Cardiovascular phenotype of long-term anabolic-androgenic steroid abusers compared with strength-trained athletes.

INTRODUCTION: Abuse of anabolic-androgenic steroids (AAS) has been linked to a variety of different cardiovascular (CV) side effects, but still the clinical effects of AAS abuse on CV risk are not clear. The aim of this study was to assess the CV phenotype of a large cohort of men with long-term AAS use compared with strength-trained athletes without AAS use. METHODS: Fifty one strength-trained men with ≥3 years of AAS use was compared with twenty one strength-trained competing athletes. We verified substance abuse and non-abuse by blood and urine analyses. The participants underwent comprehensive CV evaluation including laboratory analyses, 12-lead ECG with measurement of QT dispersion, exercise ECG, 24 h ECG with analyses of heart rate variability, signal averaged ECG, basic transthoracic echocardiography, and coronary computed tomography angiography (CCTA). RESULTS: Hemoglobin levels and hematocrit were higher among the AAS users compared with non-users (16.8 vs. 15.0 g/dl, and 0.50% vs. 0.44%, respectively, both p < 0.01) and HDL cholesterol significantly lower (0.69 vs. 1.25 mmol/L, p < 0.01). Maximal exercise capacity was 270 and 280 W in the AAS and the non-user group, respectively (p = 0.04). Echocardiography showed thicker intraventricular septum and left ventricular (LV) posterior wall among AAS users (p < 0.01 for both), while LV ejection fraction was lower (50 vs. 54%, p = 0.02). Seven AAS users (17%) had evidence of coronary artery disease on CCTA. There were no differences in ECG measures between the groups. CONCLUSIONS: A divergent CV phenotype dominated by increased CV risk, accelerated coronary artery disease, and concentric myocardial hypertrophy was revealed among the AAS users.

Left ventricular ejection fraction and adjudicated, cause-specific hospitalizations after myocardial infarction complicated by heart failure or left ventricular dysfunction.

BACKGROUND: Reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) increases risk of cardiovascular (CV) hospitalizations, but evidence regarding its association with non-CV outcome is scarce. We investigated the association between LVEF and adjudicated cause-specific hospitalizations following MI complicated with low LVEF or overt heart failure (HF). METHODS: In an individual patient data meta-analysis of 19,740 patients from 3 large randomized trials, Fine and Gray competing risk modeling was performed to study the association between LVEF and hospitalization types. RESULTS: The most common cause of hospitalization was non-CV (n = 2,368 for HF, n = 1,554 for MI, and n = 3,703 for non-CV). All types of hospitalizations significantly increased with decreasing LVEF. The absolute risk increase associated with LVEF ≪25% (vs LVEF ≫35%) was 15.5% (95% CI 13.4-17.5) for HF, 4.7% (95% CI 3.0-6.4) for MI, and 10.4% (95% CI 8.0-12.8) for non-CV hospitalization. On a relative scale, after adjusting for confounders, each 5-point decrease in LVEF was associated with an increased risk of HF (hazard ratio [HR] 1.15, 95% CI 1.12-1.18), MI (HR 1.06, 95% CI 1.03-1.10), and non-CV hospitalization (HR 1.03, 95% CI 1.01-1.05). CONCLUSIONS: In a high-risk population with complicated acute MI, the absolute risk increase in non-CV hospitalizations associated with LVEF ≪25% was two thirds of the absolute risk increase in HF hospitalizations and twice the absolute risk increase in MI hospitalizations. LVEF was an independent predictor of all types of hospitalization and appears as an integrative marker of sicker patient status.

