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The sodium–glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09–1.68; P  = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment. In a multinational trial, empagliflozin has clinical benefit when administered to hospitalized patients with acute heart failure, extending the reach of SGLT2 inhibitor therapy to this patient population.

Background: Oxidative stress is a key driver of heart failure (HF) pathophysiology, promoting myocardial injury, inflammation, and remodeling. Although numerous biomarkers of oxidative stress and DNA damage have been investigated in HF, their clinical relevance remains uncertain. This systematic review and meta-analysis aimed to evaluate alterations in these biomarkers in HF patients compared to healthy controls. Methods: A comprehensive search of PubMed, MEDLINE, the Cochrane Library, and Web of Science was conducted in accordance with PRISMA guidelines. Studies reporting oxidative stress or DNA damage biomarkers in HF patients versus controls were included. Random-effects models were used to calculate ratios of means (ROM) with 95% confidence intervals (CI). Heterogeneity and publication bias were assessed using the I2 statistic and Begg’s test. Results: Data from 3015 HF patients and 2704 controls were analyzed. HF patients had significantly higher levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) (ROM = 2.24, 95% CI: 1.75–2.88), malondialdehyde (MDA) (ROM = 1.87, 95% CI: 1.49–2.36) and isoprostanes (ROM = 2.83, 95% CI: 1.97–4.05). Telomere length was significantly shorter (ROM = 0.66, 95% CI: 0.53–0.81), indicating accelerated cellular aging. Considerable heterogeneity was observed across studies. Conclusion: This meta-analysis supports a robust association between oxidative stress, DNA damage, and HF, highlighting the potential role of these biomarkers in disease monitoring and prognosis.

BackgroundPulmonary embolism (PE) has been described in coronavirus disease 2019 (COVID-19) critically ill patients, but the evidence from more heterogeneous cohorts is limited.MethodsData were retrospectively obtained from consecutive COVID-19 patients admitted to 13 Cardiology Units in Italy, from March 1st to April 9th, 2020, and followed until in-hospital death, discharge, or April 23rd, 2020. The association of baseline variables with computed tomography-confirmed PE was investigated by Cox hazards regression analysis. The relationship between d-dimer levels and PE incidence was evaluated using restricted cubic splines models.ResultsThe study included 689 patients (67.3 ± 13.2 year-old, 69.4% males), of whom 43.6% were non-invasively ventilated and 15.8% invasively. 52 (7.5%) had PE over 15 (9–24) days of follow-up. Compared with those without PE, these subjects had younger age, higher BMI, less often heart failure and chronic kidney disease, more severe cardio-pulmonary involvement, and higher admission d-dimer [4344 (1099–15,118) vs. 818.5 (417–1460) ng/mL, p < 0.001]. They also received more frequently darunavir/ritonavir, tocilizumab and ventilation support. Furthermore, they faced more bleeding episodes requiring transfusion (15.6% vs. 5.1%, p < 0.001) and non-significantly higher in-hospital mortality (34.6% vs. 22.9%, p = 0.06). In multivariate regression, only d-dimer was associated with PE (HR 1.72, 95% CI 1.13–2.62; p = 0.01). The relation between d-dimer concentrations and PE incidence was linear, without inflection point. Only two subjects had a baseline d-dimer < 500 ng/mL.ConclusionsPE occurs in a sizable proportion of hospitalized COVID-19 patients. The implications of bleeding events and the role of d-dimer in this population need to be clarified.Graphic abstract

Cardiomyopathies, including hypertrophic (HCM), dilated (DCM), and arrhythmogenic (ACM) forms, represent a challenge in cardiovascular medicine, in particular regarding exercise participation and cardiac rehabilitation. Traditionally, physical activity was restricted in these patients due to concerns over arrhythmic risk and sudden cardiac death. However, current evidence suggests that individualized exercise programs, under clinical supervision, can enhance functional capacity, improve quality of life, and sometimes prognosis in selected patients. Contemporary European and North American guidelines suggest that participation in competitive sports may be reasonable for athletes with genetic cardiomyopathies, provided that individual risk is regularly and systematically reassessed. The aim of this review is to synthetize current evidence on exercise training, sports participation and rehabilitation in the three major cardiomyopathies-hypertrophic, dilated, and arrhythmogenic-which have informed the latest international guideline recommendations. Particular attention is given to the essential role of shared decision-making, highlighting the importance of a personalized approach based on the specific type of cardiomyopathy, arrhythmic risk stratification, and individual patient factors. In addition, the review addresses two emerging clinical scenarios: sports participation in patients with implantable cardioverter-defibrillators and current recommendations for genotype-positive/phenotype-negative individuals at risk of cardiomyopathy.

