115. The Braunwald Chronicles: At The Right Place, At The Right Time & With The Right People

CardioNerds (Amit Goyal, Daniel Ambinder, Carine Hamo, and Karan Desai) are honored to bring to you the Braunwald Chronicles. These are stories of discovery, innovation, accidents, perseverance, and more…truly these are the stories of cardiology, directly from a father of modern cardiology himself, Dr. Eugene Braunwald. Dr. Braunwald’s life and stories together are the saga which have brought us to this day in modern cardiology. So please join us for the Braunwald Chronicles, as we journey through the history of cardiology, across 6 extraordinary chapters. We begin with Chapter 1: At The Right Place, At The Right Time & With The Right People.  We learn about how serendipitous events in Dr. Braunwald’s early days, paired with his incredible grit & brilliance got him to the NIH where he quickly became the chief of cardiology at the of age 31, the precipice to an illustrious career ahead. We thank Dr. Karan Desai, Editorial APD with the CardioNerds Academy, and fellow at University of Maryland, for all the work he put into designing the Braunwald Chronicles. A very special thanks Dr. Randall Starling, advanced heart failure faculty at the Cleveland Clinic, former President of HFSA, and a dedicated mentor and support to CardioNerds for introducing us to Dr. Eugene Braunwald and for providing the following introduction. Audio editing by Pace Wetstein.


114. Cardio-Obstetrics: Pregnancy and Coronary Disease with Dr. Malissa Wood

CardioNerds Amit Goya and Daniel Ambinder, cardioobstetrics series co-chair Dr. Natalie Stokes, and episode lead Dr. Priya Kothapalli (University of Texas at Austin, Dell Medical School) discuss pregnancy and coronary artery disease with Dr. Malissa Wood, co-founder and co-director of the Corrigan Woman’s Heart Health center at Massachusetts General Hospital. They discuss the differential diagnosis of chest pain in the pregnant patient, the diagnostic approach and management of acute coronary syndromes in the patient population, and manifestations and management of SCAD in pregnancy. Episode introduction by Dr. Julie Power.

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Guest Profiles – Episode 114. Pregnancy Coronary Disease

Dr. Malissa Wood
Dr. Malissa Wood

Dr. Malissa Wood is a cardiologist at MGH, where she is one of the founders and co-director of the Corrigan Woman’s Heart Health center at MGH. She has authored two books “Smart at Heart” and “Thinfluence” and she’s made substantial contributions globally in promoting awareness of gender disparities in cardiovascular disease. She is the incoming chair elect for the ACC board of governors and current Governor of the Massachusetts ACC chapter, and is one of the leading experts in the world of Spontaneous Coronary Artery Dissection, or SCAD.

Dr. Priya Kothapalli
Dr. Priya Kothapalli

Dr. Priya Kothapalli is a second-year cardiology fellow at The University of Texas at Austin, Dell Medical School. Her clinical interests include endothelial dysfunction and vulnerable plaque. She looks forward to advanced training in interventional cardiology.

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113. Cardio-Obstetrics: Pregnancy, Heart Failure, and Peripartum Cardiomyopathy with Dr. Julie Damp

CardioNerds (Amit Goyal and Daniel Ambinder), cardioobstetrics series co-chair Dr. Natalie Stokes, Northwestern University CardioNerds Ambassador Dr. Loie Farina, and episode lead fellow, Dr. Agnes Koczo (University of Pittsburgh) join Dr. Julie Damp of Vanderbilt University Associate Director of the VUMC Cardiovascular Disease Fellowship for a discussion about pregnancy, heart failure, and peripartum cardiomyopathy. Episode introduction by Dr. Luis Calderon. Audio editing by Pace Wetstein.

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Episode Abstract

In this episode we discuss the presentation of peripartum cardiomyopathy (PPCM), tips for examining a late antepartum patient, and review management of pregnancy complicated by cardiogenic shock.  Weaved throughout the case, we discuss important concepts including the role of prolactin in PPCM which factors into both treatment decisions like prescribing bromocriptine (what!) as well as counseling on breastfeeding. Be sure to tune in to hear Dr. Damp’s review of the latest evidence regarding the diagnosis and management of PPCM, as well as her personal experience counseling patients on heart failure therapies and ICD placement in the context of important factors like breastfeeding status, contraception and future pregnancies.

Pearls

1) PPCM most typically presents in the early postpartum period and is defined as an LVEF <45% (with or without LV dilatation and RV involvement) and no other explanation for the cardiomyopathy.

2) Patients with PPCM  can present with classic heart failure symptoms, which may be challenging to distinguish from the typical symptoms and signs of pregnancy. To help differentiate pathology from normal physiology, consider the constellation of exam findings (e.g., isolated peripheral edema versus peripheral edema, +S3, elevated JVD and rales), the severity of the findings, and comparison of symptoms/findings to prior pregnancies.. There are no specific serum markers for PPCM yet.

3) Prolactin and a vascular etiology have been implicated in the  pathogenesis of PPCM. There are ongoing trials to evaluate treatment with bromocriptine, which blocks prolactin (look out for upcoming the REBIRTH RCT examining this!). Importantly, there is no clear evidence that breastfeeding is prohibitive to myocardial recovery and should not be discouraged given benefits to both mom and baby.

4) Many of these patients recover, but those at highest risk are those with severely depressed LV systolic function, dilated LVs, RV involvement, and of African descent.

5) Goal directed medical therapy with beta-blockers in both ante- and postpartum period is a cornerstone of therapy. ACEi/ARB/MRA/ARNI are contraindicated in pregnancy but may be added postpartum and with breastfeeding.

Quotables

1.  “It can be so challenging to distinguish symptoms (in a pregnant patient) from cardiac disease! One thing to keep in mind is severity – the more pronounced a finding or symptoms, the more concerning.” – Dr. Julie Damp

2. ”We often have more options than we think in medical management for heart failure through pregnancy and breastfeeding, but they do need some adjustments from our usual therapies.” -Dr. Julie Damp

3. “Start discussions about prognosis, monitoring, future pregnancies, and contraception early!” -Dr. Julie Damp

Show notes

1. How do you distinguish findings of normal pregnancy from signs and symptoms of heart failure?

  • Pregnant patients may normally have basal rales that typically clear with coughing, laterally shifted PMI, bounding PMI and pulse, JVD, S3, systolic murmur, edema/tense soft tissue, and heart rate elevation. 
  • Patients may feel short of breath, exertional fatigue, orthopnea, and palpitations. Think about the combination and severity of signs/symptoms to distinguish normal from abnormal (CHF) in your exam. For instance, isolated mild lower extremity edema in a patient who is otherwise relatively asymptomatic with no other concerning findings on exam will be approached differently than a patient with LE edema along with rales, S3 and significant dyspnea.
  • Asking patients who have had a prior pregnancy to compare their symptoms with the prior pregnancy can be helpful as well.
  • Timing of symptoms is also an important thing to consider.  For patients with underlying cardiac disease, they may start to develop symptoms earlier in pregnancy as hemodynamic changes evolve.

2. Given the prolactin hypothesis, should I use bromocriptine for treatment of PPCM and counsel my patients against breastfeeding?

  • Various etiologies regarding the pathogenesis of PPCM have been proposed including myocarditis-like process, autoimmune causes, dietary deficiencies of selenium, as well as remodeling from a maladaptive response to hemodynamic changes in pregnancy.
  • More recently, a vascular-hormonal hypothesis has been proposed where potent anti-angiogenic hormones are released creating a vasculotoxic environment. Specifically, a 16-kda fragment of prolactin, named vasohibin, has been implicated in the pathogenesis.
  • This has led to several RCTs in Germany and Burkina Faso evaluating bromocriptine (a dopamine receptor agonist which inhibits prolactin secretion) for the treatment of PPCM. As more data emerges, the role of bromocriptine will be better defined. For now, patients with more severe PPCM or risk factors that suggest a worse prognosis may benefit from its use. This certainly must be a shared decision as there are risks to bromocriptine including inhibiting lactation and thromboembolism.
  • Use of bromocriptine should be paired with anticoagulation.
  • In the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) study, 100 women were followed prospectively (15 of whom were breastfeeding at entry). While it was a small study, there was no difference in mean change in LVEF from entry to 12 months. While it is a small study, there was not even a signal towards an adverse effect with breastfeeding on myocardial recovery (graphic abstract below).

3. How should we approach patients with PPCM presenting with cardiogenic shock?

  • Note, our usual inotropic agents can still be used in pregnant patients.
  • There have been case series of successful use of mechanical support as a bridge to recovery or durable VAD for PPCM patients.
  • In one review, pregnant patient on VA-ECMO tended to have better outcomes than other patients who require this form of support. This difference is more pronounced if you look at pregnant patients with cardiac cause for decompensation. Their survival approaches 80% with fetal survival of 65%. 
  • Complications of cardiogenic shock are similar those in nonpregnant patients. However with shock in a pregnant patient, we also need to factor in timing and mode of delivery as well as anticipated bleeding with delivery. It is important that management is a discussion across a multi-disciplinary Cardio-Ob team caring for the patient.

