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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., (© 2024 European Society of Cardiology.)

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m 2 , COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF., Competing Interests: Conflict of interest: T.T. received speaker fees and/or holds advisory board seats from Böhringer Ingelheim, Sanofi-Genzyme, Takeda, Novo-Nordisk, Amicus Therapeutics, KSILINK not related to the present article. T.T. filed and licensed patents about non-coding RNAs, and he is founder and shareholder of Cardior Pharmaceuticals (not related to this article). P.R. received travel support, speaker fees, honoraria from Novartis, Vifor, Böhringer, and Daiichi Sankyo (not related to this article). L.W.V.L. received Consultancy fees to UMCU from Abbott, Medtronic, Vifor, Novartis (not related to the present article). W.L. received honoraria from Bristol-Myers Squibb (MyoKardia), Merck, Sharp& Dohme (MSD, USA), and Servier, as well as a research grant from MSD (not related to the present article). J.B. received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, not related to the present article; and research support for the department from Zoll, CVRx, Abiomed, not related to the present article. C.G.T. reports Receipt of honoraria or consultation fees: VivaLyfe, Univers Formazione, Solaris, Myocardial Solutions; and is listed as an inventor of 2 patents related to HF. All other authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1 -/- ) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct., (© 2023. Springer Nature Limited.)

Background: Several blood biomarkers have been identified as predictors for poor outcome after ischemic stroke. However, recent studies mainly focused on single or experimental biomarkers and considered rather short follow-up intervals limiting their value for daily clinical practice. We, therefore, aimed to compare various clinical routine blood biomarkers for their predictive value on post-stroke mortality over a 5-year follow-up period., Patients and Methods: This data analysis of a prospective single-center study included all consecutive ischemic stroke patients admitted to the stroke unit of our university hospital over a 1-year period. Various blood biomarkers of inflammation, heart failure, metabolic disorders, and coagulation were analyzed from standardized routine blood samples collected within 24 h of hospital admission. All patients underwent a thorough diagnostic workup and were followed for 5 years post-stroke., Results: Of 405 patients (mean age: 70.3 years), 72 deceased (17.8%) during the follow-up period. While various routine blood biomarkers were associated with post-stroke mortality in univariable analyses, only NT-proBNP remained an independent predictor (adjusted odds ratio 5.1; 95% CI 2.0-13.1; p  < 0.001) for death after stroke. NT-proBNP levels ⩾794 pg/mL ( n  = 169, 42%) had a sensitivity of 90% for post-stroke mortality with a negative predictive value of 97% and was additionally associated with cardioembolic stroke and heart failure (each p  ⩽ 0.05)., Conclusion: NT-proBNP represents the most relevant routine blood-based biomarker for the prediction of long-term mortality after ischemic stroke. Increased NT-proBNP levels indicate a vulnerable subgroup of stroke patients in which early and thorough cardiovascular assessment and consistent follow-ups could improve outcome after stroke.

Survival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to <50%), or myocardial strain decreases (>15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients., (© 2022. The Author(s).)

Aims: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations., Methods and Results: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001)., Conclusions: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Oxidative stress contributes to detrimental functional decline of the myocardium, leading to the impairment of the antioxidative defense, dysregulation of redox signaling, and protein damage. In order to precisely dissect the changes of the myocardial redox state correlated with oxidative stress and heart failure, we subjected left-ventricular tissue specimens collected from control or failing human hearts to comprehensive mass spectrometry-based redox and quantitative proteomics, as well as glutathione status analyses. As a result, we report that failing hearts have lower glutathione to glutathione disulfide ratios and increased oxidation of a number of different proteins, including constituents of the contractile machinery as well as glycolytic enzymes. Furthermore, quantitative proteomics of failing hearts revealed a higher abundance of proteins responsible for extracellular matrix remodeling and reduced abundance of several ion transporters, corroborating contractile impairment. Similar effects were recapitulated by an in vitro cell culture model under a controlled oxygen atmosphere. Together, this study provides to our knowledge the most comprehensive report integrating analyses of protein abundance and global and peptide-level redox state in end-stage failing human hearts as well as oxygen-dependent redox and global proteome profiles of cultured human cardiomyocytes.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD + ). Elevating NAD + by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD + precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD + precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines ( n = 31, aged 2 months) underwent a sham procedure ( n = 10) or loose aortic banding ( n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration-approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) ( P < 0.0001) and left atrium size ( P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA ( P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Rationale: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear., Objective: We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF., Methods and Results: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF., Conclusions: Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF., (© 2018 American Heart Association, Inc.)