Background: Isometric exercise effectively reduces blood pressure (BP) but its effects on myocardial work have been poorly studied. For the present study, we compared acute changes in myocardial work during two different isometric exercises, namely, bilateral knee extension and handgrip, in patients with hypertension and underlying ischemic heart disease (IHD). Methods: This was a randomized pilot study in which 48 stable, trained patients with hypertension and IHD were enrolled. Patients were randomly assigned to perform a single session of bilateral knee extension (IKE) or handgrip (IHG) exercises or no exercise (control), with a 1:1:1 ratio. Both exercises were performed at 30% of maximal voluntary contraction and lasted three minutes. Echocardiography and BP measurements were performed at rest, during the exercise, and after ten minutes of recovery. Results: Both exercises were tolerated well, and no side effects occurred. During the exercise, the systolic BP increased significantly in the IKE group compared with the IHG and control groups (ANOVA p < 0.001). Left ventricular global longitudinal strain decreased significantly in the IKE group (−21%) compared with the IHG and control groups (ANOVA p 0.002). The global work index increased significantly in the IKE group (+28%) compared with the IHG and control groups (ANOVA p 0.034). Global constructive work and wasted work increased significantly in the IKE group compared with the IHG and control groups (ANOVA p 0.009 and <0.001, respectively). Global work efficiency decreased significantly in the IKE group (−8%) while remaining unchanged in the IHG and control groups (ANOVA p 0.002). Conclusions: Myocardial work efficiency was impaired during isometric bilateral knee extension but not during handgrip, which evoked a limited hemodynamic response.

Background: Isometric handgrip (IHG) exercise reduces blood pressure (BP) in both normotensive and hypertensive individuals. However, there are few studies specifically addressing its effects in hypertensive patients with ischemic heart disease (IHD). This research aimed to compare acute hemodynamic responses and post-exercise hypotension to single bouts of IHG handgrip performed at two different intensities in patients with IHD. Methods: Fifty-four sedentary patients were enrolled and randomly assigned to one of three groups: (1) high-intensity isometric handgrip performed at 70% of maximal voluntary contraction (MVC) (IHG-70%); (2) low-intensity isometric handgrip performed at 30% of MVC (IHG-30%); (3) control group (no exercise). Heart rate and BP were measured, and transthoracic echocardiography was performed at baseline, during exercise (lasting 3 min), and after 15 min post-exercise. BP was also measured at 30, 45, and 60 min of recovery. Results: No significant changes in systolic BP occurred during the exercise phase between the three study groups. Systolic BP decreased significantly in IHG-70% compared to the control at 30 (−7.7 ± 1.9; p = 0.035) and 45 min (−8.1 ± 2.3; p = 0.021) post-exercise, while there were no significant differences between IHG-70% and IHG-30% at different time-points. There were no significant changes in diastolic BP between the two active groups and between IHG-70 and IHG-30 versus control at different time-points (repeated-measures ANOVA p = 0.257). Global work efficiency was unchanged in IHG-70% (−4%) and IHG-30% (+1%) compared to control (ANOVA p = 0.154). Conclusions: High-intensity and low-intensity isometric handgrip exercises did not cause hemodynamic impairment in IHD. High-intensity exercise was more effective than low-intensity in reducing post-exercise systolic BP.

