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Abstract Aims The use of loop diuretics in pulmonary arterial hypertension (PAH) is less frequent compared with heart failure. The clinical and prognostic characteristics of PAH patients according to loop diuretic use remain unexplored. In this study, we retrospectively analysed the characteristics and survival of PAH patients requiring different doses of loop diuretics. Methods and results Patients diagnosed with PAH between 2001 and 2022 at seven European centres for the management of PAH. According to the median equivalent dose of furosemide in the overall cohort, patients were divided into two subgroups: no/low‐dose loop diuretic and high‐dose loop diuretic. Primary outcome was 5 year all‐cause mortality. Among the 397 patients included, 227 (57%) were treated with loop diuretics. Median daily furosemide equivalent dose was 25 mg, and accordingly patients were divided in no/low dose (i.e. ≤25 mg, n = 257, 65%) vs. high dose (i.e. >25 mg, n = 140, 35%). Patients in the high‐dose group were older, more likely to have comorbidities, and had a more severe disease according to the ESC/ERS risk category. Crude 5 year survival was significantly shorter in patients in the high‐dose group, but after adjustment for age, sex, and risk category, high loop diuretic dose was not significantly associated with the primary outcome. Conclusions Use of high dose of loop diuretics in PAH is associated with a higher burden of comorbidities, more severe disease, and worse survival. However, in PAH, the need of high loop diuretic dose is a marker of disease severity and not an independent prognostic factor.

Abstract Aims Achieving optimized guideline‐directed medical therapy (GDMT) is recommended prior to transcatheter mitral valve edge‐to‐edge repair (M‐TEER) for secondary mitral regurgitation (SMR). We aimed to propose and validate an easy‐to‐use score for assessing the quality of GDMT in patients with heart failure with reduced ejection fraction (HFrEF) undergoing M‐TEER. Methods and results Among the 1641 EuroSMR patients enrolled in the EuroSMR Registry who underwent M‐TEER, a total of 1072 patients [median age 74, interquartile range (IQR) 67–79 years, 29% female] had complete data on GDMT and a left ventricular ejection fraction ≤ 40% and were included in the current study. We proposed a GDMT score that considers the dosage levels of three medication classes (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor‐neprilysin inhibitors, beta‐blockers, and mineralocorticoid receptor antagonists), with a maximum score of 12 points indicating optimal GDMT. The primary outcome was all‐cause mortality. The median GDMT score was 4 points (IQR 3–6). All three domains of the scoring system were associated with all‐cause mortality (P

Abstract Heart failure with preserved ejection fraction (HFpEF) has a high prevalence, affecting more than 50% of patients with heart failure. HFpEF is associated with multiple comorbidities, and obesity is one of the most common. A distinct phenotype has been proposed for obese patients with HFpEF. Recent data show the beneficial role of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) for weight loss in diabetic and non‐diabetic patients with obesity or overweight when given as adjunctive therapy to diet and exercise. The mechanisms of action are related to paracrine and endocrine signalling pathways within the gastrointestinal tract, pancreas, and central nervous system that delay gastric emptying, decrease appetite, augment pancreatic beta‐cell insulin secretion, and suppress pancreatic glucagon release. These drugs are therefore potentially indicated for treatment of patients with HFpEF and obesity or overweight. Efficacy and safety need to be shown by clinical trials with a first one, Semaglutide Treatment Effect in People with obesity and heart failure with preserved ejection fraction (STEP HFpEF), recently concluded. The aim of the present review is to provide the pathophysiological and pharmacological rationale for GLP‐1 RA administration to obese patients with HFpEF.

Abstract Aims Patients with heart failure (HF) with reduced ejection fraction (EF) (HFrEF), mildly reduced EF (HFmrEF), and preserved EF (HFpEF) may all progress to advanced HF, but the impact of EF in the advanced setting is not well established. Our aim was to assess the prognostic impact of EF in patients with at least one ‘I NEED HELP’ marker for advanced HF. Methods and results Patients with HF and at least one high‐risk ‘I NEED HELP’ criterion from four centres were included in this analysis. Outcomes were assessed in patients with HFrEF (EF ≤ 40%), HFmrEF (EF 41–49%), and HFpEF (EF ≥ 50%) and with EF analysed as a continuous variable. The prognostic impact of medical therapy for HF in patients with EF 50% was also evaluated. All‐cause death was the primary endpoint, and cardiovascular death was a secondary endpoint. Among 1149 patients enrolled [mean age 75.1 ± 11.5 years, 67.3% males, 67.6% hospitalized, median follow‐up 260 days (inter‐quartile range 105–390 days)], HFrEF, HFmrEF, and HFpEF were observed in 699 (60.8%), 122 (10.6%), and 328 (28.6%) patients, and 1 year mortality was 28.3%, 26.2%, and 20.1, respectively (log‐rank P = 0.036). As compared with HFrEF patients, HFpEF patients had a lower risk of all‐cause death [adjusted hazard ratio (HRadj) 0.67, 95% confidence interval (CI) 0.48–0.94, P = 0.022], whereas no difference was noted for HFmrEF patients. After multivariable adjustment, a lower risk of all‐cause death (HRadj for 5% increase 0.94, 95% CI 0.89–0.99, P = 0.017) and cardiovascular death (HRadj for 5% increase 0.94, 95% CI 0.88–1.00, P = 0.049) was observed at higher EF values. Beta‐blockers and renin–angiotensin system inhibitors or sacubitril/valsartan were associated with lower mortality in both EF

