Mauro Gori

Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction

Increases in serum creatinine with renin–angiotensin–aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual‐acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed.

Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction

Women are more likely to develop heart failure with preserved ejection fraction (HFpEF) than men. We studied the relationship between sex and cardiovascular structure and function in patients with HFpEF.

Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro‐inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the ‘one‐size‐fits‐all’ approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker‐guided strategy in HFpEF.

Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction

AIM Renal dysfunction is a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). We sought to determine whether renal dysfunction was associated with measures of cardiovascular structure/function in patients with HFpEF. METHODS We studied 217 participants from the PARAMOUNT study with HFpEF who had echocardiography and measures of kidney function. We evaluated the relationships between renal dysfunction [estimated glomerular filtration rate (eGFR) >30 and <60 mL/min/1.73 m(2) and/or albuminuria] and cardiovascular structure/function. RESULTS The mean age of the study population was 71 years, 55% were women, 94% hypertensive, and 40% diabetic. Impairment of at least one parameter of kidney function was present in 62% of patients (16% only albuminuria, 23% only low eGFR, 23% both). Renal dysfunction was associated with abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) (adjusted P = 0.048), lower midwall fractional shortening (MWFS) (P = 0.009), and higher NT-proBNP (P = 0.006). Compared with patients without renal dysfunction, those with low eGFR and no albuminuria had a higher prevalence of abnormal LV geometry (P = 0.032) and lower MWFS (P < 0.01), as opposed to those with only albuminuria. Conversely, albuminuria alone was associated with greater LV dimensions (P < 0.05). Patients with combined renal impairment had mixed abnormalities (higher LV wall thicknesses, NT-proBNP; lower MWFS). CONCLUSION Renal dysfunction, as determined by both eGFR and albuminuria, is highly prevalent in HFpEF, and associated with cardiac remodelling and subtle systolic dysfunction. The observed differences in cardiac structure/function between each type of renal damage suggest that both parameters of kidney function might play a distinct role in HFpEF.

Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE Cardiovascular disease (CVD) is the major cause of morbidity and mortality in diabetes; yet, heterogeneity in CVD risk has been suggested in diabetes, providing a compelling rationale for improving diabetes risk stratification. We hypothesized that N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity troponin T may enhance CVD risk stratification beyond commonly used markers of risk and that CVD risk is heterogeneous in diabetes. RESEARCH DESIGN AND METHODS Among 8,402 participants without prevalent CVD at visit 4 (1996–1998) of the Atherosclerosis Risk in Communities (ARIC) study there were 1,510 subjects with diabetes (mean age 63 years, 52% women, 31% African American, and 60% hypertensive). RESULTS Over a median follow-up of 13.1 years, there were 540 incident fatal/nonfatal CVD events (coronary heart disease, heart failure, and stroke). Both troponin T ≥14 ng/L (hazard ratio [HR] 1.96 [95% CI 1.57–2.46]) and NTproBNP >125 pg/mL (1.61 [1.29–1.99]) were independent predictors of incident CVD events at multivariable Cox proportional hazard models. Addition of circulating cardiac biomarkers to traditional risk factors, abnormal electrocardiogram (ECG), and conventional markers of diabetes complications including retinopathy, nephropathy, and peripheral arterial disease significantly improved CVD risk prediction (net reclassification index 0.16 [95% CI 0.07–0.22]). Compared with individuals without diabetes, subjects with diabetes had 1.6-fold higher adjusted risk of incident CVD. However, participants with diabetes with normal cardiac biomarkers and no conventional complications/abnormal ECG (n = 725 [48%]) were at low risk (HR 1.12 [95% CI 0.95–1.31]), while those with abnormal cardiac biomarkers, alone (n = 186 [12%]) or in combination with conventional complications/abnormal ECG (n = 243 [16%]), were at greater risk (1.99 [1.59–2.50] and 2.80 [2.34–3.35], respectively). CONCLUSIONS Abnormal levels of NTproBNP and troponin T may help to distinguish individuals with high diabetes risk from those with low diabetes risk, providing incremental risk prediction beyond commonly used markers of risk.

Sacubitril/valsartan (LCZ696) for the treatment of heart failure

ABSTRACT The PARADIGM-HF study, a large outcome trial in heart failure and reduced ejection fraction (HFrEF), has recently shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), still commonly referred to as LCZ696, compared to ACE-inhibitor therapy, possibly leading us to a new era for heart failure (HF) treatment. LCZ696 represents a first-in-class drug acting through inhibition of angiotensin receptor and neprilysin, thus modulating the renin angiotensin aldosterone system and vasoactive substances such as natriuretic peptides. Based on the PARADIGM-HF results, the FDA recently approved LCZ696 as an effective means to reduce the burden of HF with reduced ejection fraction. Furthermore, these data also provided rationale to test LCZ696 in an ongoing trial with HF and preserved ejection fraction. Despite the enthusiasm regarding this novel compound, real world data on its efficacy and safety are eagerly expected. This article summarizes all evidences regarding LCZ696 and how to implement this new drug in the current HF armamentarium.

High-Sensitive Cardiac Troponin for Prediction of Clinical Heart Failure: Are We Ready for Prime Time?

