Payman Zamani

Effect of Inorganic Nitrate on Exercise Capacity in Heart Failure With Preserved Ejection Fraction

Background— Inorganic nitrate (NO3−), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3− supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise. Methods and Results— Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3−, 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak O2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 &mgr;mol/L; P=0.0003), peak O2 (12.6±3.7 versus 11.6±3.1 mL O2·min−1·kg−1; P=0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3− led to greater reductions in systemic vascular resistance (−42.4±16.6% versus −31.8±20.3%; P=0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P=0.006) with exercise. NO3− reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P=0.03) and tended to improve mitochondrial oxidative function. Conclusions— NO3− increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and O2. NO3− increased exercise vasodilatory and cardiac output reserves. NO3− also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT01919177.

Resistive and Pulsatile Arterial Load as Predictors of Left Ventricular Mass and Geometry: The Multi-Ethnic Study of Atherosclerosis

Arterial load is composed of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac MRI and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output) and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude (Pf), and reflected wave amplitude (Pb). TAC and SVR were adjusted for body surface area to allow for appropriate sex comparisons. We performed allometric adjustment of LV mass for body size and sex and computed standardized regression coefficients (&bgr;) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (&bgr;=0.08; P<0.001), TAC (&bgr;=0.44; P<0.001), Pb (&bgr;=0.73; P<0.001), and Pf (&bgr;=−0.23; P=0.001) were significant independent predictors of LV mass. Conversely, TAC (&bgr;=−0.43; P<0.001), SVR (&bgr;=0.22; P<0.001), and Pf (&bgr;=−0.18; P=0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mm Hg per square meter; P<0.0001), whereas men demonstrated a higher indexed SVR (34.0 versus 32.8 Wood Units×m2; P<0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (ie, early load versus late load) is an important determinant of LV response to arterial load.

Reflection Magnitude as a Predictor of Mortality The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}

Reflection Magnitude as a Predictor of MortalityNovelty and Significance: The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}

Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

Rationale: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking. Objectives: To determine (1) the dose–response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in heart failure with preserved ejection fraction. Methods and Results: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3 (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (visit 1: 9.87, 95% confidence interval [CI] 9.31–10.43 minutes; visit 2: 10.73, 95% CI 10.13–11.33 minute; visit 3: 11.61, 95% CI 11.05–12.17 minutes; P=0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire total symptom (visit 1: 58.0, 95% CI 52.5–63.5; visit 2: 66.8, 95% CI 61.3–72.3; visit 3: 70.8, 95% CI 65.3–76.3; P=0.016) and functional status scores (visit 1: 62.2, 95% CI 58.5–66.0; visit 2: 68.6, 95% CI 64.9–72.3; visit 3: 71.1, 95% CI 67.3–74.8; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO3 (visit 2: 199.5, 95% CI 98.7–300.2 &mgr;mol/L; visit 3: 471.8, 95% CI 377.8–565.8 &mgr;mol/L) versus baseline (visit 1: 38.0, 95% CI 0.00–132.0 &mgr;mol/L; P<0.001). KNO3 did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95% CI −28.3 to −7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2–342.4) &mgr;mol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4–232.0) minutes. Conclusions: KNO3 is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345

The Nitrate-Nitrite-NO Pathway and Its Implications for Heart Failure and Preserved Ejection Fraction

The pathogenesis of exercise intolerance in patients with heart failure and preserved ejection fraction (HFpEF) is likely multifactorial. In addition to cardiac abnormalities (diastolic dysfunction, abnormal contractile reserve, chronotropic incompetence), several peripheral abnormalities are likely to be involved. These include abnormal pulsatile hemodynamics, abnormal arterial vasodilatory responses to exercise, and abnormal peripheral O2 delivery, extraction, and utilization. The nitrate-nitrite-NO pathway is emerging as a potential target to modify key physiologic abnormalities, including late systolic left ventricular (LV) load from arterial wave reflections (which has deleterious short- and long-term consequences for the LV), arterial vasodilatory reserve, muscle O2 delivery, and skeletal muscle mitochondrial function. In a recently completed randomized trial, the administration of a single dose of exogenous inorganic nitrate has been shown to exert various salutary arterial hemodynamic effects, ultimately leading to enhanced aerobic capacity in patients with HFpEF. These effects have the potential for both immediate improvements in exercise tolerance and for long-term “disease-modifying” effects. In this review, we provide an overview of key mechanistic contributors to exercise intolerance in HFpEF, and of the potential therapeutic role of drugs that target the nitrate-nitrite-NO pathway.

Late Systolic Central Hypertension as a Predictor of Incident Heart Failure: The Multi‐Ethnic Study of Atherosclerosis

Background Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure. Methods and Results We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001). Conclusions Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.

