Cardiology

Damman, K., M. Gori, B. Claggett, P. S. Jhund, M. Senni, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, K. Swedberg, M. R. Zile, M. Packer, A. S. Desai, S. D. Solomon and J. J. V. McMurray (2018). “Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure.” JACC Heart Fail. Apr 11. [Epub ahead of print].

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OBJECTIVES: The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. BACKGROUND: Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin-angiotensin system. METHODS: In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. RESULTS: At screening, the eGFR was 70 +/- 20 ml/min/1.73 m(2) and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m(2)/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m(2)/year] vs. -2.04 ml/min/1.73 m(2)/year [95% CI: -2.21 to -1.88 ml/min/1.73 m(2)/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). CONCLUSIONS: Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.

Cedars, A., C. Vanderpluym, D. Koehl, R. Cantor, S. Kutty and J. K. Kirklin (2018). “An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of hospitalization, functional status, and mortality after mechanical circulatory support in adults with congenital heart disease.” J Heart Lung Transplant 37(5): 619-630.

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BACKGROUND: Adult congenital heart disease (ACHD) prevalence is increasing worldwide, with advanced heart failure (HF) as a leading cause of death. Limited data are available on durable mechanical circulatory support (MCS) in ACHD patients. METHODS: ACHD patients from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database were identified and propensity matched with non-ACHD patients using risk factors from the INTERMACS Seventh Annual Report. We compared these groups for the primary outcome of post-MCS mortality. We also investigated adverse event rates, functional status, and health-related quality of life. RESULTS: ACHD (n = 128) and non-ACHD (n = 512) patients were appropriately matched by baseline characteristics. ACHD patients had a longer length of stay at MCS implant (24 vs 19 days, p = 0.006) but similar rates of post-MCS adverse events and hospitalization. There were similar improvements in functional status and health related quality of life post-MCS in both groups. ACHD patients had significantly higher mortality post-MCS exclusively during the first 5 months after implant (p = 0.003) and a lower probability of receiving a transplant (p = 0.003). Risk factors for early mortality were biventricular or total artificial heart device implant and age > 50 years. CONCLUSIONS: ACHD patients experience a higher early mortality after MCS but have similar adverse event rates and similar improvements in functional capacity and quality of life compared with non-ACHD patients. These data support expansion of MCS use in selected ACHD patients.

Carey, S. A., K. M. Tecson, K. Bass, J. Felius and S. A. Hall (2018). “Patient activation with respect to advanced heart failure therapy in patients over age 65 years.” Heart Lung. Apr 20. [Epub ahead of print].

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BACKGROUND: Clinical and ethical issues persist in determining candidacy for advanced heart failure (HF) therapies in elderly patients. Selection takes many factors into account, including “activation” (engagement and ability to self-manage). OBJECTIVE: To investigate effects of age, activation, and depression/anxiety on selection and 6-month survival of participants considered for therapy. METHODS: Consecutive people referred for advanced HF therapy completed the Patient Activation Measure and Hospital Anxiety and Depression Scale. We analyzed data from participants by age (>/=65 vs. <65 years), stratified by approval for therapy. RESULTS: Among 168 referred, 109 were approved, with no difference in activation between age groups (88% highly activated). Similarly, activation was not associated with age among those not approved. Activation was related to anxiety in older, approved participants, but not to depression. CONCLUSIONS: Concerns regarding reduced self-management in the elderly may not be valid. Age alone should not disqualify a candidate for advanced HF therapy.RE

Packer, M. and D. W. Kitzman (2018). “Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2.” JACC Heart Fail Mar 7. [Epub ahead of print].

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Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat.

Packer, M. (2018). “Role of the sodium-hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes.” Diabetes Obes Metab 20(4): 800-811.

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Diabetes is characterized by increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.