Article, see p 1494 Heart failure (HF) prevalence continues to rise, and projections show that in the next 2 decades, ≈45% more HF cases will occur, with a mortality rate remaining as high as 50% within 5 years of diagnosis and high healthcare costs. Hence, there is an unmet need to apply successful preventive programs and reduce HF incidence. Also, according to current guidelines, an effective HF preventive program requires adequately targeting the preclinical stages of the disease, including risk factors for HF, such as hypertension, diabetes mellitus, renal dysfunction, coronary artery disease, and abnormalities of cardiac structure/function associated with HF, such as left ventricular (LV) hypertrophy and low LV ejection fraction.1 Recently, efforts to better identify subjects at the highest risk were undertaken. Different biomarkers have been studied for this purpose. Although many candidate biomarkers have been described, few have made the difficult translation from initial promise to clinical application.2 Among biomarkers, high-sensitivity cardiac troponin (hs-cTn) can detect small amounts of myocyte injury. Using high-sensitivity assays, detectable levels of cardiac troponin have been demonstrated among apparently healthy individuals in the general population, including stage A HF, as well as in asymptomatic individuals with stable cardiovascular disease, stage B HF, with a prevalence of detectable levels, ranging from 60% to 80% in asymptomatic individuals.3,4 Hs-cTn elevation may be caused by multiple mechanisms, in addition to myocardial necrosis. These include cardiomyocyte damage from inflammatory cytokines or oxidative stress, apoptosis, increased cell membrane …

Angiotensin receptor-neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs

Sacubritil∗valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). This combination drug has been successfully studied in patients with heart failure with both preserved (HFpEF) and reduced ejection fraction (HFrEF). In this review, the evidences in patients with HFpEF and HFrEF are summarized, including the results of more recent studies.

Ranolazine in Heart Failure With Preserved Left Ventricular Ejection Fraction and Microvascular Dysfunction: Case Report and Literature Review

Heart failure with a normal or nearly preserved left ventricular (LV) ejection fraction (HFpEF) may represent more than 50% of heart failure cases. Despite HFpEF is being increasingly recognized, there is still a lack of information regarding of its potential pharmacological treatment. Patients with HFpEF are more frequently elderly, female, hypertensive and diabetic. Microvascular dysfunction (MVD) may be involved during the development of HFpEF mainly because of comobidities including hypertension and diabetes. Diastolic dysfunction is seen in 30–70% of patients with type 2 diabetes: the likely mechanisms include altered endothelial function, defective energy metabolism, and microvascular disease. MVD is also estimated to be more common in women. Women with angina, evidence of ischemia by stress testing, and no obstructive coronary artery disease (CAD) by angiography frequently have MVD which carries an adverse prognosis for cardiovascular events including myocardial infarction, stroke, heart failure, and sudden cardiac death. There are an estimated 2–3 million women in the United States with MVD: in this patient population persistent angina, despite treatment with nitrates, beta‐ blockers, and calcium channel blockers, remains a therapeutic challenge. MVD and myocardial ischemia are known to be associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in disturbances of intracellular ion homeostasis of cardiac myocites. Disruption of this electrolyte balance leads to abnormally elevated intracellular levels of sodium and calcium, which are thought to contribute to the discrepancy between myocardial oxygen demand and supply. The increase of intracellular sodium concentrations is mediated by either late activation or failing channel closure of the inward sodium current (INa), which mainly happen in pathological states, such as ischemia, oxidative stress, myocardial stretch, and left ventricular hypertrophy. Previous studies demonstrated that the increase of sodium current is mainly associated to a reduced net cytosolic calcium efflux, leading to higher degree of diastolic stiffness, diastolic coronary vascular compression and, consequently, diastolic dysfunction. Ranolazine reduces the sodium‐dependent calcium overload via inhibition of the late INa and thus improves diastolic tone and oxygen handling during myocardial ischemia. This molecular mechanism is associated to a symptomatic relief of chronic angina without affecting heart rate or systolic blood pressure, therefore ranolazine has been widely used for ischemic patients not only as an add‐on therapy. New experimental studies in mouse models documented a potential role of ranolazine in reversing diastolic dysfunction oxidative stress‐mediated, showing a direct effect on myofilaments and contractile apparatus. So far, no data have been published on the influence of ranolazine in HFpEF and MVD. In this case report, we describe the beneficial effect of ranolazine in an ischemic HFpEF patient symptomatic for dyspnea. The Journal of Clinical Pharmacology 53(6) 665–669

Strategy to identify subjects with diabetes mellitus more suitable for selective echocardiographic screening: The DAVID-Berg study

BACKGROUND Despite the burden of pre-clinical heart failure (HF) among diabetes mellitus (DM) patients, routine screening echocardiography is not currently recommended. We prospectively assessed risk prediction for HF/death of a screening strategy combining clinical data, electrocardiogram, NTproBNP, and echocardiogram, aiming to identify DM patients more suitable for selective echocardiography. METHODS Among 4047 screened subjects aged≥55/≤80years, the DAVID-Berg Study prospectively enrolled 623 outpatients with DM, or hypertension, or known cardiovascular disease but with no HF history/symptoms. The present analysis focuses on data obtained during a longitudinal follow-up of the 219 patients with DM. RESULTS Mean age was 68years, 61% were men, and median DM duration was 4.9years. During a median follow-up of 5.2years, 50 subjects developed HF or died. A predictive model using clinical data demonstrated moderate predictive power, which significantly improved by adding electrocardiogram (C-statistic 0.75 versus 0.70; p<0.05), but not NTproBNP (C-statistic 0.72, p=0.20). Subjects with normal clinical variables or abnormal clinical variables but normal electrocardiogram had low events rate (1.3 versus 2.4events/100-person-years, p=NS). Conversely, subjects with both clinical and electrocardiogram abnormalities (47%) carried higher risk (9.0events/100-person-years, p<0.001). The predictive power for mortality/HF development increased when echocardiography was added (13.6events/100-person-years, C-statistic 0.80, p<0.05). CONCLUSIONS Our prospective study found that a selective echocardiographic screening strategy guided by abnormal clinical/electrocardiogram data can reliably identify DM subjects at higher risk for incident HF and death. This screening approach may hold promise in guiding HF prevention efforts among DM patients.