Background Minimally invasive mitral valve repair has a favorable risk–benefit profile in patients with significant de novo mitral regurgitation. Its role in patients with prior mitral valve repair is uncertain. We aimed to appraise the outcome of patients undergoing transcatheter edge‐to‐edge repair (TEER) with prior transcatheter or surgical mitral valve repair (SMVR). Methods and Results We queried the Italian multicenter registry on TEER with MitraClip, distinguishing naïve patients from those with prior TEER or (SMVR). Inhospital and long‐term clinical/echocardiographic outcomes were appraised. The primary outcome was the occurrence of death or rehospitalization for heart failure. A total of 2238 patients were included, with 2169 (96.9%) who were naïve to any mitral intervention, 29 (1.3%) with prior TEER, and 40 (1.8%) with prior SMVR. Several significant differences were found in baseline clinical and imaging features. Respectively, device success was obtained in 2120 (97.7%), 28 (96.6%), and 38 (95.0%, P=0.261) patients; procedural success in 2080 (95.9%), 25 (86.2%), and 38 (95.0%; P=0.047); and inhospital death in 61 (2.8%), 1 (3.5%), and no (P=0.558) patients. Clinical follow‐up after a mean of 14 months showed similar rates of death, cardiac death, rehospitalization, rehospitalization for heart failure, and their composite (all P>0.05). Propensity score–adjusted analysis confirmed unadjusted analysis, with lower procedural success for the prior TEER group (odds ratio, 0.28 [95% CI, 0.09–0.81]; P=0.019) but similar odds ratios and hazard ratios for all other outcomes in the naïve, TEER, and SMVR groups (all P>0.05). Conclusions In carefully selected patients, TEER can be performed using the MitraClip device even after prior TEER or SMVR.

Acute heart failure (AHF) represents a common clinical scenario that requires prompt evaluation and therapy and that is characterized by a high risk of mortality or subsequent rehospitalizations. The pathophysiology leading to AHF decompensation is still not fully understood. Significant activation of inflammatory pathways has been identified in patients with AHF, particularly in its most severe forms, and it has been hypothesized that systemic inflammation has a role in AHF pathogenesis. Several inflammatory mediators and cytokines, such as high sensitivity C-reactive protein, tumor necrosis factor-α, interleukin-6, interleukin-1, soluble suppression of tumorigenicity 2 and galectin-3, have been shown to play a role in the pathogenesis, development and worsening of this condition with an independent prediction of adverse outcomes. This manuscript reviews the prevalence and prognostic value of systemic inflammation in AHF, as well as the potential role of anti-inflammatory therapies, focusing on available evidence from clinical trials and ongoing studies.

Abstract 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.

Abstract The coronavirus 2019 (COVID‐19) infection pandemic has affected the care of patients with heart failure (HF). Several consensus documents describe the appropriate diagnostic algorithm and treatment approach for patients with HF and associated COVID‐19 infection. However, few questions about the mechanisms by which COVID can exacerbate HF in patients with high‐risk (Stage B) or symptomatic HF (Stage C) remain unanswered. Therefore, the type of HF occurring during infection is poorly investigated. The diagnostic differentiation and management should be focused on the identification of the HF phenotype, underlying causes, and subsequent tailored therapy. In this framework, the relationship existing between COVID and onset of acute decompensated HF, isolated right HF, and cardiogenic shock is questioned, and the specific management is mainly based on local hospital organization rather than a standardized model. Similarly, some specific populations such as advanced HF, heart transplant, patients with left ventricular assist device (LVAD), or valve disease remain under investigated. In this systematic review, we examine recent advances regarding the relationships between HF and COVID‐19 pandemic with respect to epidemiology, pathogenetic mechanisms, and differential diagnosis. Also, according to the recent HF guidelines definition, we highlight different clinical profile identification, pointing out the main concerns in understudied HF populations.