Background: Short sessions of isometric exercise have been shown to reduce blood pressure (BP) in normotensive and hypertensive subjects. However, there are few data in hypertensive patients with underlying ischemic heart disease (IHD). In the present study, we compared post-exercise hypotension (PEH) induced by isometric versus combined, aerobic plus dynamic resistance exercise in IHD patients. Methods: Twenty-five stable patients with established IHD and with treated hypertension were enrolled. The study had a cross-over design. All patients performed in a random order and on different days: (1) isometric exercise session (IES) consisting of bilateral knee extension, performed at 20% of maximal voluntary contraction and lasting 20 min; (2) combined exercise session (CES) including moderate-intensity continuous exercise at and dynamic resistance exercise performed at 60% of one repetition maximum, and lasting 60 min and (3) control session (no exercise). BP was measured at rest, immediately after the training and then every 15 min up to 90 min. Results: The repeated measures ANOVA analysis showed that systolic BP significantly decreased after the CES session compared to the control (F = 6.2; p 0.001) and IES (F = 4.4; p 0.004). Systolic BP significantly decreased after IES compared to the control (F = 3.6; p 0.036). Diastolic BP did not show significant changes after CES and IES compared to the control (CES vs. control: F = 2.2; p 0.142; IES vs. control (F = 2.5; p 0.062). There were no significant differences in diastolic BP changes between CES and IES (CES vs. IES: F = 1.8; p 0.156). Conclusions: We observed that CES was more effective than IES in reducing systolic BP; IES was as effective as CES in inducing diastolic PEH in hypertensive patients with underlying IHD.

Statins are extensively used to treat dyslipidemia, but, because of their low tolerability profile, they are discontinued in a significant proportion of patients. Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated. A single-blind, single-center, randomized, prospective, and parallel group trial comparing a combination of nutraceuticals (red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid Plus, and ezetimibe for 3 months in terms of efficacy and tolerability. Patients who did not achieve their therapeutic target (low-density lipoprotein cholesterol <100 mg/dl) could add the alternative treatment on top of randomized treatment for another 12 months: 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n = 50, nutraceutical n = 50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, and creatine kinase) were assessed after 3 and 12 months. After 3 months, 14 patients in the nutraceutical group achieved their therapeutic target, whereas none of the patients in the ezetimibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined therapy group (n = 86) and 14 (100%) of the nutraceutical group reached the therapeutic goal. No patients experienced important undesirable effects. In conclusion, nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease. Further studies are needed to assess long-term effects of nutraceuticals on mortality.

Heart failure (HF) is a multifactorial and pathophysiological complex syndrome, involving not only neurohormonal activation but also oxidative stress, chronic low‐grade inflammation, and metabolic derangements. Central to the cellular defence against oxidative damage is nuclear factor erythroid 2‐related factor 2 (Nrf2), a transcription factor that orchestrates antioxidant and cytoprotective responses. Preclinical in vitro and in vivo studies reveal that Nrf2 signalling is consistently impaired in HF, contributing to the progression of myocardial dysfunction. The loss of Nrf2 activity intersects a complex network of pathological processes involving neurohormonal activation, ischaemia–reperfusion injury, and sustained inflammation, exacerbating cardiac functional decline. Nrf2 deficiency diminishes resilience to clinical conditions such as hypertension, diabetic cardiomyopathy, and cancer therapy‐related cardiotoxicity, favouring the transition from initial cardiac dysfunction to overt HF. Initial evidence supports the therapeutic potential of Nrf2 modulation. Lifestyle interventions such as exercise training, various natural compounds, and established cardiovascular agents (e.g. sodium‐glucose cotransporter‐2 inhibitors) have been shown to restore Nrf2 activity. This review analyses the emerging role of Nrf2 as both a key player in HF pathogenesis and a promising therapeutic target, highlighting available evidence across HF phenotypes and addressing the controversies surrounding its pharmacological modulation. Nrf2 signalling is impaired in heart failure, contributing to oxidative stress, mitochondrial dysfunction, and ferroptosis, which drive neurohormonal activation, inflammation, and ischaemia‐reperfusion injury. This loss of Nrf2 activity exacerbates hypertension, diabetic cardiomyopathy, and cardiotoxicity, accelerating progression to overt heart failure. Therapeutic strategies that stimulate Nrf2, including exercise training, natural compounds, and guideline‐directed medical therapies (e.g. SGLT2 inhibitors), show promise in restoring redox balance, mitochondrial function, and myocardial resilience.