Aims: Insulin-dependent positive inotropic effects (PIE) are partially Ca(2+) independent. This mechanism is potentially glucose dependent. In contrast to most animal species, human myocardium expresses high levels of sodium-glucose-transporter-1 (SGLT-1) mRNA besides the common glucose-transporters-1 and -4 (GLUT1, GLUT4)., Methods and Results: We used ventricular myocardium from 61 end-stage failing human hearts (ischaemic cardiomyopathy, ICM and dilated cardiomyopathy, DCM) and 13 non-failing donor hearts. The effect of insulin on isometric twitch force was examined with or without blocking of PI3-kinase, GLUT4-translocation, or SGLT-1. Substrate-dependent (glucose vs. pyruvate vs. palmitoyl-carnitine) effects were tested in atrial myocardium. mRNA expression of glucose transporters was analysed. Insulin increased developed force by 122 + or - 7.4, 121.7 + or - 2.5, and 134.1 + or - 5.7% in non-failing, DCM, and ICM (P < 0.05 vs. DCM), respectively. Positive inotropic effect was partially blunted by inhibition of PI-3-kinase, GLUT4, or SGLT1. Combined inhibition of PI3-kinase and glucose-transport completely abolished PIE. Positive inotropic effect was significantly stronger in glucose-containing solution compared with pyruvate or palmitoyl-carnitine containing. mRNA expression showed only a tendency towards elevated GLUT4-expression in ICM., Conclusions: Positive inotropic effect of insulin is pronounced in ICM, but underlying mechanisms are unaltered. The Ca(2+)-independent PIE of insulin is mediated via glucose-transporters. Together with the Ca(2+)-dependent PI-3-kinase mediated pathway, it is responsible for the entire PIE. Substrate-dependency affirms a glucose-dependent part of the PIE.

Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD‐induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin–angiotensin–aldosterone system inhibitors, beta‐blockers, diuretics and sodium–glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end‐diastolic/end‐systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre‐clinical evaluation. [ABSTRACT FROM AUTHOR]

Yet, there was little to no notable communication between cardiology and immunology up until very recently, despite longstanding recognition of inflammatory cardiac conditions, including rheumatic heart disease and infectious myocarditis. Immunology has made it into the hearts of cardiologists. Cardiology and immunology/rheumatology are historically distinct fields. [Extracted from the article]

Background Cardiac tumours are rare but affected patients may present with symptoms mimicking other cardiac diseases. The most frequent symptoms include heart failure, arrhythmias, or embolic phenomena. Case summary A 39-year-old man with a history of extranodal NK/T-cell lymphoma of the nasal type (ENKTL-NT) in clinical remission presented at our department with incessant ventricular tachycardia. The arrhythmia could only be controlled with a combination of intravenously administered beta-blockers, ajmaline, and amiodarone. Diagnostic workup excluded ischaemia, but imaging revealed a tumour located in the apex of the left ventricle. Endomyocardial biopsy confirmed the diagnosis of cardiac relapse of ENKTL-NT. Upon chemotherapy no further arrhythmias developed. Discussion Many malignancies can metastasize into the heart. Multimodal imaging including echocardiography, cardiac magnetic resonance imaging, and a positron-emission tomography computed tomography paved the way to the diagnosis that was finally established by endomyocardial biopsy. In the present case, a cardiac metastasis from an ENKTL-NT presented with incessant ventricular tachycardia. [ABSTRACT FROM AUTHOR]

We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension. [ABSTRACT FROM AUTHOR]

Aims: Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family.Methods and results: A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'.Conclusion: The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation. [ABSTRACT FROM AUTHOR]

