In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m² to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. NCT04788511 and NCT04916470

Given the tremendous progress in interventional cardiology over the last decade, a growing number of older patients, who have more comorbidities and more complex coronary artery disease, are being considered for technically challenging and high-risk percutaneous coronary interventions (PCI). The success of performing such complex PCI is increasingly dependent on the availability and improvement of mechanical circulatory support (MCS) devices, which aim to provide hemodynamic support and left ventricular (LV) unloading to enable safe and successful coronary revascularization. MCS as an adjunct to high-risk PCI may, therefore, be an important component for improvement in clinical outcomes. MCS devices in this setting can be used for two main clinical conditions: patients who present with cardiogenic shock complicating acute myocardial infarction (AMI) and those undergoing technically complex and high-risk PCI without having overt cardiogenic shock. The current article reviews the advancement in the use of various devices in both AMI complicated by cardiogenic shock and complex high-risk PCI, highlights the available hemodynamic and clinical data associated with the use of MCS devices, and presents suggestive management strategies focusing on appropriate patient selection and optimal timing and support to potentially increase the clinical benefit from utilizing these devices during PCI in this high-risk group of patients.

Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes.

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow‐up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all‐cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV‐related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.

Vaccination with mRNA vaccines against coronavirus disease 2019 (COVID-19) has been associated with a risk of developing myocarditis and pericarditis, with an estimated standardized incidence ratio of myocarditis being 5.34 (95% CI, 4.48 to 6.40) as compared to the expected incidence based on historical data according to a large national study in Israel. Most cases of myocarditis in vaccine recipients occur in young males, particularly following the second dose, and the presentation is usually mild. Recently, the third (booster) dose has been shown to reduce confirmed infections and severe illness even against common variants of the virus. In Israel, over 4.4 million citizens (more than 45% of the population) have been vaccinated with the third dose of Pfizer-BioNTech vaccine BNT162b2. Herein, we report the first case of a histologically confirmed severe myocarditis following the third dose of BNT162b2 COVID-19 vaccine.