4. What are the cornerstones of management for PPCM patients?

  • GDMT: most heart failure medications are considered safe in breastfeeding patients and beta blockers are a cornerstone of therapy (except atenolol). There is no data on ARNI in breastfeeding women yet.
  • ACEi/ARB/MRA/Sacubitril-Valsartan/Ivabradine should not be used during pregnancy.
  • You may use hydralazine/nitrates for afterload reduction in pregnancy.
  • Anticoagulation should be considered postpartum with LVEF < 35%.
  • For patients with PPCM who would typically qualify for an ICD, the general expert consensus experts is to wait longer before placing a device, as there is a high rate of myocardial recovery in the first 6-12 months after diagnosis. An option for these patients is a wearable defibrillator, however, keep in mind that there are logistical challenges with breastfeeding while wearing a defibrillator.
Davis, M et al. Peripartum Cardiomyopathy. J Am Coll Cardiol. 2020 Jan 21;75(2):207 221.

5. What are predictors for recovery and what’s important to remember in follow-up for these patients?

  • Low LVEF at diagnosis (particularly LVEF <30%), LV dilatation, and RV involvement are associated with poor prognosis.
  • PPCM disproportionately affects African American women in the US who also have lower rates of recovery and higher morbidity and mortality.
  • In the IPAC study, 70% of patients achieved myocardial recovery (LVEF >50%) by 1 year following diagnosis. However, none of the patients with both LVEF < 30% and LV > 6 cm at presentation recovered to normal LVEF. For those who do not recover normal cardiac function, studies show nearly 50% will go on to further deterioration with a subsequent pregnancy and are at the highest WHO classification risk for pregnancy.
  • Progesterone-releasing subcutaneous implants are first line for contraception, but likely all contraceptive methods have a benefit which outweighs potential risks of a subsequent pregnancy with abnormal baseline cardiac function.

References

Davis, M et al. Peripartum Cardiomyopathy. J Am Coll Cardiol. 2020 Jan 21;75(2):207 221.

Koczo A, Marino A, Jeyabalan A, Elkayam U, Cooper LT, Fett J, Briller J, Hsich E, Blauwet L, McTiernan C, Morel PA, Hanley-Yanez K, McNamara DM; IPAC Investigators. Breastfeeding, Cellular Immune Activation, and Myocardial Recovery in Peripartum Cardiomyopathy. JACC Basic Transl Sci. 2019 Jun 24;4(3):291-300.

Elkayam U, Schäfer A, Chieffo A, Lansky A, Hall S, Arany Z, Grines C. Use of Impella heart pump for management of women with peripartum cardiogenic shock. Clin Cardiol. 2019 Oct;42(10):974-981.

Olson TL, O’Neil ER, Ramanathan K, Lorusso R, MacLaren G, Anders MM. Extracorporeal membrane oxygenation in peripartum cardiomyopathy: A review of the ELSO Registry. Int Cardiol. 2020 Jul 15;311:71-76.

Goland S, Modi K, Bitar F, Janmohamed M, Mirocha JM, Czer LS, Illum S, Hatamizadeh P, Elkayam U. Clinical profile and predictors of complications in peripartum cardiomyopathy. J Card Fail. 2009;15:645–650. doi: 10.1016/j.cardfail.2009.03.008

Elkayam U. Risk of subsequent pregnancy in women with a history of peripartum cardiomyopathy. J Am Coll Cardiol. 2014;64:1629–1636. doi: 10.1016/j.jacc.2014.07.961

Guest Profiles

Dr. Julie Damp
Dr. Julie Damp

Dr. Julie Damp is program director of the cardiology fellowship at Vanderbilt University. She was part of the multicenter Peripartum Cardiomyopathy Network for the Investigations in Pregnancy-Associated Cardiomyopathy (IPAC) Study. In addition to her clinical and research work in cardio-obstetrics, her expertise include medical education, critical care cardiology, and noninvasive cardiac imaging.

Dr. Agnes Koczo
Dr. Agnes Koczo

Dr. Agnes Koczo is a second year cardiology fellow at the University of Pittsburgh Medical Center. She is interested in cardio-obstetrics and adult congenital heart disease. She plans to pursue a T32 postdoctoral research fellowship studying immune dysregulation in patients with cardiac complications in pregnancy.

Dr. Loie Farina
Dr. Loie Farina

Dr. Loie Farina @loiefarina is a cardiology fellow at Northwestern University. After venturing down south for undergrad at Duke (go Blue Devils!), she returned home to Chicago and has since completed both medical school and residency at Northwestern. She hopes to pursue a career in advanced heart failure and transplantation and is passionate about medical education and heart disease in women. Outside the hospital, she enjoys running along Chicago’s Lakefront Trail, cooking, and exploring new restaurants.

CardioNerds Cardioobstetrics Production Team

112. Narratives in Cardiology: Advocacy for Women’s Heart Health and Empowering Women in Cardiology with Dr. Gina Lundberg

CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Gina Lundberg (Associate Professor of Medicine at Emory University School of Medicine, Clinical Director of the Emory Women’s Heart Center, and Chair Elect for the ACC WIC Section) and Dr. Zarina Sharalaya (interventional cardiology fellow at CCF, CardioNerds Narratives FIT Council Member) for a Narratives in Cardiology episode. Dr. Lundberg highlights the disparities that exists with representation of women in cardiology and cardiology subspecialties, and how to navigate the challenges that exist for women in cardiology. Dr. Lundberg takes us through her career journey and gives several pearls for fellows-in-training regarding achieving career goals, networking, mentorship, and the use of social media to further your career. Special message from Dr. Annabelle Volgman. Audio editing and episode introduction by Gurleen Kaur.

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112. Narratives in Cardiology: Advocacy for Women’s Heart Health and Empowering Women in Cardiology with Dr. Gina Lundberg

Quotables

“Improving the work environment for women is going to be really important for job retention and for encouraging more women to go into EP, interventional cardiology, and heart failure…”

“One of the words of wisdom I say to a lot of early career women is slow down. You don’t have to drink the whole thing in your first 10 years. You can just slowly ease into it- there’s a time and a place for everything, a season for everything.”

“So start building your network. Build your ‘otter raft’ and by otter, I mean that group of people, men or women who really support you and lift you up, who might recommend you for a position or a lecture that might share opportunities with you”

Show notes

  1. What are some strategies to improve female representation in cardiology?
  • Practicing cardiologists, both men and women, need to mentor and sponsor trainees to attract more female into the field.
  • Improving the work environment is key to retention of women in cardiology (allowing for more flexibility to meet needs such as child-care etc.).
  • We need to build the pipleline to start recruiting females early on, even in high school.

2. What are some strategies to network as a fellow-in-training?

  • Start building your network early – attend ACC and AHA meetings. The ACC Legislative Conference is great because it’s a bit smaller and allows for more opportunities to meet leaders in the ACC.
  • Share your story with other people (example your old high school or sorority/fraternity) as an opportunity to mentor and inspire others.
  • Build your “otter raft”… that group of people who really support you and lift you up, who might recommend you for a position or a lecture that might share opportunities with you.

3. What is the role or value of social media for professional development?

  • Social medial democratizes the landscape, giving everyone a voice regardless of level of training, background, or beliefs.
  • It is invaluable for connecting and networking, on a global scale.
  • It empowers individuals to share – be it powerful stories, their thoughts, and of course education.
  • We of course need to be responsible with protecting our patient’s privacy, be discerning consumers, and be professional in our interactions.

CardioNerds Narratives in Cardiology
CardioNerds Narratives in Cardiology

The CardioNerds Narratives in Cardiology series features cardiovascular faculty representing diverse backgrounds, subspecialties, career stages, and career paths. Discussing why these faculty chose careers in cardiology and their passion for their work are essential components to inspiring interest in the field.

Each talk will feature a cardiology faculty from an underrepresented group, within at least one of several domains: gender, race, ethnicity, religion, national origin, international graduate status, disadvantaged backgrounds, etc.

Featured faculty will also represent a variety of practice settings, academic ranks, subspecialties (e.g. clinical cardiology, interventional cardiology, electrophysiology, etc), and career paths (e.g. division chief, journal editor, society leadership, industry consultant, etc).

Faculty will be interviewed by fellows-in-training for a two-part discussion that will focus on:

1) Faculty’s content area of expertise
2) Faculty’s personal and professional narrative

As part of their narrative, faculty  will discuss their unique path to cardiology and their current professional role with particular attention to challenges, successes, and advice for junior trainees. Specific topics will be guided by values relevant to trainees, including issues related to mentorship, work-life integration, and family planning.

To help guide this important initiative, the CardioNerds Narratives Council was founded to provide mentorship and guidance in producing the Narratives series with regards to guests and content. The CardioNerds Narratives Council members include: Dr. Pamela DouglasDr. Nosheen RezaDr. Martha GulatiDr. Quinn Capers, IVDr. Ann Marie NavarDr. Ki ParkDr. Bob HarringtonDr. Sharonne Hayes, and Dr. Michelle Albert.