All-Cause Mortality and Cardiovascular Outcomes With Non-Vitamin K Oral Anticoagulants Versus Warfarin in Patients With Heart Failure in the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Many patients with heart failure (HF) are treated with warfarin or non-vitamin K oral anticoagulants (NOACs). Randomized outcome-driven comparisons of different anticoagulant strategies in HF are lacking. Data from international, government-mandated registries may be useful in understanding the real-life use of various anticoagulants and how they are linked to outcomes. STUDY QUESTION: To assess 2015 annual all-cause mortality, myocardial infarction, and stroke rates co-reported for warfarin and NOACs in subjects with and without HF in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. STUDY DESIGN: We extracted and examined outcome cases in subjects with HF and on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban and stratified these according to anticoagulants. MEASURES AND OUTCOMES: Annual all-cause mortality, myocardial infarction, and stroke in FAERS. ANALYSIS METHOD: Odds ratio (OR) and χ(Equation is included in full-text article.)for oral anticoagulants from FAERS with and without HF among complete primary reports issued in 2015. RESULTS: FAERS reported 137,026 HF cases, with death co-reported in 42,942 (31.3%). In total, 11,278 (8.2%) HF patients were treated with anticoagulants, with more prescribed warfarin (n = 8260) than all NOACs combined (n = 3018). Very few reports for edoxaban were available. Warfarin consistently displayed a signal for excess adverse events compared to NOACs: OR (95% confidence interval) for the composite of mortality, myocardial infarction, and stroke were 1.91 (1.76-2.07) versus apixaban, 1.92 (1.81-2.03) versus dabigatran, 4.09 (3.38-4.37) versus rivaroxaban, and 2.64 (2.53-2.76) versus all NOACs combined (all P < 0.001). Warfarin, compared to all NOACs combined, demonstrated higher rates of all-cause mortality [OR = 2.69 (95% confidence interval, 2.49-2.90)], myocardial infarction [5.30 (4.17-6.74)], stroke [OR = 8.85 (6.61-11.84)], and ischemic stroke [OR = 12.73 (8.87-18.27); all P < 0.001]. CONCLUSIONS: Annual 2015 FAERS profiles in HF patients reveal that warfarin was numerically dominant. Warfarin was associated with higher risk of death, myocardial infarction, and stroke compared to NOACs. These observational data provide real-world insight into a potential safety benefit of NOACs over warfarin in the setting of HF.

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Comorbidities in Heart Failure: Are There Gender Differences?

Compared to men, women with heart failure (HF) are often older, smoke less, and have more preserved ejection fraction (EF) and hypertensive HF rather than HF of ischemic etiology. Gender-stratified outcomes on comorbidities data in HF are scarce. Women have traditionally been underrepresented in HF trials. Although data suggest that overall prognosis may be better in women, they experience lower quality of life with greater functional impairment from HF compared to men. Gender differences have been reported for comorbid diabetes, chronic obstructive pulmonary disease, renal dysfunction, anemia, and depression and may explain gender disparity in outcomes. However, possible confounding of comorbidities with known prognostic determinants in HF (such as EF) as well as gender differences in the utilization of medical therapies obscures interpretation. In this review, we will explore the evidence for gender differences in non-cardiovascular comorbidities in HF. Our findings may guide clinicians to individualize HF care, according to best practice, in the hope of improving prognosis for this chronic and debilitating condition.

Efficacy of ß blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis.

BACKGROUND: Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. ß blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of ß blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. METHODS: We extracted individual-patient data from ten randomised controlled trials of the comparison of ß blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012. FINDINGS: 18,254 patients were assessed, and of these 13,946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13,945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. ß-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. INTERPRETATION: Based on our findings, ß blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. FUNDING: Menarini Farmaceutica Internazionale (administrative support grant).

Comorbidities and polypharmacy.

Heart failure (HF) is predominantly a disease that affects the elderly population, a cohort in which comorbidities are common. The majority of comorbidities and the degree of their severity have prognostic implications in HF. Polypharmacy in HF is common, has increased throughout the past 2 decades, and may pose a risk for adverse drug interactions, accidental overdosing, or medication nonadherence. Polypharmacy, in particular in the elderly, is rarely assessed in traditional clinical trials, highlighting a need for entirely novel HF research strategies.

RAAS inhibitors and cardiovascular protection in large scale trials.

Hypertension, coronary artery disease and heart failure affect over half of the adult population in most Western societies, and are prime causes of CV morbidity and mortality. With the ever-increasing worldwide prevalence of CV disease due to ageing and the "diabetes" pandemic, guideline groups have recognized the importance of achieving cardioprotection in affected individuals as well as in those at risk for future CV events. The renin-angiotensin-aldosterone system (RAAS) is the most important system controlling blood pressure (BP), cardiovascular and renal function in man. As our understanding of the crucial role of RAAS in the pathogenesis of most, if not all, CV disease has expanded over the past decades, so has the development of drugs targeting its individual components. Angiotensin-converting enzyme inhibitors (ACEi), Ang-II receptor blockers (ARB), and mineralcorticoid receptor antagonists (MRA) have been evaluated in large clinical trials for their potential to mediate cardioprotection, singly or in combination. Direct renin inhibitors are currently under scrutiny, as well as novel dual-acting RAAS-blocking agents. Herein, we review the evidence generated from large-scale clinical trials of cardioprotection achieved through RAAS-blockade.

Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload.

Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 µl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of ß-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced ß(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.

Mechanisms of novel cardioprotective functions of CCN2/CTGF in myocardial ischemia-reperfusion injury.

