Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence.

INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL:  https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Racial and Ethnic Differences in Biomarkers, Health Status, and Cardiac Remodeling in Patients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan.

BACKGROUND: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking. METHODS: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling. RESULTS: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (g=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (g<0.10). Following S/V initiation, NT-proBNP decreased in all 3 groups (P<0.0001) associated with improvements in LV ejection fraction, LV end-diastolic volume index, and LV end-systolic volume index. Although total improvement in LV measures was similar between groups, Black patients averaged larger gains in the first half of the trial while White patients averaged larger gains in the second half. Improvements in Kansas City Cardiomyopathy Questionnaire-23 Total Symptom scores were seen in all 3 groups. Treatment with S/V was well-tolerated. CONCLUSIONS: Among Black, Hispanic, and White patients with heart failure and reduced ejection fraction, treatment with S/V was associated with similar reduction in NT-proBNP, improvement in health status, and reverse remodeling. More data regarding racial and ethnic responses to heart failure and reduced ejection fraction treatment are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Association between long-term prescription of febuxostat and the progression of heart failure with preserved ejection fraction in patients with hypertension and asymptomatic hyperuricemia.

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.

Gender Differences in Cardiac Hypertrophy.

Cardiac hypertrophy is an adaptive response to abnormal physiological and pathological stimuli, which can be classified into concentric and eccentric hypertrophy, induced by pressure overload or volume overload, respectively. In both physiological and pathological scenarios, females generally show a more favorable form of hypertrophy compared with their male counterparts. However once established, cardiac hypertrophy is a stronger risk factor for heart failure in females. Pre-menopausal women are better protected against cardiac hypertrophy compared with men, but this protection is abolished following menopause and is partially restored after estrogen replacement therapy. Estrogen exerts its protection by counteracting pro-hypertrophy signaling pathways, whereas androgen mostly plays an opposite role in cardiac hypertrophy. We here summarize the progress in the understanding of sexual dimorphisms in cardiac hypertrophy and highlight recent breakthroughs in the regulatory role of sex hormones and their intricate molecular networks, in order to shed light on gender-oriented therapeutic efficacy for pathological hypertrophy.

Assessment of ventricular remodeling in heart failure clinical trials.

Adverse remodeling involves a complicated process of structural and functional changes in the left ventricle (LV). LV remodeling is progressive and, if left unchecked, culminates in heart failure that portends a poor prognosis. Clinical trials in heart failure have employed various techniques to assess ventricular remodeling while focusing on therapeutic-specific strategies to halt or reverse remodeling. These strategies include (1) those designed to reduce wall stress by limiting LV dilatation and reducing LV loading conditions (nitrates and epicardial restraint), (2) those designed to block neurohormonal activation, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ß-adrenergic receptor blockers, and aldosterone receptor blockers, (3) ionotropic agents/cardiac glycosides, and (4) cardiac resynchronization therapy. Strategies in development include mechanical assist devices and myocardial regeneration. To date, trials have demonstrated a linkage between indices of remodeling and clinical outcomes measures. Indices of remodeling have facilitated identification of targets for novel pharmaceutical agents and new device therapies.

Complementary assessment of aortic bioprosthetic dysfunction using cardiac magnetic resonance imaging and computed tomography.

The case is reported of a 28-year-old subject with a bioprosthesis (Shelhigh 31) in the aortic position, with symptoms of heart failure and possible prosthetic dysfunction. As the echocardiographic interrogation remained inconclusive, the patient underwent cardiovascular magnetic resonance (CMR) imaging, which revealed an impaired movement of the non-coronary cusp. In addition, computed tomography (CT) demonstrated severe calcification of the immobile prosthetic component. Hence, in selected patients, both CMR and CT can be used as complementary tools to evaluate the dysfunction and pathology of heart valve bioprostheses.

[Clinical- functional assessment of organoprotective efficacy of enalapril and telmisartan in patients with arterial hypertension].

