Aims The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO 3 − ), a potential tolerance‐free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). Methods A subsample of participants in our double‐blind, randomized, factorial‐design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline ( n = 105), and at 3 months and 6 months ( n = 87) after the start of the intervention. Analysis was by modified intent‐to‐treat. Results Nitrate‐containing juice ( n = 40) decreased left ventricular (LV) end‐diastolic volume {−6.3 [95% confidence interval (CI) –11.1, –1.6] ml} and end‐systolic volume [−3.2 (95% CI −5.9, –0.5) ml], and increased end‐diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice ( n = 47). Spironolactone ( n = 44) reduced relative wall thickness compared with doxazosin ( n = 43) [−0.01 (95% CI −0.02, –0.00)]. Although spironolactone reduced LV mass index relative to baseline [−1.48 (95% CI −2.08, –0.88) g m –2.7 ], there was no difference vs . doxazosin [−0.85 (95% CI −1.76, 0.05) g m –2.7 ]. Spironolactone also decreased the E/A ratio [−0.12 (95% CI −0.19, –0.04)] and increased S′ (a tissue‐Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s –1 . BP did not differ between the juices, or between the drugs. Conclusions Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP‐independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic–diastolic function, although confirmatory, were independent of BP.
First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis. In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death). Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89–0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1. EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure–function analysis.
Abstract Background Cardiac Resynchronization Therapy (CRT) is an important therapeutic treatment for chronic heart failure. However, even in carefully selected cases up to 40% of patient fail to respond. First-phase ejection fraction (EF1), the ejection fraction up to the time of maximal ventricular contraction, is a novel and more sensitive echocardiographic measure of early systolic function. Purpose We examined the value of EF1, to predict response to CRT and clinical outcomes after CRT. Methods We analysed echocardiograms from 197 patients who underwent CRT between 2009 and 2018 and were followed to determine clinical outcomes. Results Volumetric response rate (reduction in end-systolic volume ≥15%) was 92.3% vs. 12.1%, for those with EF1 in the highest vs. lowest tertiles (p<0.001). A cut-off value of 11.9% for EF1 had >85% sensitivity and specificity for prediction of response to CRT; on multivariate logistic regression analysis incorporating previously defined predictors, EF1 was the strongest predictor of response (OR: 1.563, 95% CI: 1.371–1.782, p<0.001) (table 1). EF1 was also the strongest predictor of a clinical composite score (OR: 1.115, 95% CI: 1.044–1.191, p=0.001). Improvement in EF1 at 6 months after CRT implantation (6.5±5.8% vs 1.8±4.3% in responders vs. non-responders, p<0.001) was the best predictor of heart failure re-hospitalization and death after median follow-up of 29.2 months (HR: 0.819, 95% CI:0.765–0.876, p<0.001). Conclusion EF1 is a promising marker to identify patients likely to respond to CRT and most likely provides a measure of myocardial viability that determines response. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, Wellcome/EPSRC Centre for Medical Engineering
Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.
Myocardial wall stress (MWS) is thought to be the mechanical stimulus to ventricular hypertrophy. The objective of this study was to examine whether MWS is elevated in children with chronic kidney disease (CKD) who are at high risk of developing adverse cardiovascular events related to left ventricular (LV) hypertrophy. MWS, a function of left ventricular pressure, myocardial wall volume, and cavity volume, was obtained using carotid tonometry to estimate ventricular pressure and 2-dimensional transthoracic echocardiographic wall-tracking to obtain LV cavity and wall volumes. Ninety-two children (50 boys) aged 11.2±3.2 (mean±SD) years, including healthy controls (n=16), and those with CKD disease divided into 3 groups according to estimated glomerular filtration rate (mL/min per 1.73 m 2 ) >90 (CKD 1, n=26), 60 to 90 (CKD 2, n=23), and <60 (CKD≥3, n=27) were studied. There was no significant difference in age, height, weight, central or peripheral blood pressure, LV mass, or mass index in the 4 study groups. By contrast, peak, mean, and end-systolic MWS were higher in children with CKD and increased across stages of CKD (peak MWS, 338.8±18.5 and 397.5±14.3 s/cm 2 in controls and CKD≥3, respectively; P =0.01). Higher systolic MWS was explained by a form of LV dysfunction whereby dynamic values of the ratio of wall volume/cavity size during systole were lower in children with CKD than in those without ( P =0.001). Children with CKD exhibit blood pressure–independent LV dysfunction which results in increased systolic MWS and which may predispose to LV hypertrophy in later life.
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