CCN2/connective tissue growth factor (CTGF), a CCN family matricellular protein repressed in healthy hearts after birth, is induced in heart failure of various etiologies. Multiple cellular and biological functions have been assigned to CCN2/CTGF depending on cellular context. However, the functions and mechanisms of action of CCN2/CTGF in the heart as well as its roles in cardiac physiology and pathophysiology remain unknown. Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were generated and compared with nontransgenic littermate control (NLC) mice. Tg-CTGF mice displayed slightly lower cardiac mass and inconspicuous increase of myocardial collagen compared with NLC mice but no evidence of contractile dysfunction. Analysis of the myocardial transcriptome by DNA microarray revealed activation of several distinct gene programs in Tg-CTGF hearts involved in cardioprotection and growth inhibition. Indeed, Tg-CTGF mice subjected to ischemia-reperfusion injury by in situ transient occlusion of the left anterior descending coronary artery in vivo displayed reduced vulnerability with markedly diminished infarct size. These findings were recapitulated in isolated hearts perfused with recombinant human (h)CTGF before the ischemia-reperfusion procedure. Consistently, Tg-CTGF hearts, as well as isolated adult cardiac myocytes exposed to recombinant hCTGF, displayed enhanced phosphorylation and activity of the Akt/p70S6 kinase/GSK-3ß salvage kinase pathway and induction of several genes with reported cardioprotective functions. Inhibition of Akt activities also prevented the cardioprotective phenotype of hearts from Tg-CTGF mice. This report provides novel evidence that CTGF confers cardioprotection by salvage phosphokinase signaling leading to inhibition of GSK-3ß activities, activation of phospho-SMAD2, and reprogramming of gene expression.

Amyotrophic lateral sclerosis (ALS), a novel rare cause of elevated plasma troponin T levels.

In this article, we report on a patient with chronic and modestly elevated plasma troponin T (TnT) levels and frequent hospitalizations following the first admission until his death one year later. The patient was initially admitted for dyspnea and discharged from hospital with a diagnosis of non-ST elevation acute myocardial infarction (AMI). Coronary angiography and echocardiography were normal, but the patient received the (false) diagnosis of AMI at two further admissions, based purely on elevated TnT. Shortly thereafter, severe respiratory failure with restrictive-type spirometry pattern became the predominant clinical symptom, with constantly elevated TnT levels at frequent re-admissions. Due to inconsistent follow-up by primarily junior and non-specialist staff at a number of different wards, pulmonary function tests and previous smoking history were mis-interpreted as typical of chronic obstructive pulmonary disease (COPD). The patient received standard COPD treatment without any improvement. After a year of gradually worsening respiratory failure and repeated hospitalizations, thorough assessment by a pulmonologist and neurologist established the final diagnosis of amyotrophic lateral sclerosis (ALS). The patient died shortly thereafter. While progressive respiratory failure is well-known to determine morbidity and mortality in patients with ALS, chronically elevated TnT levels in the absence of coronary artery disease have, to our best knowledge, not been described so far. We suggest that chronic myocardial hypoxia due to ALS-related hypoxic respiratory failure was the most likely underlying etiology for the elevated TnT levels seen here but other mechanism such as immune-mediated myocardial injury cannot be excluded.

Case report: a patient with thyroid storm, refractory cardiogenic shock, and cardiac arrest treated with Lugol's iodine solution and veno-arterial extra corporal membrane oxygenation support.

BACKGROUND: Thyroid storm is a life-threatening condition. Refractory cardiogenic shock and cardiac arrest are rare complications of thyroid storm and the treatment options are limited. CASE SUMMARY: A 35-year- old woman treated for Grave's disease was admitted with thyrotoxicosis complicated by infection and neutropenia caused by thionamide treatment. After treatment including beta-blockers, steroids, and Lugol's iodine solution, she went into cardiac arrest. Echocardiography after resuscitation demonstrated severe biventricular heart failure. The patient was in refractory cardiogenic shock with recurrent cardiac arrest and mechanical circulatory support with a veno-arterial extra corporal membrane oxygenation (V-A ECMO) circuit was established. After 2 days on V-A ECMO and supportive treatment with iodine solution, glucocorticosteroids, and levosimendan, her myocardial function recovered and thyroid hormone levels were normalized. Veno-arterial extra corporal membrane oxygenation was discontinued, and the patient was treated with early total thyroidectomy. The patient made a full recovery with no neurological/cognitive impairment, as assessed after 4 weeks. DISCUSSION: Adverse reactions to standard treatment of hyperthyroidism contributed to this patient's development of thyroid storm and the following refractory cardiogenic shock. When she was critically unstable, levosimendan improved myocardial function while inotropic support with dobutamine was ineffective, likely due to prolonged beta-antagonist administration. Temporary support with V-A ECMO, until effective lowering of thyroid hormone levels and improvement in myocardial function were obtained, was life-saving in this young patient and may be considered in refractory cardiogenic shock caused by thyroid storm.

