Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial)

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by −2.8, 95% confidence interval −4.6 to −1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF

Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial)

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssyn-chrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymp-tomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spi-ronolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confi-dence interval -4.6 to -1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection frac-tion, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.(c) 2022 Elsev-ier Inc. All rights reserved. (Am J Cardiol 2023;191:39-42

Early and late renal function changes with spironolactone in patients at risk of developing heart failure: findings from the HOMAGE trial

Spironolactone reduces estimated glomerular filtration rate (eGFR) soon after initiating treatment, but mineralocorticoid receptor antagonists (MRA) may prevent longer-term decline in eGFR. We studied the effect of spironolactone (compared to usual care) on eGFR changes and its biomarker correlations in 527 people at risk of developing heart failure enrolled in the HOMAGE trial. eGFR was determined at baseline, one and nine months. Compared to usual care, spironolactone reduced eGFR from baseline to month one: -3 (-4 to -2) ml/min/1.73m2, P <0.001 (corresponding to a -4% change on average). Spironolactone caused no further reduction in eGFR from month one to month nine: -1 (-3 to 0) ml/min/1.73m2, P=0.085. eGFR decrease between baseline and one month was positively correlated with brain natriuretic peptide and kidney injury molecule 1. Thus, spironolactone induces a small, early eGFR decrease without evidence of renal tubular injury, suggesting an early hemodynamic effect

Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial

Aims The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. Methods and results Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean difference(sspiro/control): -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m(2); interaction p(across-tertiles) = 0.005; interaction p(third tertile) = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differences(spiro/control): -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction p(across-tertiles) = 0.09; interaction p(third tertile) < 0.001]. Conclusions These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1). [GRAPHICS] Patients at risk of heart failure from the HOMAGE clinical trial were classified according to the baseline degree of myocardial collagen cross-linking, non-invasively assessed by the serum collagen type I C-terminal telopeptide (CITP) to matrix metalloproteinase-1 (MMP-1) ratio (CITP:MMP-1). As highly cross-linked collagen fibres are more resistant to degradation and CITP is a cross-linked peptide, for a given MMP-1 quantity less CITP will be released and, subsequently, serum CITP:MMP-1 will be lower. Whereas patients with low collagen cross-linking (high CITP:MMP-1) benefit from the cardioprotective effects of treatment with spironolactone on left atrial remodelling [i.e. a decrease in left atrial volume index (LAVI)] and on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, these beneficial effects are not found in patients with higher collagen cross-linking (low CITP:MMP-1)

The association between markers of type I collagen synthesis and echocardiographic response to spironolactone in patients at risk of heart failure: findings from the HOMAGE trial

Aims Procollagen type I C-terminal propeptide (PICP) and procollagen type III N-terminal propeptide (PIIINP) are markers reflecting collagen synthesis in cardiac fibrosis. However, they may be influenced by the presence of non-cardiac comorbidities (e.g. ageing, obesity, renal impairment). Understanding the associations between markers of collagen synthesis and abnormalities of cardiac structure and function is important to screen for myocardial fibrosis and monitor the antifibrotic effect of medications. Methods and results The HOMAGE (Heart 'OMics' in AGEing) trial showed that spironolactone decreased serum PICP concentrations and improved cardiac remodelling over 9 months in a population at risk of developing heart failure (HF). We evaluated the associations between echocardiographic variables, PICP, PIIINP and galectin-3 at baseline and during the course of the trial. Among 527 individuals (74 +/- 7 years, 26% women), median serum concentrations of PICP, PIIINP and galectin-3 were 80.6 mu g/L (65.1-97.0), 3.9 mu g/L (3.1-5.0), and 16.1 mu g/L (13.5-19.7), respectively. After adjustment for potential confounders, higher serum PICP was significantly associated with left ventricular hypertrophy, left atrial enlargement, and greater ventricular stiffness (all p 0.05). In patients treated with spironolactone, a reduction in serum PICP during the trial was associated with a decrease in E/e ' (adjusted-beta = 0.93, 95% confidence interval 0.14-1.73; p = 0.022). Conclusions In individuals at high risk of developing HF, serum PICP was associated with cardiac structural and functional abnormalities, and a decrease in PICP with spironolactone was correlated with improved diastolic dysfunction as assessed by E/e '. In contrast, no such associations were present for serum PIIINP and galectin-3