be effective, and surgical repair with primary repair of the esophagus is the gold standard. Broad spectrum antibiotics should be utilized to treat or prevent the development of bacteremia and sepsis.
    2. Even with early identification and proper treatment, mortality is still very high with up to ~40% of patients dying after surgery.

References

  1. Arruda, M. S., Armaganijan, L., Biase, L. D., Rashidi, R., & Natale, A. (2009). Feasibility and Safety of Using an Esophageal Protective System to Eliminate Esophageal Thermal Injury: Implications on Atrial-Esophageal Fistula Following AF Ablation. Journal of Cardiovascular Electrophysiology, 20(11), 1272–1278. https://doi.org/10.1111/j.1540-8167.2009.01536.x
  2. Asad Zain Ul Abideen, Yousif Ali, Khan Muhammad Shahzeb, Al-Khatib Sana M., & Stavrakis Stavros. (2019). Catheter Ablation Versus Medical Therapy for Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 12(9), e007414. https://doi.org/10.1161/CIRCEP.119.007414
  3. Barbhaiya, C. R., Kumar, S., John, R. M., Tedrow, U. B., Koplan, B. A., Epstein, L. M., Stevenson, W. G., & Michaud, G. F. (2015). Global survey of esophageal and gastric injury in atrial fibrillation ablation: Incidence, time to presentation, and outcomes. Journal of the American College of Cardiology, 65(13), 1377–1378. https://doi.org/10.1016/j.jacc.2014.12.053
  4. Bunch, T. J., & Cutler, M. J. (2015). Is pulmonary vein isolation still the cornerstone in atrial fibrillation ablation? Journal of Thoracic Disease, 7(2), 132–141. https://doi.org/10.3978/j.issn.2072-1439.2014.12.46
  5. Calkins, H., Hindricks, G., Cappato, R., Kim, Y.-H., Saad, E. B., Aguinaga, L., Akar, J. G., Badhwar, V., Brugada, J., Camm, J., Chen, P.-S., Chen, S.-A., Chung, M. K., Nielsen, J. C., Curtis, A. B., Davies, D. W., Day, J. D., d’Avila, A., Groot, N. M. S. (Natasja) de, … Yamane, T. (2017). 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm, 14(10), e275–e444. https://doi.org/10.1016/j.hrthm.2017.05.012
  6. Chavez, P., Messerli, F. H., Dominguez, A. C., Aziz, E. F., Sichrovsky, T., Garcia, D., Barrett, C. D., & Danik, S. (2015). Atrioesophageal fistula following ablation procedures for atrial fibrillation: Systematic review of case reports. Open Heart, 2(1), e000257. https://doi.org/10.1136/openhrt-2015-000257
  7. Cummings Jennifer E., Schweikert Robert A., Saliba Walid I., Burkhardt J. David, Brachmann Johannes, Gunther Jens, Schibgilla Volker, Verma Atul, Dery MarkAlain, Drago John L., Kilicaslan Fethi, & Natale Andrea. (2005). Assessment of Temperature, Proximity, and Course of the Esophagus During Radiofrequency Ablation Within the Left Atrium. Circulation, 112(4), 459–464. https://doi.org/10.1161/CIRCULATIONAHA.104.509612
  8. Dagres, N., & Anastasiou-Nana, M. (2011). Prevention of atrial–esophageal fistula after catheter ablation of atrial fibrillation. Current Opinion in Cardiology, 26(1), 1–5. https://doi.org/10.1097/HCO.0b013e328341387d
  9. De Greef, Y., Ströker, E., Schwagten, B., Kupics, K., De Cocker, J., Chierchia, G.-B., de Asmundis, C., Stockman, D., & Buysschaert, I. (2018). Complications of pulmonary vein isolation in atrial fibrillation: Predictors and comparison between four different ablation techniques: Results from the MIddelheim PVI-registry. EP Europace, 20(8), 1279–1286. https://doi.org/10.1093/europace/eux233
  10. January Craig T., Wann L. Samuel, Calkins Hugh, Chen Lin Y., Cigarroa Joaquin E., Cleveland Joseph C., Ellinor Patrick T., Ezekowitz Michael D., Field Michael E., Furie Karen L., Heidenreich Paul A., Murray Katherine T., Shea Julie B., Tracy Cynthia M., & Yancy Clyde W. (2019). 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation, 140(2), e125–e151. https://doi.org/10.1161/CIR.0000000000000665
  11. Kapur Sunil, Barbhaiya Chirag, Deneke Thomas, & Michaud Gregory F. (2017). Esophageal Injury and Atrioesophageal Fistula Caused by Ablation for Atrial Fibrillation. Circulation, 136(13), 1247–1255. https://doi.org/10.1161/CIRCULATIONAHA.117.025827
  12. Mark, D. B., Anstrom, K. J., Sheng, S., Piccini, J. P., Baloch, K. N., Monahan, K. H., Daniels, M. R., Bahnson, T. D., Poole, J. E., Rosenberg, Y., Lee, K. L., Packer, D. L., & for the CABANA Investigators. (2019). Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA, 321(13), 1275. https://doi.org/10.1001/jama.2019.0692
  13. Nair, G. M., Nery, P. B., Redpath, C. J., Lam, B.-K., & Birnie, D. H. (2014). Atrioesophageal Fistula in the Era of Atrial Fibrillation Ablation: A Review. Canadian Journal of Cardiology, 30(4), 388–395. https://doi.org/10.1016/j.cjca.2013.12.012
  14. Scanavacca, M. I., D’ávila, A., Parga, J., & Sosa, E. (2004). Left Atrial–Esophageal Fistula Following Radiofrequency Catheter Ablation of Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 15(8), 960–962. https://doi.org/10.1046/j.1540-8167.2004.04083.x
  15. Singh, S. M., d’Avila, A., Singh, S. K., Stelzer, P., Saad, E. B., Skanes, A., Aryana, A., Chinitz, J. S., Kulina, R., Miller, M. A., & Reddy, V. Y. (2013). Clinical outcomes after repair of left atrial esophageal fistulas occurring after atrial fibrillation ablation procedures. Heart Rhythm, 10(11), 1591–1597. https://doi.org/10.1016/j.hrthm.2013.08.012

CardioNerds Case Reports: Recruitment Edition Series Production Team