Some oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous in vitro study revealed that saxagliptin impairs the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca2+-ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function. However, the link between saxagliptin and its target proteins (CaMKII and PKC) remains to be explored. Since DPP8 and DPP9 (but not DPP4) are expressed by cardiomyocytes and saxagliptin is internalized by cardiomyocytes, we investigated whether DPP8/9 contribute to saxagliptin-mediated inhibition of CaMKII and PKC activity. Structural analysis revealed that the DPP4-saxagliptin interaction motif (S630, Y547) for the cyanopyrrolidine group is conserved in DPP8 (S755, Y669) and DPP9 (S730, Y644). Conversely, F357 that facilitates binding of the anchor lock domain of sitagliptin in the S2 extensive subsite of DPP4 is not conserved in DPP8/9. In parallel, unlike saxagliptin, sitagliptin did not affect phosphorylation of CaMKII/PLB or activity of PKC in HL-1 cardiomyocytes. These findings were recapitulated by pharmacological inhibition (TC-E-5007, a DPP8/9 antagonist) and knock-down of DPP9 (but not DPP8). In primary mouse ventricular cardiomyocytes, saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration (APD). These results suggest that saxagliptin-DPP9 interaction impairs the CaMKII-PLB and PKC signaling in cardiomyocytes. We reveal a novel and potential role of DPP9 in cardiac signaling. The interaction of saxagliptin with DPP9 may represent an underlying mechanism for the link between saxagliptin and HF. Elucidation of saxagliptin-DPP9 interaction and downstream events may foster a better understanding of the role of gliptins as modulators of cardiac signaling. [ABSTRACT FROM AUTHOR]

Aims Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling. Methods and results Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. Conclusion Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by growing incidence and poor outcomes. A large majority of HFpEF patients are cared by non‐cardiologists. The availability of sodium–glucose cotransporter 2 inhibitors (SGLT2i) as recommended therapy raises the importance of prompt and accurate identification and treatment of HFpEF across diverse healthcare settings. We evaluated HFpEF management across specialties through a survey targeting cardiologists, HF specialists, and non‐cardiologists.An independent web‐based survey was distributed globally between May and July 2023. We performed a post‐hoc analysis, comparing cardiologists, HF specialists, and non‐cardiologists. A total of 1460 physicians (61% male, median age 41[34–49]) from 95 countries completed the survey; 20% were HF specialists, 65% cardiologists, and 15% non‐cardiologists. Compared with HF specialists, non‐cardiologists and cardiologists were less likely to use natriuretic peptides (p = 0.003) and HFpEF scores (p = 0.004) for diagnosis, and were also less likely to have access to or consider specific echocardiographic parameters (p < 0.001) for identifying HFpEF. Diastolic stress tests were used in less than 30% of the cases, regardless of the specialty (p = 1.12). Multidrug treatment strategies were similar across different specialties. While SGLT2i and diuretics were the preferred drugs, angiotensin receptor blockers and angiotensin receptor–neprilysin inhibitors were the least frequently prescribed in all three groups. However, when constrained to choose one drug, the proportion of physicians favoring SGLT2i varied significantly among specialties (66% HF specialists, 52% cardiologists, 51% non‐cardiologists). Additionally, 10% of non‐cardiologists and 8% of cardiologists considered beta blocker the drug of choice for HFpEF.Significant differences among specialty groups were observed in HFpEF management, particularly in the diagnostic work‐up. Our results highlight a substantial risk of underdiagnosis and undertreatment of HFpEF patients, especially among non‐HF specialists. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 (SGLT2) were originally developed as kidney-targeting anti-diabetic drugs. However, due to their beneficial cardiac off-target effects (as SGLT2 is not expressed in the heart), these antagonists currently receive intense clinical interest in the context of heart failure (HF) in patients with or without diabetes mellitus (DM). Since the mechanisms by which these beneficial effects are mediated are still unclear yet, inflammation that is present in DM and HF has been proposed as a potential pharmacological intervention strategy. Therefore, we tested the hypothesis that the SGLT2 inhibitor, empagliflozin, displays anti-inflammatory potential along with its glucose-lowering property. Lipopolysaccharide (LPS) was used to induce inflammation in vitro and in vivo. In cardiomyocytes and macrophages empagliflozin attenuated LPS-induced TNFα and iNOS expression. Analysis of intracellular signalling pathways suggested that empagliflozin activates AMP kinase (AMPK) in both cell types with or without LPS-treatment. Moreover, the SGLT2 inhibitor increased the expression of anti-inflammatory M2 marker proteins in LPS-treated macrophages. Additionally, empagliflozin-mediated AMPK activation prevented LPS-induced ATP/ADP depletion. In vivo administration of LPS in mice impaired cardiac contractility and aortic endothelial relaxation in response to acetylcholine, whereby co-administration of empagliflozin preserved cardiovascular function. These findings were accompanied by improved cardiac AMPK phosphorylation and ATP/ADP, reduced cardiac iNOS, plasma TNFα and creatine kinase MB levels. Our data identify a novel cardio protective mechanism of SGLT2 inhibitor, empagliflozin, suggesting that AMPK activation-mediated energy repletion and reduced inflammation contribute to the observed cardiovascular benefits of the drug in HF. [ABSTRACT FROM AUTHOR]