Abstract Heart failure (HF) is a major cause of mortality, hospitalizations, and reduced quality of life and a major burden for the healthcare system. The number of patients that progress to an advanced stage of HF is growing. Only a limited proportion of these patients can undergo heart transplantation or mechanical circulatory support. The purpose of this review is to summarize medical management of patients with advanced HF. First, evidence‐based oral treatment must be implemented although it is often not tolerated. New therapeutic options may soon become possible for these patients. The second goal is to lessen the symptomatic burden through both decongestion and haemodynamic improvement. Some new treatments acting on cardiac function may fulfil both these needs. Inotropic agents acting through an increase in intracellular calcium have often increased risk of death. However, in the recent Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial, omecamtiv mecarbil was safe and effective in the reduction of the primary outcome of cardiovascular death or HF event compared with placebo (hazard ratio, 0.92; 95% confidence interval, 0.86–0.99; P = 0.03) and its effects were larger in those patients with more severe left ventricular dysfunction. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit, whereas patients without severe HF did not (P = 0.005 for interaction). Lastly, clinicians should take care of the end of life with an appropriate multidisciplinary approach. Medical treatment of advanced HF therefore remains a major challenge and a wide open area for further research.

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.

Severe aortic stenosis (AS) is the most common valvular heart disease with a prevalence rate of more than 4% in 75-year-old people or older. Similarly, cardiac amyloidosis (CA), especially “wild-type transthyretin” (wTTR), has shown a prevalence rate ranging from 22% to 25% in people older than 80 years. The detection of the concomitant presence of CA and AS is challenging primarily because of the similar type of changes in the left ventricle caused by AS and CA, which share some morphological characteristics. The aim of this review is to identify the imaging triggers in order to recognize occult wtATTR-CA in patients with AS, clarifying the crucial step of the diagnostic process. Multimodality imaging methods such as echocardiography, cardiac magnetic resonance, cardiac computed tomography, and DPD scintigraphy will be analyzed as part of the available diagnostic workup to identify wtATTR-CA early in patients with AS.

Abstract Cardiogenic shock (CS) is a complex multifactorial clinical syndrome, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large phenotypic variability in CS, as a result of the diverse aetiologies, pathogenetic mechanisms, haemodynamics, and stages of severity. Although early revascularization remains the most important intervention for CS in settings of acute myocardial infarction, the administration of timely and effective antithrombotic therapy is critical to improving outcomes in these patients. In addition, other clinical settings or non‐acute myocardial infarction aetiologies, associated with high thrombotic risk, may require specific regimens of short‐term or long‐term antithrombotic therapy. In CS, altered tissue perfusion, inflammation, and multi‐organ dysfunction induce unpredictable alterations to antithrombotic drugs' pharmacokinetics and pharmacodynamics. Other interventions used in the management of CS, such as mechanical circulatory support, renal replacement therapies, or targeted temperature management, influence both thrombotic and bleeding risks and may require specific antithrombotic strategies. In order to optimize safety and efficacy of these therapies in CS, antithrombotic management should be more adapted to CS clinical scenario or specific device, with individualized antithrombotic regimens in terms of type of treatment, dose, and duration. In addition, patients with CS require a close and appropriate monitoring of antithrombotic therapies to safely balance the increased risk of bleeding and thrombosis.

Background Malnutrition is associated with poor prognosis in several cardiovascular diseases. However, its prognostic impact in patients undergoing transcatheter edge‐to‐edge mitral valve repair (TEER) is not well known. This study sought to assess the prevalence, clinical associations, and prognostic consequences of malnutrition in patients undergoing TEER. Methods and Results A total of 892 patients undergoing TEER from the international MIVNUT (Mitral Valve Repair and Nutritional Status) registry were studied. Malnutrition status was assessed with the Controlling Nutritional Status score. The association of nutritional status with mortality was analyzed with multivariable Cox regression models, whereas the association with heart failure admission was assessed by Fine‐Gray models, with death as a competing risk. According to the Controlling Nutritional Status score, 74.4% of patients with TEER had any degree of malnutrition at the time of TEER (75.1% in patients with body mass index

Abstract Research about heart failure (HF) has made major progress in the last years. We give here an update on the most recent findings. Landmark trials have established new treatments for HF with reduced ejection fraction. Sacubitril/valsartan was superior to enalapril in PARADIGM‐HF trial, and its initiation during hospitalization for acute HF or early after discharge can now be considered. More recently, new therapeutic pathways have been developed. In the DAPA‐HF and EMPEROR‐Reduced trials, dapagliflozin and empagliflozin reduced the risk of the primary composite endpoint, compared with placebo [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.65–0.85; P

