It is reported that more is more for HFrEF patients and angiotensin converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB) therapy. In a recent meta-analysis of six randomized trials*, higher doses of ACE-I/ARBs were associated with a reduction in all-cause mortality. Of note, when the ARB trial (HEAAL) was taken out of the analysis, higher dose ACE-I alone did not reach statistical significance.
What about hospitalizations? Four out of the 6 trials found no difference between high dose and low dose ACE-I/ARB and all-cause or HF hospitalizations. When HF hospitalizations and all-cause mortality outcomes were combined in 3 trials, higher doses had a significant hospitalization reduction.
No surprise, potassium was elevated – higher doses of ACE-I/ARB were associated with 2x the risk of hyperkalemia. No differences in drug discontinuation, hypotension, or kidney failure were seen between high and low dose regimens, however.
*High dose vs low dose ACE-I or ARB were defined as:
Lisinopril 32.5-35 vs 2.5-5mg (ATLAS),
Enalapril 2.5-5 vs 10mg BID (NETWORK),
Enalapril 20 vs 60mg (Nanas et al),
Enalapril 5 BID vs 20mg BID (Pacher et al),
Captopril 25 BID vs 50mg BID (CHIPS).
Losartan 50 vs 150mg (HEAAL)
In a heartbeat…
Higher doses of ACE-I/ARBs when compared to lower doses are associated with a reduction in all-cause mortality in HFrEF.
Commentary and thoughts on titrating ACEI/ARB in clinical practice: Goldilocks Dilemma of Dose Titration in Heart Failure With Reduced Ejection Fraction: Too Little, Too Much, or Just Right?
Contributor: Jennifer Huang
Data from over 3 million US Veterans explored connections between HF and kidney disease, common co-morbid players. The data showed that having HF increases the risk of developing kidney disease and accelerates the process.
Hemodynamic changes (low cardiac output and increased renal venous pressure), neurohormonal changes (activation of the sympathetic nervous and renin angiotensin systems), increased oxidative stress, and inflammatory activation are likely to blame. Additionally, elevated renal G-Protein Coupled Receptor – G protein – was associated with renal tissue damage, fibrosis, and inflammation.
Everything should be taken with a grain (<2 gm) of salt. The limitations of this study are its observational nature, more than 90% male participants, and use of ICD-9 codes to define HF with no differentiation between HFpEF and HFrEF.
In a heartbeat…
Having HF is associated with future development of kidney disease through various mechanisms. As such, patients with known HF (HFpEF or HFrEF) may benefit from aggressive renoprotective measures.
Relaxing can be hard in hypertensive heart disease (HHD). Specifically, for the stiff ventricle destined for HFpEF. Is it a problem with relaxation of myocytes, or is it due to stiffening from fibrosis?
Entry of Ca2+ into the myocyte begins a flood of stored Ca2+, stimulating contraction. The cell can relax only when this Ca2+ is taken away from the contractile apparatus. Along with SERCA and phospholamban, the sarcolemmal Na+/Ca2+ exchanger (NCX) handles this important duty.
In heart failure, this calcium handling system becomes deficient, and high intracellular Ca2+ causes longer myocyte contraction and slower myocyte relaxation.
How can we put this in a clinical perspective? Well, myocytes taken during coronary artery bypass graft surgery from (a) patients without hypertension or HF, and from patients with hypertensive heart disease (b) without, and (c) with clinical HFpEF were studied in a paper by Runte et al. These myocyte samples were then put in a beating prep in the laboratory while movements of Ca2+ and Na+ were measured. Turns out that despite the five-star laboratory accommodations, the myocytes from hypertensive patients (groups b and c) still could not relax normally.
Myocardial Ca2+ was elevated in cells from hypertensive patients, with and without HFpEF, but higher Ca2+ elevations were seen in HFpEF. When myocytes were made to go from 60-180 beats per minute Ca2+ elevations were particularly pronounced. Na+, on the other hand, was not elevated. In addition, drugs blocking Na+ influx, such as ranolazine, furosemide or amiloride, did not affect relaxation in these cells, which may have clinical implications.
In a heartbeat…
Myocytes from patients with hypertensive heart disease with and without HFpEF have impaired myocardial relaxation. In the same cells, myocardial Ca2+ was elevated during diastole while Na+ was not.