The Narratives Council includes three FIT advisors who will lead the CardioNerds’ diversity and inclusion efforts, including the current project: Dr. Zarina SharalayaDr. Norrisa Haynes, and Dr. Pablo Sanchez.


Guest Profiles

Dr. Gina Lundberg
Dr. Gina Lundberg

Gina Price Lundberg MD FACC FAHA is an Associate Professor of Medicine at Emory University School of Medicine and has served as the Clinical Director of the Emory Women’s Heart Center since it was founded in 2013. She is a Preventive Cardiologist and specializes in heart disease in women, lipid abnormalities and cardiovascular risk reduction. She founded the first women’s heart prevention program in the state of Georgia in 1998. Dr Lundberg’s service at Emory University includes improving outcomes for women with cardiovascular disease but also improving gender equity for women in cardiology and encouraging more women to choose cardiology for their careers. She attended the Medical College of Georgia at Augusta University and trained in Internal Medicine at Atlanta Medical Center. Her cardiology fellowship was at Rush University in Chicago. She is active with the ACC, AHA, and NLA. She is the Chair-elect for the ACC Women in Cardiology Leadership Council and is the co-chair for the WIC Communications and Social Media Committee. She is the Co-chair for the NLA Social Media and Communications committee and the co-Chair for NLA DE&I Committee. She serves on the AHA Clinical Cardiology Communications and Social Media committee and the AHA Familial Hypercholesterolemia and Hyperlipidemia working group. And she serves as the Social Media Supervisor for JACC Case Reports.

Dr. Zarina Sharalaya - CardioNerds
Dr. Zarina Sharalaya

Dr. Zarina Sharalaya is an interventional cardiology fellow at the Cleveland Clinic. She completed medical school at The Ohio State University and then completed her residency at The University of North Carolina Chapel Hill. She moved back to her home state of Ohio to do general cardiology fellowship at The Cleveland Clinic. Zarina has been very involved with the Ohio ACC and this year has served as co-chair of the FIT Council. She is passionate about the Women in Cardiology initiative has been able to help formulate the first WIC chapter for Ohio ACC. She enjoys traveling, music, and spending time with her husband and new puppy Zuma.


Narratives in Cardiology Production Team

111. Cardio-Obstetrics: Normal Pregnancy Physiology with Dr. Garima Sharma

CardioNerd Amit Goyal, cardioobstetrics series co-chair Dr. Natalie Stokes, and episode lead Dr. Daniela Crousillat discuss normal cardiovascular physiology in pregnancy with Dr. Garima Sharma, Director of the Cardio-Obstetrics Program and the Ciccarone Center ‘s Associate Director of Preventive Cardiology Education in the Division of Cardiology. They discuss physiology from conception to post-partum, including the key hemodynamic, hormonal, and structural changes associated with normal pregnancy in the absence of pre-existing cardiovascular disease. Series introduction by Dr. Sharonne N. Hayes.

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AbstractPearlsQuotablesNotesReferencesGuest ProfilesProduction Team


Episode Abstract

Join us for a thrilling ride with our expert as we dive into the normal cardiovascular physiology of women through pregnancy. We discuss physiology from conception to post-partum, including the key hemodynamic, hormonal, and structural changes associated with normal pregnancy in the absence of pre-existing cardiovascular disease. We discuss how these physiologic changes manifest the history, physical exam, and key diagnostic testing (ECG, laboratory markers, and echocardiogram). Armed with these basic principles, we join Dr. Garima Sharma on patient consults to learn about potential signs and symptoms of cardiovascular disease in pregnancy and appropriate ways to risk stratify women with pre-existing or acquired cardiovascular disease in pregnancy. Importantly, we delve deeper into the importance of the growing field of cardio-obstetrics in the context of rising maternal mortality and staggering racial disparities in the care and outcomes of women in pregnancy.

Pearls

  • In normal pregnancy, plasma volume increases by up to 50% resulting in an adaptive decrease in systemic vascular resistance (SVR) by 25% and an increase in cardiac output (CO) by ~50% by the 2nd trimester.
  • Brisk carotid upstrokes, an S3 gallop, soft systolic ejection murmurs, pedal edema, and a mildly elevated jugular venous pressure (JVP) can all be normal physiologic findings in pregnancy in the context of no other signs/symptoms to suggest heart failure.
  • A normal NT-proBNP among pregnant patients with pre-existing cardiovascular disease has a high negative predictive value for predicting adverse maternal cardiac outcomes.
  • Pregnancy risk predictor tools (mWHO, CARPREG II, ZAHARA) are a crucial component of pre-conception counseling to help predict which women with existing cardiovascular disease are at highest risk for adverse maternal outcomes.
  • The U.S. ranks 1st in the world for maternal mortality among developed nations and cardiovascular disease is the leading cause of pregnancy-associated mortality in the U.S. Non-Hispanic Black are 3.5 times more likely to die from pregnancy as compared to White women.

Quotables

  • “You don’t know where you are going until you know where you have been” – Dr. Garima Sharma on the importance of holding on to hope when encountering difficult situations in our training and career pathways.
  • “Do not fear the pregnant patient! The pregnant patient is going through a normal physiologic process in her life, and the more we are familiar with it, the less we fear it” – Dr. Garima Sharma on taking care of pregnant patients.
  • “If you are going to move the needle on maternal mortality and in making a long-term sustainable change in the lives of these women, you have to focus on prevention” – Dr. Garima Sharma on the importance of prevention in reducing maternal mortality.
  • “Be empathetic. For most women, pregnancy is a normal state.  These women need your help!” – Dr. Garima Sharma on the importance of taking care of women in pregnancy.

Show notes

  1. What are the normal hemodynamic changes that occur in pregnancy? Let’s talk physiology!
  • Pregnancy, nature’s most grueling stress test, is a dynamic process associated with significant hemodynamic and physiological adaptations in the cardiovascular system which have evolved to support the needs of a developing fetus.
  • Predictable and expected hemodynamic changes occur during pregnancy for all women. Healthy women can adapt without significant consequences, whereas in women with underlying cardiac conditions, these changes may unmask a previously unknown condition or exacerbate existing abnormal hemodynamics.

Adaptive Physiologic Changes of the Cardiovascular System (1)

Source:  Me Mehta LS, Warnes CA, Bradley E et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association. Circulation 2020;141:e884-e903. Supplemental Table 1: Physiologic Changes Throughout Normal Pregnancy Compared to Pre Pregnancy State (2)
  • Plasma volume
    • Increases by about 50-75% by the 2nd trimester of pregnancy to meet greater circulatory needs of placenta and maternal organs
    • Erythropoietin causes an increase in red cell mass by 20-30% leading to relative dilution and “physiologic” anemia of pregnancy
  • Systemic vascular resistance (SVR)
    • To accommodate the increase in plasma volume, vasodilatation and vascular remodeling occur with a reduction in SVR
    • SVR decreases starting early in the 1st trimester and falls by 25-30% in the 2nd trimester potentiated by progesterone and estrogen-induced vasodilatation
    • Decreased SVR results in activation of the renal angiotensin-aldosterone system (RAAS) to maintain blood pressure and salt/water balance
  • Cardiac output (CO)
    • Increases by ~ 50% during pregnancy (up to 75% for a twin gestation!), starting at 5 weeks of gestation, and peaks at about 18-24 weeks in the 2nd trimester
    • CO (stroke volume (SV) x heart rate (HR)) increases predominantly via an increase in SV, but also an increase in HR by about 10-15 bpm by the 3rd trimester due to activation of the sympathetic system

There are a multitude of other physiological changes that allow our cardiovascular systems to adapt to the normal hemodynamics of pregnancy.

  • Respiratory:  Increase in metabolic rate & O2 consumption, minute ventilation and tidal volume resulting in a mild compensatory respiratory alkalosis.
  • Renal: Systemic vasodilation results in 50% increase in renal plasma flow and glomerular filtration rate (GFR), activation of RAAS to maintain fluid and electrolyte balance.
  • Hematologic: “Physiologic” anemia of pregnancy due to increase in plasma volume > red blood cell mass, increased production of coagulation factors with promotion of a pro-thrombotic state.
  • Endocrine: Increase in total cholesterol, triglycerides, LDL (by 50%) and decrease in HDL; mild insulin resistance.

Labor & Delivery and Post-Partum Period:

Labor: 

  • The maximum CO associated with pregnancy occurs during labor and immediately post-partum.
  • Repeated Valsalva maneuvers with a doubling of CO (up to 10L!) in active labor
  • Each uterine contraction displaces about 300-500 mL of blood back into the maternal systemic circulation

Post-partum:

  • Immediate: Caval decompression from evacuation of gravid uterus leads to marked increase in venous return (“auto transfusion”) back into the maternal systemic circulation
  • Two weeks post-partum: Maternal hemodynamics largely return to the pre-pregnancy state!