Abstract Heart failure (HF) remains a major cause of mortality, morbidity, and poor quality of life. It is an area of active research. This article is aimed to give an update on recent advances in all aspects of this syndrome. Major changes occurred in drug treatment of HF with reduced ejection fraction (HFrEF). Sacubitril/valsartan is indicated as a substitute to ACEi/ARBs after PARADIGM‐HF (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73 to 0.87 for sacubitril/valsartan vs. enalapril for the primary endpoint and Wei, Lin and Weissfeld HR 0.79, 95% CI 0.71–0.89 for recurrent events). Its initiation was then shown as safe and potentially useful in recent studies in patients hospitalized for acute HF. More recently, dapagliflozin and prevention of adverse‐outcomes in DAPA‐HF trial showed the beneficial effects of the sodium–glucose transporter type 2 inhibitor dapaglifozin vs. placebo, added to optimal standard therapy [HR, 0.74; 95% CI, 0.65 to 0.85;0.74; 95% CI, 0.65 to 0.85 for the primary endpoint]. Trials with other SGLT 2 inhibitors and in other patients, such as those with HF with preserved ejection fraction (HFpEF) or with recent decompensation, are ongoing. Multiple studies showed the unfavourable prognostic significance of abnormalities in serum potassium levels. Potassium lowering agents may allow initiation and titration of mineralocorticoid antagonists in a larger proportion of patients. Meta‐analyses suggest better outcomes with ferric carboxymaltose in patients with iron deficiency. Drugs effective in HFrEF may be useful also in HF with mid‐range ejection fraction. Better diagnosis and phenotype characterization seem warranted in HF with preserved ejection fraction. These and other burning aspects of HF research are summarized and reviewed in this article.

Conflicting results are available regarding the influence of ACEi/ARBs on the risk of COVID-19 infection, while less is known about their impact on the clinical outcome of patients with STEMI diagnosed with COVID-19. Our aim was to evaluate the impact of ACEi/ARBs therapy on in-hospital mortality and clinical outcomes of patients with STEMI during the COVID-19 pandemic. We retrospectively analyzed consecutive patients with STEMI hospitalized from February 20 to May 10, 2020 in four Hospitals in Lombardy. SARS-COV-2 diagnosis was performed by nasopharyngeal swab test. Procedural outcome, respiratory complications, and in-hospital mortality were reported. Univariate and multivariate analyses were performed by logistic regressions. Our population was represented by 182 patients with STEMI, 76.9% of which were males, and mean age was 67 ± 12.5. Hypertension was reported in 53.3%, and 29.1% was treated with ACEi/ARBs. COVID-19 diagnosis was confirmed in 17.1% of the patients. In-hospital mortality (13.2%) was significantly higher in patients with COVID-19 (31 vs. 10%, p = 0.003), even if ejection fraction [OR 0.93 (95% CI) 0.87–0.99; p = 0.03] and respiratory complications [OR 9.39 (95% CI) 1.91–45.9; p = 0.006] were the only two independent predictors. The incidence of COVID-19 infection was not influenced by ACEi/ARBs (16.5 in naïve vs. 18.8%) whose presence on admission did not correlate with respiratory complications or mortality both in the case of discontinuation and maintenance. In conclusion, in a high-risk population, such as that of patients with STEMI, the potential benefit of ACEi/ARB discontinuation in patients with COVID-19 is overcome by its detrimental effect. Intensive care, additional preventive respiratory investigations, regardless of swab test result, should be suggested for all patients admitted for STEMI during the pandemic.

A close and intriguing relationship has been suggested between heart failure (HF) and coronavirus disease 2019 (COVID-19). First, COVID-19 pandemic represented a global public health emergency in the last year and had a catastrophic impact on health systems worldwide. Several studies showed a reduction in HF hospitalizations, ranging from 30 to 66% in different countries and leading to a subsequent increase in HF mortality. Second, pre-existing HF is a risk factor for a more severe clinical course of COVID-19 and an independent predictor of in-hospital mortality. Third, patients hospitalized for COVID-19 may develop both an acute decompensation of chronic HF and de-novo HF as a consequence of myocardial injury and cardiovascular (CV) complications. Myocardial injury occurred in at least 10% of unselected COVID-19 cases and up to 41% in critically ill patients or in those with concomitant CV comorbidities. Few cases of COVID-19-related acute myocarditis, presenting with severe reduction in the left ventricular (LV) ejection fraction and peculiar histopathological findings, were described. However, recent data suggested that COVID-19 may be associated with both systolic and diastolic LV dysfunction, with LV diastolic impairment, pulmonary hypertension, and right ventricular dysfunction representing the most frequent findings in echocardiographic studies. An overview of available data and the potential mechanisms behind myocardial injury, possibly leading to HF, will be presented in this review. Beyond the acute phase, HF as a possible long-term consequence of cardiac involvement in COVID-19 patients has been supposed and need to be investigated yet.