Atrial fibrillation

Nature Reviews Disease Primers, Год журнала: 2022, Номер 8(1)

Опубликована: Апрель 7, 2022

Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand pathophysiology of condition and develop improved treatments. Identifying underlying causative mechanisms AF in individual patients difficult efficacy current therapies suboptimal. Consequently, incidence steadily rising there a pressing need for novel therapies. Research has revealed that defects specific molecular pathways underlie pathogenesis, resulting electrical conduction disorders drive AF. The severity this so-called electropathology correlates with stage disease progression determines response treatment. Therefore, unravelling expected fuel development innovative personalized diagnostic tools mechanism-based Moreover, co-creation studies implement prerequisite successful management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical nutraceutical therapy, substrate-based ablative neuromodulation, are available maintain sinus rhythm might offer holistic strategy treat increasing prevalence as populations age. This Primer provides an overview epidemiology, AF, approaches treatments, highlights important directions improve understanding management patients.

Язык: Английский

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Evolving concepts in NAD+ metabolism

Cell Metabolism, Год журнала: 2021, Номер 33(6), С. 1076 - 1087

Опубликована: Апрель 29, 2021

Язык: Английский

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Hallmarks of cardiovascular ageing

Nature Reviews Cardiology, Год журнала: 2023, Номер 20(11), С. 754 - 777

Опубликована: Май 16, 2023

Язык: Английский

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Therapeutic targets for cardiac fibrosis: from old school to next-gen

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(5)

Опубликована: Фев. 28, 2022

Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite profound contributions myocardial fibrosis to dysfunction and heart failure, there currently exist limited clinical interventions that effectively target fibroblast its role in tissue deposition. Exploration novel strategies designed mitigate or reverse myofibroblast activation will likely yield powerful therapeutic approaches for treatment multiple heart, including failure preserved reduced ejection fraction, acute coronary syndrome, cardiovascular disease linked type 2 diabetes. In this Review, we provide an overview classical regulators highlight emerging, next-generation epigenetic regulatory targets have potential revolutionize expanding patient population.

Язык: Английский

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Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models

Circulation Research, Год журнала: 2022, Номер 130(12), С. 1906 - 1925

Опубликована: Июнь 9, 2022

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest challenges facing cardiovascular medicine today. Despite being most common form heart worldwide, there has been limited success in developing therapeutics for this syndrome. This is largely due to our incomplete understanding biology driving its systemic pathophysiology and heterogeneity clinical phenotypes, which are increasingly recognized as distinct HFpEF phenogroups. Development efficacious fundamentally relies on robust preclinical models that not only faithfully recapitulate key features syndrome but also enable rigorous investigation putative mechanisms disease context clinically relevant phenotypes. In review, we propose a research strategy conceptually grounded model diversification aims better align evolving HFpEF. Although often viewed major obstacle research, challenge notion argue embracing it may be demystifying pathobiology. Here, first provide an overarching guideline through stepwise approach comprehensive cardiac extra-cardiac phenotyping. We then present overview currently available models, focused 3 leading phenogroups, primarily based aging, cardiometabolic stress, chronic hypertension. discuss how well these reflect their phenogroup highlight some more recent mechanistic insights they providing into complex underlying

Язык: Английский

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Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity

Circulation, Год журнала: 2022, Номер 145(25), С. 1853 - 1866

Опубликована: Июнь 21, 2022

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed lifelong study to assess health lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced receptor (IGF1R) signaling. Male mice human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, treadmill coupled indirect calorimetry. In vitro assays included histology, mitochondrial respiration, ATP synthesis, autophagic flux, targeted metabolome profiling, immunoblots downstream targets explanted failing nonfailing hearts, as well. Results: Young increased exhibited superior function that progressively declined an accelerated fashion compared wild-type animals, resulting heart failure lifespan. contrast, low inferior early life, but performance during aging, maximum lifespan, Mechanistically, late-life detrimental effects activation correlated suppressed flux impaired oxidative phosphorylation heart. Low activity consistently improved myocardial bioenergetics autophagy-dependent manner. humans, not those compensated hypertrophy, displayed exaggerated expression activity. Conclusions: Our findings indicate relationship between linear, rather biphasic. Hence, pharmacological inhibitors pathway, albeit unsuitable for young individuals, might be worth considering older adults.

Язык: Английский

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Deranged Myocardial Fatty Acid Metabolism in Heart Failure

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(2), С. 996 - 996

Опубликована: Янв. 17, 2022

The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial acid metabolism, such as energy production using fuel, for which it is known that coordinated control of uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important efficient adenosine triphosphate (ATP) without unwanted side effects. taken up by cardiomyocytes not only used substrates but also the synthesis triglycerides replacement reaction chains in cell membrane phospholipids. Alterations metabolism affect structure function heart. Recently, breakthrough studies have focused on key transcription factors signaling systems modify their functions. In this article, we reviewed latest research role pathogenesis failure provide an outlook future challenges.

Язык: Английский

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Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction

Circulation Research, Год журнала: 2024, Номер 134(4), С. 371 - 389

Опубликована: Янв. 24, 2024

Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It highly heterogeneous multiple comorbidities, including obesity and diabetes, making human studies difficult.

Язык: Английский

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Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 26, 2024

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role HFpEF their shared mechanisms inflammation and metabolism. Here, show inhibiting HDAC6 TYA-018 effectively reverses established heart its associated symptoms male mouse models. Additionally, mice lacking Hdac6 gene, progression is delayed they are resistant TYA-018's effects. The comparable sodium-glucose cotransporter 2 (SGLT2) inhibitor, combination shows enhanced Mechanistically, restores gene expression related hypertrophy, fibrosis, mitochondrial energy production tissues. Furthermore, also inhibits activation human cardiac fibroblasts enhances respiratory capacity cardiomyocytes. In this work, findings impacts on pathophysiology promising target for treatment.

Язык: Английский

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Titin (TTN): from molecule to modifications, mechanics, and medical significance

Cardiovascular Research, Год журнала: 2021, Номер 118(14), С. 2903 - 2918

Опубликована: Окт. 13, 2021

Abstract 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 disease, which aids the regulation myocardial function, including filling output. Due enormous size, complexity, malleability molecule, properties also vulnerable dysregulation, as observed various disorders. This review provides an overview how can be changed at molecular level, role isoform diversity post-translational modifications (acetylation, oxidation, phosphorylation) play regulating contractility. We then consider this becomes unbalanced heart with emphasis on changes quality control. In context, new insights into key pathomechanisms human cardiomyopathy due truncation gene (TTN) discussed. Along way, we touch potential for therapeutically targeted treat acquired or inherited conditions, such HFpEF TTN-truncation cardiomyopathy.

Язык: Английский

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