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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e952 CLINICAL STATEMENTS AND GUIDELINES with HFrEF. However, the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial45 randomized 110 patients with EF ≥50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QOL, exercise tolerance, or NT-proBNP levels. Although the routine use of nitrates in patients with HFpEF does not appear beneficial, patients with HFpEF and symptomatic CAD may still receive symptomatic relief with nitrates. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial13 randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance (peak observed VO2, <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. This study did not show improvement in oxygen consumption or exercise tolerance. 7.8 Cardiac Amyloidosis 7.8.1 Diagnosis of Cardiac Amyloidosis Recommendations for Diagnosis of Cardiac Amyloidosis Referenced studies that support the recommendations are summarized in the Online Data Supplements. COR LOE Recommendations 1 B-NR 1. Patients for whom there is a clinical suspicion for cardiac amyloidosis*1–5 should have screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum free light chains.6 1 B-NR 2. 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.7 1 B-NR 3. 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.8 *LV wall thickness ≥14 mm in conjunction with fatigue, dyspnea, or edema, especially in the context of discordance between wall thickness on echocardiogram and QRS voltage on ECG, and in the context of aortic stenosis, HFpEF, carpal tunnel syndrome, spinal stenosis, and autonomic or sensory polyneuropathy. Synopsis Cardiac amyloidosis is a restrictive cardiomyopathy with extracellular myocardial protein deposition, most commonly monoclonal immunoglobulin light chains (amyloid cardiomyopathy [AL-CM]) or transthyretin amyloidosis (ATTR-CM). ATTR can be caused by pathogenic variants in the transthyretin gene TTR (variant transthyretin amyloidosis, ATTRv) or wild-type transthyretin (wild-type transthyretin amyloidosis, ATTRwt). A diagnostic approach is outlined in Figure 13.9 Recommendation-Specific Supportive Text 1. Diagnosis of ATTR-CM requires a high index of suspicion. LV thickening (wall thickness ≥14 mm) along with fatigue, dyspnea, or edema should trigger consideration of ATTR-CM, especially with discordance between wall thickness on echocardiogram and QRS voltage on ECG,10 or other findings such as apical sparing of LV longitudinal strain impairment on echocardiography and diffuse late-gadolinium enhancement on cardiac MRI. ATTR-CM is prevalent in severe aortic stenosis,1 HFpEF,2 carpal tunnel syndrome,3 lumbar spinal stenosis,4 and autonomic or sensory polyneuropathy.5 Practically, screening for the presence of a monoclonal light chain and technetium pyrophosphate (99mTc-PYP) scan can be ordered at the same time for convenience, but the results of the 99mTc-PYP scan are interpreted only on the context of a negative monoclonal light chain screen. 99mTc-PYP scans may be positive even in AL amyloidosis7 and, thus, a bone scintigraphy scan alone, without concomitant testing for light chains, cannot distinguish ATTR-CM from AL-CM. Serum free light chain (FLC) concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. IFE is preferred because serum plasma electrophoresis and urine plasma electrophoresis are less sensitive. Together, measurement of serum IFE, urine IFE, and serum FLC is >99% sensitive for AL amyloidosis.6,11 2. The use of 99mTc bone-avid compounds for bone scintigraphy allows for noninvasive diagnosis of ATTR-CM.7 99mTc compounds include PYP, 3,3-diphosphono-1,2-propanodicarboxylic acid, and hydromethylene diphosphonate, and PYP is used in the United States. In the absence of a light-chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2/3 cardiac uptake or an H/CL ratio of >1.5. In fact, the presence of grade 2/3 cardiac uptake in the absence of a monoclonal protein in serum or urine has a very high specificity and positive predictive value for ATTR-CM.7 SPECT is assessed in all positive scans to confirm that uptake represents myocardial retention of the tracer and not blood pool or rib uptake signal.12 Downloaded from http://ahajournals.org by on October 7, 2026