Functional Mitral Regurgitation and Heart Failure With Preserved Ejection Fraction: Clinical Implications and Management.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and associated with worse cardiovascular outcomes. The pathophysiology of HFpEF mostly relies on the development of elevated left ventricle filling pressure, diastolic dysfunction, and atrial dilatation and impairment. This dynamic process may eventually lead to the development of functional mitral regurgitation (MR), characterized by mitral annular dilatation and consequent leaflet remodeling, in the context of preserved left ventricular ejection fraction. These observations highlight the possible common pathophysiology of MR and HFpEF. However, less is known about the prevalence and the clinical value of MR in the context of HFpEF. This review aims to provide an overview of the association and interplay between functional MR and HFpEF, discuss the underlying mechanisms that are common to these diseases, and summarize potential targeted pharmacological treatments.

Device-based percutaneous treatments to decompress the left atrium in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure hospital admissions in the last years and is burdened by high mortality and poor quality of life. Providing effective management for HFpEF patients is a major unmet clinical need. Increase in left atrial pressure is the key determinant of pulmonary congestion, with consequent dyspnoea and exercise limitation. Evidence on benefits of medical treatment in HFpEF patients is limited. Thus, alternative strategies, including devices able to reduce left atrial pressure, through an interatrial communication determining a left-right shunt, were developed. This review aims to summarize evidence regarding the use of percutaneous interatrial shunting devices. These devices are safe and effective in improving hemodynamic and clinical parameters, including pulmonary capillary wedge pressure, 6-min walking distance, and New York Heart Association functional class. Data on cardiovascular mortality and re-hospitalization for heart failure are still scarce.

Cardiac contractility modulation: an effective treatment strategy for heart failure beyond reduced left ventricular ejection fraction?

Heart failure (HF) with preserved ejection fraction (HFpEF) causes a progressive limitation of functional capacity, poor quality of life (QoL) and increased mortality, yet unlike HF with reduced ejection fraction (HFrEF) there are no effective device-based therapies. Both HFrEF and HFpEF are associated with dysregulations in myocardial cellular calcium homeostasis and modifications in calcium-handling proteins, leading to abnormal myocardial contractility and pathological remodelling. Cardiac contractility modulation (CCM) therapy, based on a pacemaker-like implanted device, applies extracellular electrical stimulation to myocytes during the absolute refractory period of the action potential, which leads to an increase in cytosolic peak calcium concentrations and thereby the force of isometric contraction promoting positive inotropism. Subgroup analysis of CCM trials in HFrEF has demonstrated particular benefits in patients with LVEF between 35% and 45%, suggesting its potential effectiveness also in patients with higher LVEF values. Available evidence on CCM in HFpEF is still preliminary, but improvements in terms of symptoms and QoL have been observed. Future large, dedicated, prospective studies are needed to evaluate the safety and efficacy of this therapy in patients with HFpEF.

Varicella zoster virus and cardiovascular diseases.

Varicella zoster virus (VZV) is a Herpesviridae family double-stranded DNA virus that only affects humans. The first clinical manifestation appears to be varicella, typical of childhood. VZV, on the other hand, becomes latent in ganglion neurons throughout the neuroaxis after primary infection. The VZV reactivates and travels along peripheral nerve fibers in the elderly and immunocompromised individuals, resulting in Zoster. It can, however, spread centrally and infect cerebral and extracranial arteries, resulting in vasculopathy, which can lead to transient ischemic attacks, strokes, aneurysms, cavernous sinus thrombosis, giant cell arteritis, and granulomatous aortitis. Although the mechanisms of virus-induced pathological vascular remodeling are not fully understood, recent research indicates that inflammation and dysregulation of ligand-1 programmed death play a significant role. Few studies, on the other hand, have looked into the role of VZV in cardiovascular disease. As a result, the purpose of this review is to examine the relationship between VZV and cardiovascular disease, the efficacy of the vaccine as a protective mechanism, and the target population of heart disease patients who could benefit from vaccination.

Endothelial Dysfunction in Heart Failure: What Is Its Role?

