Cardiology

Roberts, W.C. and Siddiqui, S. (2021). “Huge Right Ventricular Outflow Tract Aneurysm Late Following Total Repair of Tetralogy of Fallot Leading to Orthotopic Heart Transplantation.” Cardiovasc Pathol Mar 2;107332. [Epub ahead of print].

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Described herein are 3 patients who underwent successful orthotopic heart transplantation (OHT) because of huge, calcified right ventricular outflow tract (RVOT) aneurysms after repair of tetralogy of Fallot 35, 43, and 59 years earlier. Two of the 3 patients developed recurring episodes of ventricular tachycardia simulating arrhythmogenic right ventricular cardiomyopathy.

McMurray, J.J.V. and Packer, M. (2021). “How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction?: A Redefinition of Evidence-Based Medicine.” Circulation 143(9): 875-877.

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Large-scale trials have demonstrated the efficacy of sacubitril/valsartan, β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as disease-modifying agents that (when combined) represent foundational therapy for heart failure and a reduced ejection fraction (HFrEF). The conventional approach to achieving treatment with all 4 drug classes is to prescribe them in the precise sequence in which they were tested in clinical trials over the past 40 years. Physicians are asked to start with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, to be followed by a β-blocker, then an MRA, then a neprilysin inhibitor, and, finally, a SGLT2i. Prescribers are advised to titrate the dose of each drug class to the target dose used in large-scale trials before initiating the next recommended drug class. This approach recapitulates the sequence by which these agents were developed for the treatment of heart failure.[No abstract; excerpt from article].

Shahzeb Khan, M., Kristensen, S.L., Vaduganathan, M., Kober, L., Abraham, W.T., Desai, A.S., Solomon, S.D., Swedberg, K., Dickstein, K., Zile, M.R., Packer, M., McMurray, J.J. and Butler, J. (2021). “Natriuretic Peptide Plasma Concentrations and Risk of Cardiovascular Versus Non-Cardiovascular Events in Heart Failure with Reduced Ejection Fraction Insights from the PARADIGM-HF and ATMOSPHERE Trials.” Am Heart J Feb 20;S0002-8703(21)00054-5. [Epub ahead of print].

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BACKGROUND: N-terminal pro-B-type natriuretic peptide (NTproBNP) plasma concentrations are independent prognostic markers in patients with heart failure with reduced ejection fraction (HFrEF). Whether a differential risk association between NTproBNP plasma concentrations and risk of cardiovascular (CV) versus non-CV adverse events exists is not well known. OBJECTIVE: To assess if there is a differential proportional risk of CV versus non CV adverse events by NTproBNP plasma concentrations. METHODS: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV versus non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/ml) at baseline using Cox regression adjusting for traditional risk factors. RESULTS: 14,737 patients with mean age of 62±8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/ml group to 142.3 in the ≥3000 pg/ml group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to presence of AF at baseline and prior HF hospitalization within last 12 months. CONCLUSION: The absolute CV event rates per patient years of follow up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Rohde, L.E., Vaduganathan, M., Claggett, B.L., Polanczyk, C.A., Dorbala, P., Packer, M., Desai, A.S., Zile, M., Rouleau, J., Swedberg, K., Lefkowitz, M., Shi, V., McMurray, J.J.V. and Solomon, S.D. (2021). “Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.” Eur J Heart Fail Feb 9. [Epub ahead of print].

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AIMS: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. METHODS AND RESULTS: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (P(interaction)  < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). CONCLUSIONS: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Ferreira, J.P., Pocock, S.J., Rocca, H.B., Janssens, S., Tsutsui, H., Zhang, J., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T., Schnee, J. and Zannad, F. (2021). “Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.” Eur Heart J 42(6): 671-680.

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AIMS: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. METHODS AND RESULTS: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated. CONCLUSION: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.