Functional mitral regurgitation (FMR) is associated with poor outcomes in patients with heart failure (HF). However, it is not clear whether FMR is just a consequence of left ventricular (LV) ...remodelling or a factor contributing to cardiomyopathy progression. There will be more clarity about this controversy when the effects of FMR correction on outcomes will be shown. FMR correction can be performed surgically or, more often, percutaneously with the MitraClip procedure. MitraClip is the most widely used device with more than 70 000 implants performed to date. Observational studies suggest that MitraClip treatment of FMR is safe and associated with improved symptoms, quality of life and functional status in HF patients. Two recently randomized controlled clinical trials have investigated the impact of MitraClip on the outcomes of HF patients: Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA‐FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT). Both trials randomized patients to MitraClip plus guideline‐directed medical therapy (GDMT) or GDMT alone. No reduction in the primary endpoint of all‐cause mortality or HF hospitalizations was shown in MITRA‐FR, whereas a significant reduction in HF hospitalizations (primary endpoint) as well as in mortality alone were shown in COAPT. The aim of this review is to summarize the pathophysiology, prevalence, prognostic role and management of FMR, focusing on the differences between MITRA‐FR and COAPT and trying to provide possible explanations for the diverging results. We speculate that the two trials should be interpreted as complementary rather than opposite. Patients with severe FMR (effective regurgitant orifice area > 30 mm2) despite maximum tolerated GDMT (including cardiac resynchronization therapy), and without too advanced cardiomyopathy seem to be the best candidates for MitraClip treatment. MITRA‐FR and COAPT provide us a long awaited ‘proof of concept’: FMR may be considered a leading actor in cardiomyopathy progression rather than a mere marker of severity.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding ...the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.
In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.
During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval CI, 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m
of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.
Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). ...Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF.
We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF.
Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio HR 0.84 95% CI, 0.78-0.90), cardiovascular death (HR 0.84 95% CI, 0.76-0.92), heart failure hospitalization (HR 0.84 95% CI, 0.77-0.91), and all-cause mortality (HR 0.88 95% CI, 0.81-0.96). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction
=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions.
The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men.
https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).
Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality, but the identification of LVAD candidates at risk for ...RVF remains challenging. We undertook a systematic review and meta‐analysis of observational studies of risk factors associated with RVF after LVAD implant. Thirty‐six studies published between 1 January 1995 and 30 April 2015, comprising 995 RVF patients out of a pooled final population of 4428 patients, were identified. Meta‐analysed prevalence of post‐LVAD RVF was 35%. A need for mechanical ventilation odds ratio (OR) 2.99, or continuous renal replacement therapy (CRRT; OR 4.61, area under the curve 0.78, specificity 0.91) were the clinical variables with the highest effect size (ES) in predicting RVF. International normalized ratio INR; standardized mean difference (SMD) 0.49 and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) (SMD 0.52) were the biochemical markers that best discriminated between RVF and No‐RVF populations, though NT‐proBNP was highly heterogeneous. Right ventricular stroke work index (RVSWI) and central venous pressure (CVP) (SMD −0.58 and 0.47, respectively) were the haemodynamic measures with the highest ES in identifying patients at risk of post‐LVAD RVF; CVP was particularly useful in risk stratifying patients undergoing continuous‐flow LVAD implant (SMD 0.59, P < 0.001, I2 = 20.9%). Finally, pre‐implant moderate to severe right ventricular (RV) dysfunction, as assessed qualitatively (OR 2.82), or a greater RV/LV diameter ratio (SMD 0.51) were the standard echocardiographic measurements with the highest ES in comparing RVF with No‐RVF patients. Longitudinal systolic strain of the RV free wall had the highest ES (SMD 0.73) but also the greatest heterogeneity (I2 = 74%) and was thus only marginally significant (P = 0.05). Patients on ventilatory support or CRRT are at high risk for post‐LVAD RVF, similarly to patients with slightly increased INR, high NT‐proBNP or leukocytosis. High CVP, low RVSWI, an enlarged right ventricle with concomitant low RV strain also identify patients at higher risk.
