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[Figure: see text].

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

BackgroundConsiderable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.Methods and resultsImmunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared with non-β-AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIδC transgenic mice were treated with the β1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n≥29; P

BackgroundConsiderable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.Methods and resultsImmunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared with non-β-AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKIIδC transgenic mice were treated with the β1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n≥29; P

Aims: Takotsubo syndrome (TTS) is an acute heart failure (AHF) syndrome mimicking the symptoms of acute myocardial infarction. Impaired outcome has been shown, making risk stratification and novel therapeutic concepts a necessity. We hypothesized insulin resistance with elevated plasma glucose and potentially myocardial glucose deprivation to contribute to the pathogenesis of TTS and investigated the therapeutic benefit of insulin in vivo. Methods and results: First, we retrospectively analysed patient data of n = 265 TTS cases (85.7% female, mean age 71.1 ± 14.1 years) with documented initial plasma glucose from the Department of Cardiology of the University Hospital Heidelberg in Germany (May 2011 to May 2021). Median split of the study population according to glucose levels (≤123 mg/dL vs. >123 mg/dL) yielded significantly elevated mean heart rate (80.75 ± 18.96 vs. 90.01 ± 22.19 b.p.m., P < 0.001), left ventricular end‐diastolic pressure (LVEDP, 18.51 ± 8.35 vs. 23.09 ± 7.97 mmHg, P < 0.001), C‐reactive protein (26.14 ± 43.30 vs. 46.4 ± 68.6 mg/L, P = 0.006), leukocyte count (10.12 ± 4.29 vs. 15.05 ± 9.83/nL, P < 0.001), peak high‐sensitive Troponin T (hs‐TnT, 515.44 ± 672.15 vs. 711.40 ± 736.37 pg/mL, P = 0.005), reduced left ventricular ejection fraction (EF, 34.92 ± 8.94 vs. 31.35 ± 8.06%, P < 0.001), and elevated intrahospital mortality (2.3% vs. 12.1%, P = 0.002) in the high‐glucose group (Student's t‐test, Mann–Whitney U test, or chi‐squared test). Linear regression indicated a significant association of glucose with HR (P < 0.001), LVEDP (P = 0.014), hs‐TnT kinetics from admission to the next day (P < 0.001), hs‐TnT the day after admission (P < 0.001), as well as peak hsTnT (P < 0.001). Logistic regression revealed significant association of glucose with a composite intrahospital outcome including catecholamine use, respiratory support, and resuscitation [OR 1.010 (1.004–1.015), P = 0.001]. To further investigate the potential role of glucose in TTS pathophysiology experimentally, we utilized an in vivo murine model of epinephrine (EPI)‐driven reversible AHF. For this, male mice underwent therapeutic injection of insulin (INS, 1 IU/kg) or/and glucose (GLU, 0.5 g/kg) after EPI (2.5 mg/kg), both of which markedly improved mean EF (EPI 34.3% vs. EPI + INS + GLU 43.7%, P = 0.025) and significantly blunted mean hs‐TnT (EPI 14 393 pg/mL vs. EPI + INS 6864 pg/mL at 24 h, P = 0.039). Particularly, insulin additionally ameliorated myocardial pro‐inflammatory gene expression, suggesting an anti‐inflammatory effect of acute insulin therapy. Conclusions: Elevated initial plasma glucose was associated with adverse outcome‐relevant parameters in TTS and may present a surrogate parameter of heightened catecholaminergic drive. In mice, insulin‐ and glucose injection both improved EPI‐induced AHF and myocardial damage, indicating insulin resistance rather than detrimental effects of hyperglycaemia itself as the underlying cause. Future studies will investigate the role of HbA1c as a risk stratifier and of insulin‐based therapy in TTS. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH‐LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH‐LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH‐LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre‐clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early‐stage development of candidate therapies for PH‐LHF. [ABSTRACT FROM AUTHOR]

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure., Author(s): Lorenz H Lehmann [1, 2, 3]; Zegeye H Jebessa [1, 2]; Michael M Kreusser [1, 2, 3]; Axel Horsch [1, 2]; Tao He [1, 2]; Mariya Kronlage [1, 2, [...]