2. How are the normal physiological changes of pregnancy reflected in the physical exam and diagnostic cardiac testing? When should we worry?

  • Physical Exam (2)
    • Heart rate: Increases by 10-15 bpm by 3rd trimester, mild sinus tachycardia
    • Blood pressure: Decrease of 10-15 mm Hg in both SBP and DBP, nadiring in 2nd trimester, improving to pre-pregnancy state in 3rd trimester
    • Weight: 25-35 lbs considered normal total gestational weight gain in patients who are normal weight pre-partum
    • Cardiac exam: Mildly elevated jugular venous pressure with more prominent x and y descents, brisk carotid upstrokes, soft, systolic ejection murmur (flow murmur), S3 gallop, mild pedal edema, varicose veins, mammary flow murmur
  • ECG:
    • Mild sinus tachycardia
    • Infrequent premature atrial and ventricular atrial contractions
    • Leftward axis deviation
    • Q waves in inferior (II, III, aVF) and/or lateral (V4-V6) leads due to heart’s spatial shift left, anterior, and in the transverse plane to accommodate the gravid uterus
  • Cardiac Biomarkers
    • NT-proBNP
      • Increase up to two-fold in pregnancy but should remain within normal range
      • Important clinical utility in patients with pre-existing cardiac disease to serially assess changes throughout pregnancy
        • BNP <100 pg/nL among women with cardiovascular disease has a 100% negative predictive value for identifying cardiac events during pregnancy (3)
        • NT pro BNP <128 at 20 weeks has 97% NPV for maternal complications (4)
  • Echocardiography: (5)
    • Increase in LV volumes (but remaining within normal limits) and 50% increase in LV and RV mass as response to increased blood volume and CO
    • “Physiologic” left ventricular hypertrophy
    • Left ventricular ejection fraction remains unchanged
    • Mild increase in aortic root diameter
    • Trivial MR, TR, and PR (not typically AR!)
    • Trace, physiologic pericardial effusion (can be normal in up to 40%)

When should we worry?

  • Diastolic murmurs
  • Signs of congestive heart failure (crackles, elevated JVP/Kussmaul’s sign, marked lower extremity edema or weight gain)
  • Loud P2 or RV heave which could signal elevated pulmonary pressures/pulmonary HTN
  • Elevated NT-proBNP
  • Large pericardial effusion or symptoms of pericarditis

3. What are the available pregnancy risk predictor scores for the risk stratification of women with pre-existing cardiovascular disease who are interested in achieving pregnancy?

Modified World Health Organization (mWHO) Classification (6)

  • Most commonly used risk prediction tool to estimate individual maternal cardiovascular risk in women with pre-existing CVD based on known cardiac pathology
  • Classification ranges from simple lesions in Class I (mitral valve prolapse, repaired ASDs) to Class IV (pulmonary arterial hypertension, severe MS/AS, peripartum cardiomyopathy) in which pregnancy is typically advised against due to high (20-25%) maternal risk of adverse events

CARPREG (CArdiac Disease in PREGnancy Study) II Risk Score (7)

  • Developed from the prospective Canadian Cardiac Disease in Pregnancy Study in women with pre-existing cardiac disease, the score includes 10 predictors of a cardiac event,  including a prior history of cardiac events, baseline NYHA functional class, and late access to prenatal care to better determine overall risk (different than the mWHO classification which is based on just the cardiac lesion)
  • Weight-based point system: 5% risk of complications in lowest risk group (0 to 1 points) versus >40% risk with > 4 points
Source: Silversides CK, Grewal J, Mason J et al. Pregnancy Outcomes in Women With Heart Disease: The CARPREG II Study. J Am Coll Cardiol 2018;71:2419-2430. (7)

ZAHARA Risk Score

  • Weighted scoring system based on retrospective cohort of patients with pre-existing congenital heart disease only
  • Least commonly used risk tool as based on limited patient population (ACHD)

4. What are the most common cardiac complications which can occur in women with pre-existing cardiovascular disease in pregnancy and when do they occur?

  • Arrythmias: Atrial fibrillation is the most common arrythmia in women with underlying structural heart disease. PACs/PVCs can be common in normal pregnancy. If they occur, arrythmias are most common in the 2nd trimester.
  • Heart failure: Worsening/decompensation of left ventricular function, particularly in women with personal or family history of cardiomyopathy and history of peripartum cardiomyopathy. The development of heart failure and pulmonary edema are most common in the 3rd trimester or immediately (<1 week) post-partum. (7)
  • Don’t forget about other adverse pregnancy outcomes (APOs) which are associated with long term cardiovascular complications! (8)
    • Maternal Complications: Hypertensive disorders of pregnancy (i.e. pre-eclampsia), gestational diabetes
    • Obstetrical/Fetal Complications: Preterm birth, small for gestational age infant

5. What is the state of maternal mortality in the U.S. compared to the rest of the world, and what is this rise in maternal mortality attributed to?

  • The United States ranks 1st among developed nations in maternal mortality (9)
  • Cardiovascular disease is the leading cause of pregnancy-associated mortality in the United States and has gradually increased over time (7 to 17 deaths per 100,000 live births from 1989-2017)
  • Maternal mortality is attributed to 1) rising maternal age, 2) comorbid pre-existing conditions (HTN, diabetes, obesity), and 3) the growing number of women with congenital heart disease achieving childbearing age
    • Increase in obesity (41% of U.S. population) and chronic hypertension are two of the most important preventable risk factors!
    • Pre-pregnancy HTN has doubled among women in past decade and disproportionately affects rural communities and racial groups (10)
  • Over 700 women a year die of complications related to pregnancy each year in the United States, and it is thought that about two-thirds of those deaths are preventable.
  • Non-Hispanic Blacks and American Indian/Alaskan Native women are 3-4x more likely to die from a pregnancy-related cause compared to White women (11).
Source: Petersen EE, Davis NL, Goodman D, et al. Racial/ethnic disparities in pregnancy-related deaths — United States, 2007–2016. MMWR Morb Mortal Wkly Rep. 2019;68:762–765. (11

References

  1. Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 2014;130:1003-8.
  2. Mehta LS, Warnes CA, Bradley E et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement From the American Heart Association. Circulation 2020;141:e884-e903.
  3. Tanous D, Siu SC, Mason J et al. B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol 2010;56:1247-53.
  4. Kampman MA, Balci A, van Veldhuisen DJ et al. N-terminal pro-B-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease. Eur Heart J 2014;35:708-15.
  5. Liu S, Elkayam U, Naqvi TZ. Echocardiography in Pregnancy: Part 1. Current cardiology reports 2016;18:92.
  6. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Kardiologia polska 2019;77:245-326.
  7. Silversides CK, Grewal J, Mason J et al. Pregnancy Outcomes in Women With Heart Disease: The CARPREG II Study. J Am Coll Cardiol 2018;71:2419-2430.
  8. Søndergaard MM, Hlatky MA, Stefanick ML et al. Association of Adverse Pregnancy Outcomes With Risk of Atherosclerotic Cardiovascular Disease in Postmenopausal Women. JAMA cardiology 2020;5:1390-8.
  9. Pregnancy Mortality Surveillance System.       https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pregnancy-mortality-surveillancesystem.htm?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Freproductivehealth%2Fmaternalinfanthealth%2Fpmss.html. Accessed January 18th, 2021.
  10. Cameron NA, Molsberry R, Pierce JB et al. Pre-Pregnancy Hypertension Among Women in Rural and Urban Areas of the United States. J Am Coll Cardiol 2020;76:2611-2619.
  11. Petersen EE, Davis NL, Goodman D et al. Racial/Ethnic Disparities in Pregnancy-Related Deaths – United States, 2007-2016. MMWR Morbidity and mortality weekly report 2019;68:762-765.

Guest Profiles

Garima Sharma M.B.B.S.
Garima Sharma M.B.B.S.

Dr. Garima Sharma is an Assistant Professor of Medicine in the Division of Cardiology and Department of Medicine at Johns Hopkins University. She serves as Director of the Cardio-Obstetrics Program and the Ciccarone Center ‘s Associate Director of Preventive Cardiology Education in the Division of Cardiology. Her clinical and research interests are in CVD in pregnancy specifically adverse pregnancy outcomes and CV risks, hypertensive disorders of pregnancy, and gender equity.

Daniella Crousillat, MD
Daniella Crousillat, MD

Dr. Daniella Crousillat is an advanced echocardiography fellow at Massachusetts General Hospital in Boston, MA. She is interested in sex differences in valvular heart disease and pregnancy-associated CVD with a special focus on health disparities and the care of vulnerable patient populations.