Effective Arterial Elastance Is Insensitive to Pulsatile Arterial Load

Effective arterial elastance (EA) was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. Theoretical modeling studies suggest that EA is minimally affected by pulsatile load, but little human data are available. We assessed the relationship between EA and arterial load determined noninvasively from central pressure–flow analyses among middle-aged adults in the general population (n=2367) and a diverse clinical population of older adults (n=193). In a separate study, we investigated the sensitivity of EA to changes in pulsatile load induced by isometric exercise (n=73). The combination of systemic vascular resistance and heart rate predicted 95.6% and 97.8% of the variability in EA among middle-aged and older adults, respectively. EA demonstrated a quasi-perfect linear relationship with the ratio of systemic vascular resistance/heart period (middle-aged adults, R=0.972; older adults, R=0.99; P<0.0001). Aortic characteristic impedance, total arterial compliance, reflection magnitude, and timing accounted together for <1% of the variability in EA in either middle-aged or older adults. Despite pronounced changes in pulsatile load induced by isometric exercise, changes in EA were not independently associated with changes pulsatile load but were rather a nearly perfect linear function of the ratio of systemic vascular resistance/heart period (R=0.99; P<0.0001). Our findings demonstrate that EA is simply a function of systemic vascular resistance and heart rate and is negligibly influenced by (and insensitive to) changes in pulsatile afterload in humans. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.

Right ventricular response to pulsatile load is associated with early right heart failure and mortality after left ventricular assist device

BACKGROUND Right ventricular (RV) adaptation to afterload is crucial for patients undergoing continuous-flow left ventricular assist device (cf-LVAD) implantation. We hypothesized that stratifying patients by RV pulsatile load, using pulmonary arterial compliance (PAC), and RV response to load, using the ratio of central venous to pulmonary capillary wedge pressure (CVP:PCWP), would identify patients at high risk for early right heart failure (RHF) and 6-month mortality after cf-LVAD. METHODS During the period from January 2008 to June 2014, we identified 151 patients at our center with complete hemodynamics prior to cf-LVAD. Pulsatile load was estimated using PAC indexed to body surface area (BSA), according to the formula: indexed PAC (PACi) = [SV / (PAsystolic - PAdiastolic)] / BSA, where SV is stroke volume and PA is pulmonary artery. Patients were divided into 4 hemodynamic groups by PACi and CVP:PCWP. RHF was defined as the need for unplanned RVAD, inotropic support ≥14 days or death due to RHF within 14 days. Risk factors for RHF and 6-month mortality were examined using logistic regression and Cox proportional hazards modeling. RESULTS Sixty-one patients (40.4%) developed RHF and 34 patients (22.5%) died within 6 months. Patients with RHF had lower PACi (0.92 vs 1.17 ml/mm Hg/m2, p = 0.008) and higher CVP:PCWP (0.48 vs 0.37, p = 0.001). Higher PACi was associated with reduced risk of RHF (adjusted odds ratio [adj-OR] 0.61, 95% confidence interval [CI] 0.39 to 0.94, p = 0.025) and low PACi with increased risk of 6-month mortality (adjusted hazard ratio [adj-HR] 3.18, 95% CI 1.40 to 7.25, p = 0.006). Compared to patients with low load (high PACi) and adequate right heart response to load (low CVP:PCWP), patients with low PACi and high CVP:PCWP had an increased risk of RHF (OR 4.74, 95% CI 1.23 to 18.24, p = 0.02) and 6-month mortality (HR 8.68, 95% CI 2.79 to 26.99, p < 0.001). CONCLUSIONS A hemodynamic profile combining RV pulsatile load and response to load identifies patients at high risk for RHF and 6-month mortality after cf-LVAD.

Novel Vasodilators in Heart Failure

Heart failure is an important public health problem that is increasing in prevalence throughout the world. Not only is this condition common, but it is associated with significant morbidity and mortality as well as high costs to medical care systems. Vasodilator drugs help unload the heart and may have other effects that could benefit heart failure patients. Consequently, they have emerged as an important therapeutic approach for patients with this condition. Novel vasodilator therapies that are currently in development target new pathways, potentially giving clinicians alternate options for improving outcomes in this vulnerable population. This review focuses on investigational drugs that have the ability to dilate blood vessels amongst their therapeutic properties. These drugs include the natriuretic peptides that activate particulate guanylate cyclase, the novel agent cinaciguat that activates the soluble guanylate cyclase system, and finally a recombinant form of the naturally occurring vasodilating agent relaxin, a hormone that mediates many of the changes that allows the cardiovascular system to successfully adapt to pregnancy.