A 69-year-old man was referred to the cardiology clinic after being found to have a reduced left ventricular ejection fraction and left ventricular hypertrophy. For the last several months he has been experiencing progressively worsening fatigue and shortness of breath while getting to the 2^nd floor in his house. He has a history of bilateral carpal tunnel syndrome and chronic low back pain. He takes no medications. On exam, his heart rate is 82 bpm, blood pressure is 86/60 mmHg, O2 saturation is 97% breathing ambient air, and BMI is 29 kg/m2. He has a regular rate and rhythm with normal S1 and S2, bibasilar pulmonary rales, and 1+ pitting edema in both legs. EKG shows normal sinus rhythm with a first-degree AV delay and low voltages. Transthoracic echocardiogram shows a moderately depressed LVEF of 35-39%, severe concentric hypertrophy with a left ventricular posterior wall thickness of 1.5 cm and strain imaging showing globally reduced longitudinal strain with apical sparring. There is also biatrial enlargement and a small pericardial effusion. A pharmacologic nuclear stress test did not reveal any perfusion defects. A gammopathy panel including SPEP, UPEP, serum and urine immunofixation studies, and serum free light chains are unrevealing. A ^99mTc-Pyrophosphate scan was positive with grade 3 uptake. In addition to starting diuretics, what is the next most appropriate step for managing for this patient?

A

Start metoprolol succinate

B

Start sacubitril/valsartan

C

Perform genetic sequencing of the TTR gene

D

Perform endomyocardial biopsy

Explanation

The correct answer is C – perform genetic sequencing of the TTR gene.

This patient has findings which raise suspicion for cardiac amyloidosis. There are both cardiac (low voltages on EKG and echocardiogram showing marked LVH with biatrial enlargement and small pericardial effusion as well as a characteristic strain pattern) and extra-cardiac (bilateral carpal tunnel syndrome and low back pain) features to suggest amyloidosis. The diagnosis of cardiac amyloidosis requires a high index of suspicion and most commonly occurs due to a deposition of monoclonal immunoglobulin light chains (AL-CM) or transthyretin (ATTR-CM). ATTR may cause cardiac amyloidosis as either a pathogenic variant (ATTRv) or as a wild-type protein (ATTRwt).

Patients for whom there is a clinical suspicion for cardiac amyloidosis should have screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum free light chains (Class 1, LOE B-NR). Immunofixation electrophoresis (IFE) is preferred because serum or urine plasma electrophoresis (SPEP or UPEP) are less sensitive. Together, measurement of serum IFE, urine IFE, and serum FLC is >99% sensitive for AL amyloidosis. Negative studies as in our patient essentially exclude AL amyloidosis from consideration.

In patients with high clinical suspicion for cardiac amyloidosis, without evidence of serum or urine monoclonal light chains, bone scintigraphy should be performed to confirm the presence of transthyretin cardiac amyloidosis (Class 1, LOE B-NR). As in this patient’s case, the ^99mTc-Pyrophosphate scan with a grade 2/3 cardiac uptake in the absence of a serum or urinary monoclonal protein has a very high specificity and positive predictive value for ATTR-CM. This allows for a noninvasive diagnosis of ATTR-CM, obviating the need for an endomyocardial biopsy and so option D is inaccurate.

In patients for whom a diagnosis of transthyretin cardiac amyloidosis is made, genetic testing with TTR gene sequencing is recommended to differentiate hereditary variant from wild-type transthyretin cardiac amyloidosis (Class 1, LOE B-NR). Differentiating ATTRv from ATTRwt is important because confirmation of ATTRv would trigger genetic counseling and potential cascade screening of family members and TTR silencer therapies, such as inotersen and patisiran (currently only approved for the treatment of polyneuropathy caused by ATTRv amyloidosis).

Routine guideline-directed medical treatment (GDMT) for neurohormonal blockade may be poorly tolerated in patients with ATTR-CM and EF ≤40%. Due to restrictive physiology, they may be predisposed to more hypotension with ARNi, ACEi, and ARB. Similarly, patients with ATTR-CM rely on their heart rate response to preserve the cardiac output, thus BB may worsen HF symptoms. In this case, our patient already has a borderline blood pressure without these medications. Both options A and B are false.

Main Takeaway

In patients for whom a diagnosis of transthyretin cardiac amyloidosis is made, TTR gene sequencing is recommended to differentiate pathologic variant (ATTRv) from wild-type transthyretin cardiac amyloidosis (ATTRwt). This has implications in terms of screening for family members and management options for ATTRv.

For patients with ATTR-CM and EF ≤40%, GDMT may be poorly tolerated.

Guideline Loc.

Section 7.8, Figure 13