CardioNerds Cardioobstetrics 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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Jump to: Patient summaryCase mediaCase teachingReferences


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

109. Nuclear and Multimodality Imaging: Cardiac Amyloidosis

CardioNerd Amit Goyal is joined by Dr. Erika Hutt (Cleveland Clinic general cardiology fellow), Dr. Aldo Schenone (Brigham and Women’s advanced cardiovascular imaging fellow), and Dr. Wael Jaber (Cleveland Clinic cardiovascular imaging staff and co-founder of Cardiac Imaging Agora) to discuss nuclear and complimentary multimodality cardiovascular imaging for the evaluation of multimodality imaging evaluation for cardiac amyloidosis. Show notes were created by Dr. Hussain Khalid (University of Florida general cardiology fellow and CardioNerds Academy fellow in House Thomas). To learn more about multimodality cardiovascular imaging, check out Cardiac Imaging Agora!

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Show Notes & Take Home Pearls – Nuclear and Multimodality Imaging: Cardiac Amyloidosis

Episode Abstract:

Previously thought to be a rare, terminal, and incurable condition in which only palliative therapies were available, multimodality imaging has improved our ability to diagnose cardiac amyloidosis earlier in its disease course. Coupled with advances in medical therapies this has greatly improved the prognosis and therapeutic options available to patients with cardiac amyloidosis. Multimodality imaging involving echocardiography with strain imaging, 99mTc-PYP Scan, and cardiac MRI can help diagnose cardiac amyloidosis earlier, monitor disease progression, and even potentially differentiate ATTR from AL cardiac amyloidosis.

Five Take Home Pearls

  1. Cardiac amyloidosis results from the deposit of amyloid fibrils into the myocardial extracellular space. The precursor protein can either be from immunoglobulin light chain produced by clonal plasma cells (in the setting of plasma cell dyscrasias) or transthyretin (TTR) produced by the liver (which can be  “wild type” ATTR caused by the deposition of normal TTR or a mutant ATTR  which is hereditary). These represent AL Cardiac Amyloidosis and ATTR Cardiac Amyloidosis respectively.
  2. Remember that amyloidosis can affect all aspects of the heart:the coronaries, myocardium, valves, electrical system, and pericardium! Be suspicious in a patient with history of HTN who has unexpected decrease in the need for antihypertensive agents with age or presents with a lower-than-expected blood pressure.
  3. Multimodality imaging can assist with the diagnosis of cardiac amyloidosis in patients with a high clinical suspicion, monitor disease progression, and even potentially differentiate ATTR from AL cardiac amyloidosis.
  4. Strain imaging assessment of global longitudinal strain (GLS) in patients with amyloid may demonstrate relatively better longitudinal function in the apex compared to the base, termed “apical sparing” or “cherry on top” (though in advanced stages the base to apex strain difference tends to become smaller). This has a 93% sensitivity and 82% specificity in identifying patients with cardiac amyloidosis and is particularly helpful with differentiating true cardiac amyloidosis from “mimics” such as hypertrophic cardiomyopathy, aortic stenosis, or hypertensive heart disease.
  5. When the clinical suspicion for cardiac amyloidosis is high, a semiquantitative grade ≥ 2 (myocardial uptake ≥ bone) on 99mTc-PYP Scan combined with negative free light chain and immunofixation assays (to rule out AL cardiac amyloidosis) can diagnose ATTR cardiac amyloidosis and exclude AL cardiac amyloidosis w/ 100% PPV! Furthermore, this can circumvent the need for endomyocardial biopsy. Echocardiography and cardiac MRI (CMR) are helpful for building the clinical suspicion for cardiac amyloidosis.
  6. When there is suspicion for AL cardiac amyloidosis, tissue biopsy is mandatory.

Quotable: – Nuclear and Multimodality Imaging: Cardiac Amyloidosis

“Even if you’re starting fresh, you should not do this test (technetium pyrophosphate scan) without a SPECT CT; you could be sending patients to therapy that costs anywhere between $25,000 to $250,000 per year for a disease that they don’t have.” –13:22

Detailed Show Notes

1. What is amyloidosis? What are the main precursor proteins in cardiac amyloidosis?

  • Amyloidoses are protein-folding disorders in which proteinaceous deposits known as amyloid can infiltrate multiple organs. Cardiac amyloidosis is typically secondary to two main subtypes: 1) immunoglobulin light chain produced by clonal plasma cells (AL cardiac amyloidosis), and 2) transthyretin produced by the liver (ATTR cardiac amyloidosis). AL and ATTR account for >95% of cardiac amyloidosis. Rare precursors include serum amyloid A (AA) and apolipoprotein A-1 (ApoA-1).
    • AL cardiac amyloidosis
      • Overall incidence of AL amyloidosis is estimated to be 8.0-14.4 million persons per year in the USA with cardiac involvement in ~50% of patients. Median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Survival has improved with earlier detection and advancements in oncologic treatments.
      • AL may deposit in any tissue outside the CNS and so patients often have multiorgan involvement (kidneys, liver, etc).
    • ATTR cardiac amyloidosis
      • ATTR typically results in cardiac amyloidosis, peripheral neuropathy, and MSK sequelae (i.e., bilateral carpal tunnel, lumbar spinal stenosis, biceps tendon rupture) with relative proportions dependent on the mutant variant.
      • Transthyretin amyloidosis can occur secondary to the deposition ofnormal TTR (known as “ATTR wild type” or “ATTRwt”) or a mutant form (hereditary form known as “ATTR mutant” or “ATTRm”).
        • ATTRwt
          • Has a 15:1 male to female prevalence ratio and usually occurs in older patients  (>65 y.o.)
          • Almost always involves the heart
            • May be responsible for as many as 30% of heart failure with preserved ejection fraction (HFpEF) cases in patients >75 years old!
        • ATTRm
          • Has only a slight male predominance and occurs in younger patients (>40 y.o.)
          • Inherited in an autosomal dominant fashion with multiple genotypes with variable degrees of penetrance and cardiac involvement
          • There are more than 100 genetic variants of ATTR that are associated with amyloidosis. However, only a few of these variants, including Val30Met, Thr60Ala, Ser77Tyr, and Val122Ile, are responsible for the majority of cases of hereditary ATTR
            • As stated in Podcast Episode #7, the specific mutation is closely linked with the age of onset, natural history, and phenotype of the affected individual!
            • The Val122Ile mutation is the most common variant in the USA and a has prevalence of 3-4% in the US African American population. It is associated with cardiac amyloidosis with minimal neuropathy.
            • Thr60Ala is the 2nd most common variant in the USA and is seen most commonly in those of Irish descent. It is associated with a mixed cardiomyopathy and neuropathy phenotype.
            • Val30Met causes a prototypical hATTR polyneuropathy (heriditary ATTR with polyneuropathy also known as “Familial Amyloid Polyneuropathy”
            • The specific genetic variant affects treatment decision and screening is indicated for individuals with known or suspected familial amyloidosis presenting w/ new symptomatic heart failure.

2. What are some classic cardiac and extracardiac manifestations of amyloidosis?

  • For fantastic case presentations of cardiac amyloidosis including suggestive history and physical exam findings, diagnostic considerations, and recommended management, tune in to CardioNerds Podcast Episodes #7-10 and #54! As  described in Podcast Episode #7, amyloidosis is associated with many classic extracardiac findings based on which organ it deposits in, and can also deposit in every layer of the heart—coronary, ventricular, valvular, electrical, and pericardial tissues! Below is a brief outline of some of the classic extracardiac and cardiac manifestations of amyloidosis.
    • Extracardiac:
      • ATTR: peripheral nerves (sensorimotor and autonomic defects) and musculoskeletal sequelae (bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture). Degree of cardiac vs nerve involvement differs by mutant variant as above. A prior Cleveland Clinic study showed Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients undergoing carpal tunnel release surgery
      • AL: any tissue outside the CNS. For instance, typical organs involved include the kidneys (nephrotic syndrome), liver, intestines, and nervous system. On exam one may find macroglossia and periorbital bruising.
    • Cardiovascular:
      • Decreased antihypertensive medication requirements with increasing age or presenting with lower than expected blood pressure
      • Postural hypotension
      • Coronary microvascular disease
        • Chronically elevated but flat troponin (infiltration into the coronary microvasculature)
        • Almost all patients with cardiac amyloidosis have significantly reduced peak stress myocardial blood flow (<1.3 ml/g/min) which may explain symptoms of angina in these patients with absence of epicardial coronary artery disease
      • Myocardial
        • Signs and symptoms of both left and right heart failure
        • Restrictive physiology
        • LVH tends to be greater in ATTR than in AL by time of symptom onset. This is because AL is also directly toxic, thereby causing a toxic-infiltrative cardiomyopathy. ATTR is more likely to deposit asymmetrically and thus may more closely mimic hypertrophic cardiomyopathy
      • Valvular
        • Thickened AV valves and interatrial septum
        • Paradoxical low-flow, low-gradient severe aortic stenosis (~15% of patients who undergo transcatheter aortic valve replacement have ATTRwt). The low flow and low gradient are because of restrictive filling and significant diastolic dysfunction
      • Electrical
        • AV Block, Bundle Branch Block
        • Atrial fibrillation from infiltration of the atria (especially ATTR), chronically high left atrial pressure, and/or aging.
        • Low voltage EKG[NJ1] [GU2]  (in most cases, however in up to ~10% of cases you may see voltage criteria for LVH on the EKG. However, the magnitude of electrocardiographic LVH  would still pale in comparison to the degree of hypertrophy you would see on echocardiography)
        • Pseudoinfarct pattern with septal Q-waves mimicking an anteroseptal MI
      • Pericardium
        • Pericardial Effusion

3. How can multimodality imaging help in the evaluation and management of cardiac amyloidosis? What are features suggestive of cardiac amyloidosis on echocardiography, Technetium-99m pyrophosphate (99mTc-PYP) scan, and cardiac MRI (CMR)?

