The giant sarcomere protein titin is a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous size, complexity, and malleability of the titin molecule, titin properties are also vulnerable to dysregulation, as observed in various cardiac disorders. This review provides an overview of how cardiac titin properties can be changed at a molecular level, including the role isoform diversity and post-translational modifications (acetylation, oxidation, and phosphorylation) play in regulating myocardial stiffness and contractility. We then consider how this regulation becomes unbalanced in heart disease, with an emphasis on changes in titin stiffness and protein quality control. In this context, new insights into the key pathomechanisms of human cardiomyopathy due to a truncation in the titin gene (TTN) are discussed. Along the way, we touch on the potential for titin to be therapeutically targeted to treat acquired or inherited cardiac conditions, such as HFpEF or TTN-truncation cardiomyopathy.

Stable expression of truncated titin proteins and titin haploinsufficiency characterizeTTNcardiomyopathy and represent targets for therapy.

Background: The global rise of obesity and its association with cardiovascular risk factors (CVRF) have highlighted its connection to chronic heart failure (CHF). Paradoxically, obese CHF patients often experience better outcomes, a phenomenon known as the ‘obesity paradox’. This study evaluated the ‘obesity paradox’ within a large cohort in Germany and explored how varying degrees of obesity affect HF outcome. Methods: Anonymized health claims data from the largest German insurer (AOK) for the years 2014–2015 were utilized to analyze 88,247 patients hospitalized for myocardial infarction. This analysis encompassed baseline characteristics, comorbidities, interventions, complications, and long-term outcomes, including overall survival, freedom from CHF, and CHF-related rehospitalization. Patients were categorized based on body mass index. Results: Obese patients encompassed 21.3% of our cohort (median age 68.69 years); they exhibited a higher prevalence of CVRF (p < 0.001) and comorbidities than non-obese patients (median age 70.69 years). Short-term outcomes revealed lower complication rates and mortality (p < 0.001) in obese compared to non-obese patients. Kaplan–Meier estimations for long-term analysis illustrated increased incidences of CHF and rehospitalization rates among the obese, yet with lower overall mortality. Multivariable Cox regression analysis indicated that obese individuals faced a higher risk of developing CHF and being rehospitalized due to CHF but demonstrated better overall survival for those classified as having low-level obesity (p < 0.001). Conclusions: This study underscores favorable short-term outcomes among obese individuals. The ‘obesity paradox’ was confirmed, with more frequent CHF cases and rehospitalizations in the long term, alongside better overall survival for certain degrees of obesity.

Background/Objectives: Heart failure (HF) with preserved ejection fraction (HFpEF) poses a diagnostic challenge, as it lacks a definitive hallmark beyond preserved left ventricular (LV)EF. This retrospective study aims to analyze the demographic and clinical characteristics of HFpEF patients within a real-world hospital cohort, with a particular focus on obesity and associated comorbidities. Methods: A total of 4019 patients who underwent echocardiography in 2020–2021 at a university hospital were screened for HFpEF. After stringent manual verification, 219 patients fulfilled the European Society of Cardiology (ESC) criteria for HFpEF. Demographic, clinical, and comorbidity data were analyzed and stratified by body mass index (BMI) categories and sex distribution. Results: Among the 219 HFpEF patients, 71.3% were classified as pre-obese or obese. Hypertension (93.6%), atrial fibrillation (74.3%), and obesity were common in the cohort, while sex distribution was balanced. Edema was more prevalent among obese patients, though HFpEF severity, as reflected by New York Heart Association (NYHA) classification and natriuretic peptide levels, did not differ significantly across BMI groups. Medical treatment patterns varied with BMI, with obese patients more frequently receiving diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and angiotensin receptor blockers (ARB). No significant differences were observed between male and female patients in terms of HFpEF severity markers. Conclusions: Obesity is a predominant feature in HFpEF and is associated with a high burden of comorbidities. However, sex does not appear to influence HFpEF severity in this cohort. These findings underscore the need for targeted therapeutic strategies in obese HFpEF patients.

Aims: Chronic left ventricular heart failure (CLHF) represents a significant public health challenge globally, marked by high morbidity and mortality. CLHF is a leading cause of hospitalization, placing considerable strain on healthcare systems. This study aims to analyze in-hospital outcomes for CLHF patients in Germany over nine years (2014–2022), examining trends in morbidity, mortality, healthcare costs, and complications. Methods and results: Data were sourced from the Federal Statistical Office (DESTATIS), covering 2,616,462 inpatient CLHF cases (ICD-10-GM I50.11-I50.14) in Germany from 2014 to 2022. CLHF hospitalizations increased from 288,019 in 2014 to 311,782 in 2019, then declined in 2020 but started again to rise from 2021 to 2022. The proportion of patients with advanced CLHF (NYHA stage IV) decreased slightly from 54.09% in 2014 to 50.36% in 2020 (p < 0.0001). Notable comorbidity trends included rising rates of atrial fibrillation and chronic kidney disease. Complications such as cardiogenic shock and acute kidney injury increased over time (both p < 0.0001). Despite a decrease in mortality rates from 2014 to 2019 (p < 0.0001), in-hospital mortality rose to 8.84% in 2022 (p < 0.0001). Median revenue volume and hospitalization duration showed a pre-pandemic increase but declined in 2020. Conclusion: The study highlights a complex interplay of factors affecting CLHF management in Germany, as a representative example for a high-income country. While advancements in treatment have improved some outcomes, the COVID-19 pandemic significantly impacted hospitalization trends and in-hospital mortality. The findings underscore the need for ongoing improvements in CLHF management and resilient healthcare strategies to address future challenges. Graphical Overview of CLHF hospitalizations in Germany (2014–2022). Key findings include an 8.3% increase in hospitalizations from 2014 to 2019, followed by a temporary drop during the COVID-19 pandemic. Despite this, CLHF-related mortality peaked in 2022, highlighting the ongoing burden of severe cases. Rising costs and complications, alongside increasing comorbidities, emphasize the need for strengthened CLHF management and a resilient healthcare system. AF: atrial fibrillation, CLHF: Chronic left ventricular heart failure; CKD: chronic kidney disease, NYHA: New York Heart Association, Tsd: thousands.