In recent years, several studies have shown the usefulness and clinical relevance of left ventricular global longitudinal systolic strain (GLS) in different cardiovascular diseases. In line with ...this, the role of GLS in patients with heart failure with preserved ejection fraction (HFpEF) has achieved great importance in this predominant form of heart failure in the last years. In this regard, GLS has shown to be not only a sensitive parameter to detect subtle myocardial abnormalities but also a parameter of clinical and prognostic relevance in patients with HFpEF. In this review, we analyze the current evidence concerning the clinical relevance of GLS in patients with HFpEF and we discuss the potential usefulness of GLS in this complex and heterogeneous condition for which so far no effective therapy exists.
Abstract Little is known about specific modes of death in patients with heart failure with preserved ejection fraction (HFpEF). Herein, the authors critically appraise the current state of data and ...offer potential future directions. They conducted a systematic review of 1,608 published HFpEF papers from January 1, 1985, to December 31, 2015, which yielded 8 randomized clinical trials and 24 epidemiological studies with mode-of-death data. Noncardiovascular modes of death represent an important competing risk in HFpEF. Although sudden death accounted for ∼25% to 30% of deaths in trials, its definition is nonspecific; it is unclear what proportion represents arrhythmic deaths. Moving forward, reporting and definitions of modes of death must be standardized and tailored to the HFpEF population. Broad-scale systematic autopsies and long-term rhythm monitoring may clarify the underlying pathology and mechanisms driving mortal events. There is an unmet need for a longitudinal multicenter, global registry of patients with HFpEF to map its natural history.
Sacubitril/valsartan represents the first of a new class of drugs able to act as a neprilysin inhibitor and as an angiotensin receptor blocker. This double inhibition has the advantage of ...concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (angiotensin receptor blocker component) while stimulating an anti-fibrotic/anti-hypertrophic mechanism (neprilysin inhibitor component). Furthermore, the novel drug has natriuretic and diuretic properties, better preserves renal function, provides better blood pressure control as compared to renin angiotensin system inhibitors, and improves ventricular-arterial coupling. Consequently, sacubitril/valsartan provides greater target organ protection than angiotensin receptor blocker therapy alone, including cardiac, vascular, and renal protection. Up to now, this drug does not have an indication in patients with heart failure with preserved ejection fraction (HFpEF). However, its complex mechanism of action and previous experimental and clinical data seem to suggest its possible success in HFpEF. In this review we highlight and discuss the rationale, clinical insights, and perspectives behind the use of sacubitril/valsartan in HFpEF, specifically referring to its possible efficacy in pathophysiologic mechanisms, such as myocardial hypertrophy, fibrosis, and ischemia, renal dysfunction, impaired ventricular-arterial coupling, which are all tightly related to elevated left ventricular end diastolic pressure, a common hallmark for this multifaceted syndrome.
•Trials of conventional heart failure medications have been inconclusive in HFpEF.•LCZ696 is a novel drugs able to act as a neprilysin inhibitor and as an angiotensin receptor blocker.•The PARAMOUNT-HF trial gave promising results on the effectiveness of LCZ696 in HFpEF.
The autonomic nervous system, the renin–angiotensin–aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major ...targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin‐1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on‐target and off‐target effects when this agent is more widely prescribed.
Approximately 4% of subjects aged 75 years or more have clinically relevant tricuspid regurgitation (TR). Primary TR results from anatomical abnormality of the tricuspid valve apparatus and is ...observed in only 8-10% of the patients with tricuspid valve disease. Secondary TR is more common and arises as a result of annular dilation caused by right ventricular enlargement and dysfunction as a consequence of pulmonary hypertension, often caused by left-sided heart disease or atrial fibrillation. Irrespective of its aetiology, TR leads to volume overload and increased wall stress, both of which negatively contribute to detrimental remodelling and worsening TR. This vicious circle translates into impaired survival and increased heart failure symptoms in patients with and without reduced left ventricular ejection fraction. Interventions to correct TR are underutilised in daily clinical practice owing to increased surgical risk and late patient presentation. The recently introduced transcatheter tricuspid valve interventions aim to address this unmet need. Dedicated expertise and an interdisciplinary Heart Team evaluation are essential to integrate these new techniques successfully and select patients. The present article proposes a standardised approach to evaluate patients with TR who may be candidates for transcatheter interventions. In addition, a state-of-the-art review of the available transcatheter therapies, the main criteria for patient and device selection, and information concerning the remaining uncertainties are provided.
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