  • Multimodality imaging has several roles in the evaluation of possible cardiac amyloidosis: establishing the clinical suspicion, diagnosing ATTR CA, surveillance of ATTR mutation carriers, monitoring disease progression, and assessing response to therapy.
    • Echocardiography
      • RV and LV wall hypertrophy (>12 mm) with normal chamber size
      • Biatrial enlargement
      • Thickened AV valves and interatrial septum
      • Possible concurrent LFLG aortic stenosis
      • Reduced Global Longitudinal Strain (GLS) with relatively preserved longitudinal function in the apex compared to the base. This “apical sparing” or “cherry on top” pattern has a 93% sensitivity and 82% specificity in identifying patients with cardiac amyloidosis in differentiating from “mimics” such as hypertrophic cardiomyopathy, aortic stenosis, or hypertensive heart disease.
      • Speckled pattern of the myocardium (less apparent with contemporary imaging)
      • Restrictive filling pattern on mitral inflow with ≥ Grade 2 Diastolic Dysfunction
      • Small pericardial effusion
    • Technetium-99m pyrophosphate (99mTc-PYP) Scan
      • 99mTc-PYP is a bone-avid radiotracer. In the 1980s there was excitement in the possibility of using 99mTc-PYP scan for diagnosis of cardiac amyloidosis however, enthusiasm waned when there started to be reports of low sensitivity. There was a resurgence of interest after the 2005 paper by Perugini et al. that showed that PYP scan can differentiate ATTR cardiac amyloidosis from AL cardiac amyloidosis with high sensitivity and specificity. It is likely that the previously reported low sensitivities were due to cases of AL amyloidosis.
      • How does 99mTc-PYP bind to amyloid protein and how does this differentiate ATTR from AL cardiac amyloidosis? 
        • Mechanisms of 99mTc-PYP binding to amyloid include the possible binding to “amyloid P component” (which binds the amyloid fibrils together via a calcium-dependent mechanism) via a calcium mediated mechanism or 99mTc-PYP binding to small microcalcifications which are much more prevalent in ATTR cardiac amyloidosis than with AL cardiac amyloidosis.
        • Usually there is no reason to have large myocardial uptake of 99mTc-PYP unless an individual has ATTR cardiac amyloidosis! Patients with AL cardiac amyloidosis can have myocardial uptake of 99mTc-PYP but usually at a much lower quantity. One rare caveat of this is in patients who are treated with hydroxychloroquine as hydroxychloroquine toxicity can present with restrictive cardiomyopathy in which you can have myocardial uptake of 99mTc-PYP. Remember that PYP was used to grade the size of myocardial infarction in the past, and following an acute MI we may see uptake as well (see below).
      • How and why is a 99mTc-PYP Scan combined with Single-photon emission computerized tomography (SPECT) to evaluate for ATTR amyloidosis?
        1. The 99mTc-PYP radiotracer is injected into the patient
        2. Planar imaging (a 2-D Nuclear image similar to CXR A/P) AND Cardiac SPECT images are obtained either 1 or 3 hours after injection of the radiotracer
        3. The planar images are examined both quantitatively and semiquantitatively.
          • Quantitative: Two circular regions of interest of the same size are drawn over the heart  and the contralateral chest (to account for background and ribs). The total and absolute mean counts are measured from both regions of interest. The heart to contralateral (H/CL) ratio is calculated. A ratio of ≥1.5 is considered positive for ATTR amyloid on a 1 hour protocol and a ratio of ≥1.3 is considered positive for ATTR amyloid on a 3 hour protocol
            • 99mTc-PYP radiotracer has peak myocardial counts 60 minutes after injection with gradual decline at 2 and 3 hours. Bone counts, however, increase gradually and peak 2-3 hours after injection. Because of this, the sensitivity of a 1 hour protocol is increased and specificity decreased (myocardial counts + blood pool counts which are at close to peak / Bone counts which are not at peak will give a higher H/CL). The sensitivity of the 3 hour protocol is decreased and the specificity is increased (myocardial counts + blood pool counts which are now reduced from peak / Bone counts which are now at peak will give a lower H/CL ratio). Because of this, the H/CL uptake ratio threshold of ≥ 1.5 has been established for 1 hour imaging and a lower cutoff of ≥ 1.3 established for 3-hour imaging. These cutoffs have been suggested to identify ATTR amyloid and distinguish it from AL amyloid with high sensitivity and specificity.
          • Semiquantitative: The myocardial uptake of 99mTc-PYP is visually compared to bone uptake
            • Grade 0: no myocardial uptake
            • Grade 1: myocardial uptake < bone uptake
            • Grade 2: myocardial uptake equal to bone uptake
            • Grade 3: myocardial uptake > bone uptake
        4. The Cardiac SPECT images are examined to:
          • Distinguish overlying rib uptake adding to counts over the region of interest over the heart on planar imaging
          • Distinguish blood pool activity from myocardial activity
          • This co-registration with CT is important to make sure you’re not counting tracer in the blood pool of the ventricle chamber (perhaps due to low cardiac output) or in the ribs (perhaps from rib fracture(s)) as myocardial uptake!
        5. Information from the planar Images (in point 3 above) and the Cardiac SPECT images (point 4 above) are synthesized to obtain a final interpretation regarding diagnosis of ATTR Cardiac Amyloidosis
          • Positive scan: Semiquantitative Grade ≥ 2 w/ confirmation of myocardial uptake on SPECT (rather than bone or blood-pool uptake). When there is Semiquantitative Grade ≥ 2 combined with negative free light chain and immunofixation assays this can diagnose ATTR cardiac amyloidosis and exclude AL cardiac amyloidosis w/ 100% PPV!
          • Equivocal scan: Semiquantitative Grade 1 with H/CL ratio 1-1.5 (on a 1 hour protocol) or 1-1.3 (on a 3 hour protocol). May represent AL cardiac amyloidosis or early ATTR cardiac amyloidosis. These patients need further specialized assessment for diagnosing cardiac amyloid; histological confirmation and typing of cardiac amyloidosis is recommended.
          • Negative scan: Semiquantitative Grade 0 with H/CL ratio <1
      • What are some limitations of 99mTc-PYP Scan and examples of why concomitant Cardiac SPECT is useful?
        • Most early experience highlighting the high accuracy of 99mTc-PYP scans for diagnosis of ATTR cardiac amyloidosis was with patients who were presenting with advanced disease and clinical heart failure where all the manifestations of amyloidosis including the imaging manifestations were more readily apparent
          • Sensitivity: More and more we are starting to send genetic testing for ATTRm and we may identify family members who are asymptomatic but have high risk genes. These are NYHA Functional Class 1, Stage A patients  at risk for disease but without clinical manifestations. We don’t have large scale population studies on these groups of patients and thus we don’t have sensitivity data.
          • Specificity: In the setting of rib fracture on the left, you can have active bone regeneration overlying the heart on planar images and your H/CL ratio will be increased resulting in false positive. Alternatively, rib fractures on the right can lead to a false negative. Persistent blood pool presence of the radiotracer even up to 3 hours despite no uptake in the myocardium will give ratios in the 1.3 to 1.4 range and can be misdiagnosed as ATTR cardiac amyloidosis
          • Originally, several decades ago, 99mTc-PYP Scan was done to identify the infarct area in the setting of acute MI. However, after around 1-2 weeks, you should no longer have 99mTc-PYP Scan uptake in that area. So early after MI, you may have a false positive result for ATTR and late following MI (when muscle is replaced by scar) you may have a false negative (lack of amyloid deposition and PYP tracer uptake in the scarred segments).
          • Patients who are high risk based on genetics and family history but do not yet have clinical disease can have negative blood work, ECG, imaging, and then a few years later—while they are still asymptomatic—can have a positive 99mTc-PYP Scan. These tests are not static—they can change over time! We don’t know what the appropriate intervals for follow-up testing for these patients with preclinical disease
          • Phe64Leu and Val30Met mutations are associated with false negative 99mTc-PYP scans!
    • Cardiac MRI (CMR)
      • Same anatomical evaluation as with echocardiography: diffuse increase in wall thickness, longitudinal apical function better than basal, etc.
      • Additionally, we get tissue characterization looking for scar
      • As the amyloid fibrils deposit into the myocardium, there is edema and infiltration, with increased space between cells (extracellular space) leading to elevated T1 times. As T1 relaxation time prolongs compared to normal myocardium, that is reflective of edema or diffuse fibrosis.
      • The space between the cells, the extracellular volume, is significantly increased by amyloid fiber deposition. Global extracellular volume (ECV) > 40% increase is suggestive of cardiac amyloidosis. This is not a specific sign for cardiac amyloidosis—anything that can give inflammation or fibrosis in the myocardium can increase the extracellular volume; however, the degree of elevation is far beyond what we see with other pathologies.
      • GLS on echocardiography and CMR w/ECV may be useful in monitoring response to therapy!
      • Gadolinium deposits into the extracellular space in areas that have been expanded by fibrosis. The classic area of deposition of amyloid fibrils is in the subendocardium. Diffuse subendocardial late gadolinium enhancement (LGE) in a non-coronary artery distribution with a dark blood pool is classic for cardiac amyloidosis; as the disease becomes more advanced, this can evolve into transmural LGE
      • Cardiac MRI does not have the power to discriminate between AL or ATTR cardiac amyloidosis. You can get some suggestion of the difference. Because AL cardiac amyloidosis is a relatively acute process, you may have more subendocardial LGE, a little less increased wall thickness, and some evidence of edema along with fibrosis when we look at T2 imaging compared to ATTR cardiac amyloidosis which is a more indolent process that takes years to develop.
    • What is in the works regarding the multimodality imaging evaluation of Cardiac Amyloidosis?
      • Novel Cardiac SPECT radiotracers and Cardiac PET radiotracers have shown promise in being able to follow response to treatment and assess prognosis respectively
      • PET radiotracers originally developed for imaging B-amyloid and Alzheimer’s disease (e.g. 18-F-florbetapir) can bind to the beta-pleated motif of amyloid fibrils regardless of the precursor protein (e.g., can bind to both ATTR and AL cardiac amyloid).
        • Researchers are also attempting to repurpose clinically available radiotracers to adequately image AL amyloid burden in the heart
        • PET tracers are quantitative and allow the possibility of quantifying amyloid burden and detecting changes in burden of disease (potential use for monitoring response to therapy). The 18-F-tracers have a long half-life of 109.7 minutes and allows delivery to sites without a cyclotron on site.