The endothelium is a continuous layer of cells that coats the interior walls of arteries, capillaries, and veins. It has an essential regulatory role in hemostatic function, vascular tone, inflammation, and platelet activity. Endothelial dysfunction is characterized by a shift to a proinflammatory and prothrombic state, and it could have a bidirectional relationship with heart failure (HF). Due to neurohormonal activation and shear stress, HFrEF may promote endothelial dysfunction, increase ROS synthesis, and reduce nitric oxide production. Different studies have also shown that endothelium function is damaged in HFpEF because of a systemic inflammatory state. Some clinical trials suggest that drugs that have an effect on endothelial dysfunction in patients with HF or cardiovascular disease may be a therapeutic option. The aim of this review is to highlight the pathogenetic correlation between endothelial dysfunction and heart failure and the related potential therapeutic options.

Medical therapy of cardiogenic shock: Contemporary use of inotropes and vasopressors.

Cardiogenic shock is a primary cardiac disorder that results in both clinical and biochemical evidence of tissue hypoperfusion and can lead to multi-organ failure and death depending on its severity. Inadequate cardiac contractility or cardiac power secondary to acute myocardial infarction remains the most frequent cause of cardiogenic shock, although its contribution has declined over the past two decades, compared with other causes. Despite some advances in cardiogenic shock management, this clinical syndrome is still burdened by an extremely high mortality. Its management is based on immediate stabilization of haemodynamic parameters so that further treatment, including mechanical circulatory support and transfer to specialized tertiary care centres, can be accomplished. With these aims, medical therapy, consisting mainly of inotropic drugs and vasopressors, still has a major role. The purpose of this article is to review current evidence on the use of these medications in patients with cardiogenic shock and discuss specific clinical settings with indications to their use.

Characteristics and outcomes of patients with tricuspid regurgitation and advanced heart failure.

AIMS: To evaluate the role of tricuspid regurgitation in advanced heart failure. METHODS: The multicenter observational HELP-HF registry enrolled consecutive patients with heart failure and at least one 'I NEED HELP' criterion evaluated at four Italian centers between January 2020 and November 2021. Patients with no data on tricuspid regurgitation and/or receiving tricuspid valve intervention during follow-up were excluded. The population was stratified by no/mild tricuspid regurgitation vs. moderate tricuspid regurgitation vs. severe tricuspid regurgitation. Variables independently associated with tricuspid regurgitation, as well as the association between tricuspid regurgitation and clinical outcomes were investigated. The primary outcome was all-cause mortality. RESULTS: Among the 1085 patients included in this study, 508 (46.8%) had no/mild tricuspid regurgitation, 373 (34.4%) had moderate tricuspid regurgitation and 204 (18.8%) had severe tricuspid regurgitation. History of atrial fibrillation, any prior valve surgery, high dose of furosemide, preserved left ventricular ejection fraction, moderate/severe mitral regurgitation and pulmonary hypertension were found to be independently associated with an increased likelihood of severe tricuspid regurgitation. Estimated rates of 1-year all-cause death were of 21.4, 24.5 and 37.1% in no/mild tricuspid regurgitation, moderate tricuspid regurgitation and severe tricuspid regurgitation, respectively (log-rank P  < 0.001). As compared with nonsevere tricuspid regurgitation, severe tricuspid regurgitation was independently associated with a higher risk of all-cause mortality (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.88, P  = 0.042), whereas moderate tricuspid regurgitation did not. CONCLUSION: In a contemporary, real-world cohort of patients with advanced heart failure, several clinical and echocardiographic characteristics are associated with an increased likelihood of severe tricuspid regurgitation. Patients with severe tricuspid regurgitation have an increased risk of mortality.

Soluble ST2 in Heart Failure: A Clinical Role beyond B-Type Natriuretic Peptide.