Hypertension and heart failure with preserved ejection fraction: position paper by the European Society of Hypertension.

Hypertension constitutes a major risk factor for heart failure with preserved ejection fraction (HFpEF). HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality. Specific guideline-directed medical therapy (GDMT) for HFpEF is not established due to lack of positive outcome data from randomized controlled trials (RCTs) and limitations of available studies. Although available evidence is limited, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers provides the backbone of BP-lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, we propose that this core drug treatment strategy is also applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor. In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors, currently already indicated for high-risk patients with diabetes to reduce heart failure hospitalizations, and finerenone represent promising therapies and results from ongoing RCTs are eagerly awaited. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high-quality RCTs are major unmet needs in hypertension research and calls for action.

Separate mechanisms cause anemia in ischemic vs. nonischemic murine heart failure.

In ischemic congestive heart failure (CHF), anemia is associated with poor prognosis. Whether anemia develops in nonischemic CHF is uncertain. The hematopoietic inhibitors TNF-alpha and nitric oxide (NO) are activated in ischemic CHF. We examined whether mice with ischemic or nonischemic CHF develop anemia and whether TNF-alpha and NO are involved. We studied mice (n = 7-9 per group) with CHF either due to myocardial infarction (MI) or to overexpression of the Ca(2+)-binding protein calsequestrin (CSQ) or to induced cardiac disruption of the sarcoplasmic reticulum Ca(2+)-ATPase 2 gene (SERCA2 KO). Hematopoiesis was analyzed by colony formation of CD34(+) bone marrow cells. Hemoglobin concentration was 14.0 +/- 0.4 g/dl (mean +/- SD) in controls, while it was decreased to 10.1 +/- 0.4, 9.7 +/- 0.4, and 9.6 +/- 0.3 g/dl in MI, CSQ, and SERCA2 KO, respectively (P < 0.05). Colony numbers per 100,000 CD34(+) cells in the three CHF groups were reduced to 33 +/- 3 (MI), 34 +/- 3 (CSQ), and 39 +/- 3 (SERCA2 KO) compared with 68 +/- 4 in controls (P < 0.05). Plasma TNF-alpha nearly doubled in MI, and addition of anti-TNF-alpha antibody normalized colony formation. Inhibition of colony formation was completely abolished with blockade of endothelial NO synthase in CSQ and SERCA2 KO, but not in MI. In conclusion, the mechanism of anemia in CHF depends on the etiology of cardiac disease; whereas TNF-alpha impairs hematopoiesis in CHF following MI, NO inhibits blood cell formation in nonischemic murine CHF.

Medical Therapies for Heart Failure With Preserved Ejection Fraction.

Current cardiovascular pharmacotherapy targets maladaptive overactivation of the renin-angiotensin-aldosterone system (RAAS), which occurs throughout the continuum of cardiovascular disease spanning from hypertension to heart failure with reduced ejection fraction. Over the past 16 years, 4 prospective, randomized, placebo-controlled clinical trials using candesartan, perindopril, irbesartan, and spironolactone in patients with heart failure with preserved ejection fraction (HFpEF) failed to demonstrate increased efficacy of RAAS blockade added to guideline-directed medical therapy. We reappraise these trials and their weaknesses, which precluded statistically significant findings. Recently, dual-acting RAAS blockade with sacubitril-valsartan relative to stand-alone valsartan failed to improve outcome in the PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared with Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The majority of patients with HFpEF experience hypertension, frequently with subclinical left ventricular dysfunction, contributed to by comorbidities such as coronary disease, diabetes mellitus, overweight, and atrial fibrillation. Contrasting the findings in HFpEF, trials evaluating RAAS blockade on either side of HFpEF on the cardiovascular continuum in patients with high-risk hypertension and heart failure with reduced ejection fraction, respectively, showed positive outcomes. We do not have a biologically plausible explanation for such divergent efficacy of RAAS blockade. Based on considerations of well-established clinical efficacy in hypertension and heart failure with reduced ejection fraction and the shortcomings of aforementioned clinical trials in HFpEF, we argue that RAAS blockers including MRAs (mineralocorticoid receptor antagonists; aldosterone antagonists) should be used in the treatment of patients with HFpEF.

Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies.

There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control.