4. What are the ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis? A summary of the consensus recommendations is provided below. A link to the recommendations is provided in the “References” section below.

  • In the absence of a clonal plasma cell process, 99mTc-PYP/DPD/HMDP scintigraphy consistent with ATTR cardiac amyloidosis combined with consistent echo or CMR findings obviates the need for invasive endomyocardial or extracardiac biopsy!
  • For asymptomatic gene carriers, echocardiography and 99mTc-PYP Scan were rated as “Appropriate” while CMR was rated as “May Be Appropriate”
    • ECV has the potential to identify disease earlier in asymptomatic gene carriers compared with echocardiography
    • In patients with suspicion for cardiac AL amyloidosis (biopsy-proven systemic AL amyloidosis or MGUS w/abnormal FLC levels) 99mTc-PYP was rated as “Rarely Appropriate”
  • For patients with new symptomatic heart failure or those who are ATTR gene carriers/patients with AL or ATTR amyloidosis with new or worsening cardiac symptoms (chest pain, fatigue, effort intolerance, dyspnea, palpitations, dizziness/lightheadedness, syncope, orthopnea, PND, bloating, leg swelling, leg or jaw claudication) in which we are screening for cardiac amyloidosis, echocardiography, CMR, and 99mTc-PYP were rated as “Appropriate”
    • Again, for patients suspicion for cardiac AL amyloidosis (biopsy-proven systemic AL amyloidosis or MGUS w/abnormal FLC levels) 99mTc-PYP was rated as “Rarely Appropriate” apart from the rare instance in long-term survivors of AL amyloidosis where concurrent ATTR cardiac amyloidosis is suspected
  • For patients with biopsy-proven AL and ATTR cardiac amyloidosis, CMR and echocardiography were rated as “Appropriate” for assessing amyloid burden, response to therapy, or eligibility for stem cell transplant.
    • 99mTc-PYP was rated as “Rarely Appropriate”
    • 24 month assessment of response to therapy for echocardiography or CMR was rated as “Appropriate” with more frequent evaluation varying across expert amyloidosis centers
  • For patients with conditions with high risk for potential cardiac amyloidosis (bilateral carpal tunnel syndrome; biceps tendon rupture; unexplained neuropathy; arrhythmias in the absence of usual risk factors and no signs/symptoms of heart failure) echocardiography was rated as “Appropriate” and CMR and 99mTc-PYP were rated as “May Be Appropriate”
  • For patients with prior suggestive echocardiogram of cardiac amyloidosis, CMR was rated as “Appropriate”. For patients with prior suggestive CMR of cardiac amyloidosis, echocardiography was rated as “Appropriate”
    • 99mTc-PYP was rated as “May Be Appropriate” as it should only be used in cases of suspected ATTR cardiac amyloidosis.

Detailed Show Notes

Guest Profiles

Wael Jaber, MD, is a staff cardiologist in the Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, at the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic. Dr. Jaber specializes in cardiac imaging (both nuclear cardiology and echocardiography) and valvular heart disease. Dr. Jaber attended college at the American University in Beirut, graduating with a Bachelor of Science in biology. He then went on at the American University to receive his medical degree while making the Dean’s honor list. He completed his residency in internal medicine at the St. Luke’s-Roosevelt Hospital Center at Columbia University College of Physicians and Surgeons, where he also completed fellowships in cardiovascular medicine and nuclear cardiology. Dr. Jaber is currently is the Medical Director of the Nuclear Lab and of the Cardiovascular Imaging Core Laboratory in C5Research. He is fluent in English, French and Arabic. He is the author of Nuclear Cardiology review: A Self-Assessment Tool and cofounder of Cardiac Imaging Agora.

Dr. Aldo L Schenone is one of the current Chief Non-Invasive Cardiovascular Imaging Fellows at the Brigham and Women’s Hospital. He completed medical school at the University of Carabobo in Valencia, Venezuela, and then completed both his Internal Medicine residency and Cardiology fellowship at the Cleveland Clinic where he also served as a Chief Internal Medicine Resident.

Dr. Erika Hutt @erikahuttce is a cardiology fellow at the Cleveland Clinic. Erika was born and raised in Costa Rica, where she received her MD degree at Universidad de Costa Rica. She then decided to pursue further medical training in the United States, with the goal of becoming a cardiologist. She completed her residency training at Cleveland Clinic and went on to fellowship at the same institution. Her passions include infiltrative heart disease, atrial fibrillation, valvular heart disease and echocardiography among many. She is looking forward to a career in advanced cardiovascular imaging.


References and Links

Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. Mar 2013;6(2):195-201.

2.         Bullock-Palmer R. Top 10 Things To Know When Performing Cardiac Imaging to Assess Cardiac Amyloidosis. 2020. https://www.acc.org/latest-in-cardiology/articles/2020/02/27/14/47/top-10-things-to-know-when-performing-cardiac-imaging-to-assess-cardiac-amyloidosis.

3.         Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging. J Card Fail. Nov 2019;25(11):e1-e39.

4.         Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization. J Card Fail. Nov 2019;25(11):854-865.

5.         Dorbala S, Bokhari S, Miller E, Bullock-Palmer R, Soman P, Thompson R. 99m Technetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis. https://www.asnc.org/Files/Practice%20Resources/Practice%20Points/ASNC%20Practice%20Point-99mTechnetiumPyrophosphateImaging2016.pdf. Accessed March 11, 2021.

6.         Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. Jun 2016;133(24):2404-2412.

7.         Grogan M, Dispenzieri A, Gertz MA. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 07 2017;103(14):1065-1072.

8.         Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. Apr 2017;135(14):1357-1377.

9.         Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. Sep 2005;46(6):1076-1084.

10.       Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 06 2019;73(22):2872-2891.

11.       Singh V, Falk R, Di Carli MF, Kijewski M, Rapezzi C, Dorbala S. State-of-the-art radionuclide imaging in cardiac transthyretin amyloidosis. J Nucl Cardiol. 02 2019;26(1):158-173.

12.       Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. J Am Coll Cardiol. 10 2018;72(17):2040-2050.

108. Narratives in Cardiology: Physician Scientists & Women in Electrophysiology with Dr. Christine Albert and Dr. Rachita Navara

CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Christine Albert (Professor of Medicine, Founding Chair of the Department of Cardiology at Cedars-Sinai, and President of Heart Rhythm Society) and Dr. Rachita Navara (FIT at Washington University, soon to be EP fellow at UCSF) for a Narratives in Cardiology episode. We learn from their experiences as physician scientists and women in cardiology, and specifically in electrophysiology.

Claim free CME just for enjoying this episode!

Narratives in Cardiology: Physician Scientists & Women in Electrophysiology with Dr. Christine Albert and Dr. Rachita Navara

Show notes

1. Over the last several decades, what have we learned about the contribution of lifestyle factors to atrial fibrillation?