Soluble (s)ST2 has been proposed as a useful biomarker for heart failure (HF) patient management. Myocardial damage or mechanical stress stimulate sST2 release. ST2 competes with a membrane bound receptor (ST2 ligand, or ST2L) for interleukin-33 (IL-33) binding, inhibiting the effects induced by the ST2L/IL-33 interaction so that excessive sST2 may contribute to myocardial fibrosis and ventricular remodeling. Compared to natriuretic peptides (NPs), sST2 concentration is not substantially affected by age, sex, body mass index, kidney function, atrial fibrillation, anemia, or HF etiology, and has low intra-individual variation. Its prognostic role as an independent marker is well reported in the literature. However, there is a gap on its use in combination with NPs, currently the only biomarkers recommended by European and American guidelines for HF management. Reflecting the activation of two distinct biological systems, a benefit from the use of sST2 and NP in combination is advocated. The aim of this review is to report the current scientific knowledge on sST2 in the acute and chronic HF settings with a particular attention to its additive role to natriuretic peptides (NPs).

Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials.

An increasing awareness of the disease, new diagnostic tools and novel therapeutic opportunities have dramatically changed the management of patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Supportive therapies have shown limited benefits, mostly related to diuretics for the relief from signs and symptoms of congestion in patients presenting heart failure (HF). On the other hand, huge advances in specific (disease-modifying) treatments occurred in the last years. Therapies targeting the amyloidogenic cascade include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Tafamidis, a TTR stabilizer that demonstrated to prolong survival and improve quality of life in the ATTR-ACT trial, is currently the only approved drug for patients with ATTR-CM. The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen have been approved for the treatment of patients with hereditary ATTR polyneuropathy regardless of the presence of cardiac involvement, with patisiran also showing preliminary benefits on the cardiac phenotype. Ongoing phase III clinical trials are investigating another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR-CM. CRISPR-Cas9 represents a promising strategy of genome editing to obtain a highly effective blockade of TTR gene expression.

Endothelial Dysfunction in Systemic Lupus Erythematosus and Systemic Sclerosis: A Common Trigger for Different Microvascular Diseases.

This review describes the complex interplay between inflammation, vasculopathy and fibrosis that involve the heart and peripheral small vessels, leading to endothelial stiffness, vascular damage, and early aging in patients with systemic lupus erythematosus and systemic sclerosis, which represents two different models of vascular dysfunction among systemic autoimmune diseases. In fact, despite the fact that diagnostic methods and therapies have been significantly improved in the last years, affected patients show an excess of cardiovascular mortality if compared with the general population. In addition, we provide a complete overview on the new techniques which are used for the evaluation of endothelial dysfunction in a preclinical phase, which could represent a new approach in the assessment of cardiovascular risk in these patients.

Endothelial function evaluation in idiopathic vs. ischemic dilated cardiomyopathy.

AIMS: In the latest years an emerging interest has risen towards the role of endothelial dysfunction (ED) in the pathogenesis of heart failure (HF) since the very first steps of the disease. Since the prevalent etiology of HF is ischemic cardiomyopathy (ICM), it is still not clear whether the connection with ED is linked to HF itself or to atherosclerosis. The aim is to determine the presence of ED in subjects with idiopathic dilated cardiomyopathy (IDCM) compared to ICM. METHODS: In this observational study 107 patients were enrolled, 65 of them suffering from IDCM and 42 from ICM. ED was assessed as peripheral arterial tonometry by means of EndoPAT device. The Reactive Hyperaemia Index (RHI) was calculated, ED being established with RHI values ≤1.67 and normal endothelial function >2.00 (grey area between 1.67 and 2.00). RESULTS: ED, expressed both as RHI ≤1.67 and RHI ≤2.00, showed a similar prevalence in the two groups. However, they differed as regards sex, dyslipidemia and statin use. CONCLUSION: Endothelial function, evaluated through peripheral artery tonometry, seems equally compromised in patients with IDCM and ICM.

Heart failure: an update from the last years and a look at the near future.

In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium-lowering agents may counteract hyperkalaemia and facilitate renin-angiotensin-aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre-specified meta-analysis of major randomized controlled trials, sodium-glucose co-transporter-2 inhibitors reduced all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM-HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66-1.02; P = 0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article.