Effect of enalapril and telmisartan on hemodynamic indices, structural-functional parameters of the left ventricle, and vasomotor function of arterial endothelium was studied in 49 patients (mean age 48.3+/-3.2 years) with 1-2 degree arterial hypertension (AH) and abnormal relaxation type of left ventricular diastolic dysfunction. Enalapril was given to 24 and telmisartan to 25 patients. Examination included 24-hour arterial pressure monitoring, echocardiography, duplex scanning of the left brachial artery. At the background of therapy with enalapril target levels of systolic and diastolic arterial pressure (AP) were achieved in 79.2 and 70.85% of patients. This was associated with 54.2% reduction of number of non-dippers and night peakers. Therapy with telmisartan (30 weeks) besides effective AP control provided normalization of 24-hour AP profile in 90% of patients with pathological circadian rhythm. This was accompanied by improvement of vasomotor endothelial function of arteries, positive dynamics of structural-functional parameters of the left heart chambers, improvement of indices of left ventricular diastolic function.

MR assessment of myocardial perfusion, viability, and function after intramyocardial transfer of VM202, a new plasmid human hepatocyte growth factor in ischemic swine myocardium.

PURPOSE: VM202, a newly constructed plasmid human hepatocyte growth factor, was transferred intramyocardially after infarction for the purpose of evaluating this strategy as a therapeutic approach for protection from left ventricular (LV) remodeling. MATERIALS AND METHODS: The institutional animal care and use committee approved this study. Pigs underwent coronary artery occlusion and reperfusion and served as either control (n = 8) or VM202-treated (n = 8) animals. VM202 was transferred intramyocardially into four infarcted and four periinfarcted sites. Cardiac magnetic resonance (MR) imaging (cine, perfusion, delayed enhancement) was performed in acute (3 days) and chronic (50 days +/- 3 [standard error of the mean]) infarction. Histopathologic findings were used to characterize and quantify neovascularization. The t test was utilized to compare treated and control groups and to assess changes over time. RESULTS: In acute infarction, MR imaging estimates of function, perfusion, and viability showed no difference between the groups. In chronic infarction, however, VM202 increased maximum signal intensity and upslope at first-pass perfusion imaging and reduced infarct size at perfusion and delayed-enhancement imaging. These changes were associated with a decrease in end-diastolic (2.15 mL/kg +/- 0.12 to 1.73 mL/kg +/- 0.10, P < .01) and end-systolic (1.33 mL/kg +/- 0.07 to 0.92 mL/kg +/- 0.08, P < .001) volumes and an increase in ejection fraction (38.2% +/- 1.3 to 47.0% +/- 1.8, P < .001). In contrast, LV function deteriorated further in control animals. Compared with control animals, VM202-treated animals revealed peninsulas and/or islands of viable myocardium in infarcted and periinfarcted regions and greater number of capillaries (218 per square millimeter +/- 19 vs 119 per square millimeter +/- 17, P < .05) and arterioles (21 per square millimeter +/- 4 vs 3 per square millimeter +/- 1, P < .001). CONCLUSION: Intramyocardial transfer of VM202 improved myocardial perfusion, viability, and LV function.

Serial magnetic resonance imaging based assessment of the early effects of an ACE inhibitor on postinfarction left ventricular remodeling in rats.

In vivo assessment of treatment efficacy on postinfarct left ventricular (LV) remodeling is crucial for experimental studies. We examined the technical feasibility of serial magnetic resonance imaging (MRI) for monitoring early postinfarct remodeling in rats. MRI studies were performed with a 7-Tesla unit, 1, 3, 8, 15, and 30 days after myocardial infarction (MI) or sham operation, to measure LV mass, volume, and the ejection fraction (EF). Three groups of animals were analyzed: sham-operated rats (n = 6), MI rats receiving lisinopril (n = 11), and MI rats receiving placebo (n = 8). LV dilation occurred on day 3 in both MI groups. LV end-systolic and end-diastolic volumes were significantly lower in lisinopril-treated rats than in placebo-treated rats at days 15 and 30. EF was lower in both MI groups than in the sham group at all time points, and did not differ between the MI groups during follow-up. Less LV hypertrophy was observed in rats receiving lisinopril than in rats receiving placebo at days 15 and 30. We found acceptable within- and between-observer agreement and an excellent correlation between MRI and ex vivo LV mass (r = 0.96; p < 0.001). We demonstrated the ability of MRI to detect the early beneficial impact of angiotensin-converting enzyme (ACE) inhibitors on LV remodeling. Accurate and noninvasive, MRI is the tool of choice to document response to treatment targeting postinfarction LV remodeling in rats.