  • Particularly in women, the development of obesity (BMI > 30 kg/m2) is associated with a 41% increase in the risk of developing atrial fibrillation (AF). Even short-term weight gains are associated with a 18% increased risk of developing AF. Fortunately, losing weight could modify or even reverse this elevated risk [1]
  • Exercise is beneficial for reducing the risk of AF, but higher frequency of vigorous exercise is actually associated with an increased risk of developing AF in young men and joggers. This risk decreases with age, and is offset by the other benefits of vigorous exercise on AF risk factors [2]
  • The link between alcohol consumption and AF was first described in 2008: for healthy middle-aged women, consuming two or more alcoholic drinks is associated with a statistically increased risk of developing AF [3]
  • The recent VITAL trial is the largest and longest randomized trial on primary prevention of AF, following over 25,000 men and women over five years. As recently presented at AHA 2020, Dr. Christine Albert and her study team found that neither vitamin D nor fish oil prevents the development of AF [4]

2. What is some practical advice on giving presentations and preparing research grants from Dr. Albert, renowned physician-scientist, and leader in electrophysiology?

  • Whenever possible, Dr. Albert recommends memorizing your presentation to avoid referencing notes frequently, and to allow for continued eye contact with the audience. Practice delivering your presentation multiple times prior to the scheduled talk.
  • When preparing a grant, start early and seek feedback and edits from those in and out of your field.
  • In many cases, a grant review involves individuals who may not be in your exact scientific field, so the priority is to interest the grant readers regardless of their scientific background.

3. Whether in research or clinical care, what are the common features of a well-oiled clinical team?

  • In an ideal team, every individual adds value and has a clear role. Team members show mutual respect and provide the autonomy for other team members to demonstrate their expertise.
  • Don’t be intimidated by the individuals on your team who are extremely talented or experienced in a given domain – this in turn elevates you by being on the same team!
  • Leaders are most successful when they enable others to succeed. The spirit of collaboration and respect comes from the top, so leaders need to demonstrate respect for every team member and give each person a role, eliminating the need for team members to compete with each other.

4. What is some advice for female trainees navigating a male-dominated field (e.g. electrophysiology)? What makes a good mentor and mentee?

  • It is very important to seek female or otherwise relatable role models in your field. While representation increases, it can also be valuable to seek female mentors outside your specific field.
  • It is just as important for male mentors to continue to support female trainees, especially in fields where females are underrepresented.
  • Often, as a mentee you may change your area of interest or seek a new area of specialization that may no longer be fully aligned with your mentor’s expertise. A good mentor will continue to mentor you and connect you with those who can help you explore your new interests.
  • A good mentee also recognizes that mentors often have very limited time, so it is best to package all of your questions together and prepare for each meeting so that shared time is most high yield.

CardioNerds Narratives in Cardiology
CardioNerds Narratives in Cardiology

The CardioNerds Narratives in Cardiology series features cardiovascular faculty representing diverse backgrounds, subspecialties, career stages, and career paths. Discussing why these faculty chose careers in cardiology and their passion for their work are essential components to inspiring interest in the field.

Each talk will feature a cardiology faculty from an underrepresented group, within at least one of several domains: gender, race, ethnicity, religion, national origin, international graduate status, disadvantaged backgrounds, etc.

Featured faculty will also represent a variety of practice settings, academic ranks, subspecialties (e.g. clinical cardiology, interventional cardiology, electrophysiology, etc), and career paths (e.g. division chief, journal editor, society leadership, industry consultant, etc).

Faculty will be interviewed by fellows-in-training for a two-part discussion that will focus on:

1) Faculty’s content area of expertise
2) Faculty’s personal and professional narrative

As part of their narrative, faculty  will discuss their unique path to cardiology and their current professional role with particular attention to challenges, successes, and advice for junior trainees. Specific topics will be guided by values relevant to trainees, including issues related to mentorship, work-life integration, and family planning.

To help guide this important initiative, the CardioNerds Narratives Council was founded to provide mentorship and guidance in producing the Narratives series with regards to guests and content. The CardioNerds Narratives Council members include: Dr. Pamela DouglasDr. Nosheen RezaDr. Martha GulatiDr. Quinn Capers, IVDr. Ann Marie NavarDr. Ki ParkDr. Bob HarringtonDr. Sharonne Hayes, and Dr. Michelle Albert.

The Narratives Council includes three FIT advisors who will lead the CardioNerds’ diversity and inclusion efforts, including the current project: Dr. Zarina SharalayaDr. Norrisa Haynes, and Dr. Pablo Sanchez.


Guest Profiles – Physician Scientists Women Electrophysiology

Christine M. Albert, MD, MPH
Dr. Christine M. Albert

Dr. Christine Albert is currently President of Heart Rhythm Society. She recently transitioned from Professor of Medicine at Harvard and Director of the Center of Arrhythmia Prevention at the Brigham to now Founding Chair of the Department of Cardiology at Cedars-Sinai. She is an Epidemiologist and R01-grant funded physician scientist with over 200 peer-reviewed publications – with landmark contributions demonstrating the role of lifestyle and genetics on heart rhythm disorders. She has served as PI for numerous large-scale award-winning clinical trials, her latest studying primary prevention of cardiovascular disease and cancer in 25,000 patients across the country. She has served as the associate editor for Circulation, and continues to serve on the editorial board of numerous journals in not only cardiology but also epidemiology, clinical nutrition, and endocrinology and metabolism.

Rachita Navara - CardioNerds
Dr. Rachita Navara

Dr. Rachita Navara is a bioengineer and senior cardiology fellow at Washington University in St. Louis. She is excited to enter her dream specialty of electrophysiology at UCSF, the birthplace of catheter ablation for arrhythmias. Her interest in EP emerged during bioengineering training at the innovative Olin College of Engineering. She went on to medical school at UT Southwestern, where she was the lead singer of her med school band “The Pacemakers.” Dr. Navara completed her internal medicine training at Stanford University, where she was accepted into the inaugural Biodesign Pathway of Distinction and researched complex atrial fibrillation mechanisms under the mentorship of Dr. Sanjiv Narayan. She joined cardiology fellowship at Wash U, where she researched novel noninvasive cardiac radioablation under the mentorship of Dr. Phillip Cuculich. Dr. Navara’s startup company “SafeBeat Rx LLC” was competitively selected into BioGenerator’s Grants-to-business program, and she recently submitted her first NIH STTR grant. She was appointed as the youngest member of the National ACC EP Leadership Council, and she is currently an HRS representative to the AMA. Dr. Navara aims to lead a research lab conducting trials on EP devices and mapping/ablating technologies she has designed herself. In her free time, she enjoys painting, singing and tandem biking with her husband, and competitive scrabble tournaments (nerd level: ultimate).


References – Physician Scientists Women Electrophysiology

  1. Tedrow, Usha B., David Conen, Paul M. Ridker, Nancy R. Cook, Bruce A. Koplan, JoAnn E. Manson, Julie E. Buring, and Christine M. Albert. “The long-and short-term impact of elevated body mass index on the risk of new atrial fibrillation: the WHS (Women’s Health Study).” Journal of the American College of Cardiology 55, no. 21 (2010): 2319-2327.
  2. Aizer, Anthony, J. Michael Gaziano, Nancy R. Cook, Joann E. Manson, Julie E. Buring, and Christine M. Albert. “Relation of vigorous exercise to risk of atrial fibrillation.” The American journal of cardiology 103, no. 11 (2009): 1572-1577.
  3. Conen, David, Usha B. Tedrow, Nancy R. Cook, M. V. Moorthy, Julie E. Buring, and Christine M. Albert. “Alcohol consumption and risk of incident atrial fibrillation in women.” Jama 300, no. 21 (2008): 2489-2496.
  4. VITamin D and OmegA-3 TriaL (VITAL) results presented at AHA 2020 ahead of publication:  https://www.cedars-sinai.org/newsroom/study-vitamin-d-fish-oil-dont-lower-atrial-fibrillation-risk/

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

CardioNerds (Daniel Ambinder & Karan Desai) join Thomas Jefferson University FITs, Drs. Sean Dikdan, Rachel Debenham and Harsh Doshi. They discuss a profound story about a young man who presented with ventricular arrhythmias and cardiogenic shock that was ultimately found to be due to giant cell myocarditis. From the evaluation of cardiogenic shock to the role of endomyocardial biopsy to facing inequities in organ allocation, there are learning pearls for every listener! Dr. Enrico Ammirati, an advanced heart failure and transplant cardiologist in Milan, Italy, provides the E-CPR segment. For more insights from Dr. Ammirati, check out episodes 29 and 30 which feature an in-depth discussion on myocarditis with Dr. Ammirati, along with Drs. JoAnn Lindenfeld and Javid Moslehi. Audio editing by CardioNerds Academy intern, Gurleen Kaur.

CME is unavailable for this episode.

Jump to: Patient summaryCase mediaCase teachingReferences


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


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