Cardiac Function and Diastolic Dysfunction Mechanisms

Cardiac function is governed by the coordinated contraction and relaxation of cardiomyocytes, ensuring sufficient blood ejection during systole and complete filling during diastole. Diastolic dysfunction arises when ventricular relaxation, compliance or filling is impaired, leading to elevated filling pressures, pulmonary congestion and symptoms of heart failure despite a preserved ejection fraction. Underlying mechanisms include extracellular matrix remodelling and fibrosis, maladaptive cardiomyocyte hypertrophy, altered calcium handling and energetic deficits driven by mitochondrial dysfunction. Inflammation and metabolic disturbances further amplify stiffness and impair lusitropy. Advances in molecular and cellular research have revealed critical signalling axes—such as the unfolded protein response, post-translational modifications of contractile proteins and epigenetic regulators—that link comorbidities like hypertension, obesity and ageing with diastolic impairment. Combined, these insights support a unifying paradigm in which systemic stressors provoke maladaptive myocardial remodelling and energetic derangements, producing the clinical syndrome of heart failure with preserved ejection fraction.

Research from Nature Portfolio

Selective inhibition of histone deacetylase 6 has been shown to reverse established symptoms of heart failure with preserved ejection fraction in preclinical models. Pharmacological blockade restored gene programmes governing mitochondrial energy production, attenuated myocardial fibrosis and reduced cardiomyocyte hypertrophy, with efficacy comparable to established sodium-glucose cotransporter 2 inhibition. This work highlights epigenetic control of inflammatory and metabolic gene expression as a promising therapeutic avenue. Separately, integrative human and murine genetic studies have uncovered sex-dependent differences in mitochondrial function as key determinants of diastolic performance. A mitochondrial acyl-CoA synthetase emerged as a genetic modifier of ventricular stiffness, and its modulation in vivo altered diastolic filling. These findings reveal that intrinsic variations in mitochondrial bioenergetics contribute to the higher prevalence of diastolic dysfunction in women and point to novel targets for tailored interventions.

Research from all publishers

Experimental models have demonstrated that maladaptive T cell responses, characterised by dysregulation of the IRE1α–XBP1 branch of the unfolded protein response, drive myocardial inflammation and diastolic impairment. Restoration of T cell proteostasis alleviated cardiomyocyte hypertrophy and improved filling pressures, establishing immune-metabolic crosstalk as a central mechanism in heart failure with preserved ejection fraction. A collective review of animal models has underscored the limitations and strengths of rodent and large-animal platforms for recapitulating human diastolic dysfunction, emphasising the need for multifactorial models incorporating hypertension, obesity and ageing. Foundational work on low-grade systemic inflammation has further elucidated how age-related inflammasome activation promotes myocardial fibrosis and stiffness, suggesting that targeting innate immune signalling may mitigate diastolic decline in elderly populations.

Cardiac Function and Diastolic Dysfunction Mechanisms publication trend

The graph below shows the total number of articles in cardiac function and diastolic dysfunction mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Heart failure with preserved ejection fraction (HFpEF): A clinical syndrome of symptomatic heart failure despite normal or near-normal left ventricular ejection fraction, marked by diastolic impairment.

Diastolic dysfunction: Impaired relaxation and filling of the ventricles during diastole, leading to elevated filling pressures and congestion.

Unfolded protein response (UPR): A cellular stress pathway activated by misfolded proteins in the endoplasmic reticulum, involving sensors such as IRE1α and XBP1.

Histone deacetylase 6 (HDAC6): An enzyme that removes acetyl groups from histones and non-histone proteins, influencing gene expression and protein function.

Mitochondrial respiration: The process by which mitochondria generate ATP through oxidative phosphorylation and electron transport chain activity.

References

1. Heart failure with preserved ejection fraction: present status and future directions. Experimental & Molecular Medicine (2019).
2. Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice. Nature Communications (2024).
3. Sex differences in heart mitochondria regulate diastolic dysfunction. Nature Communications (2022).
4. Impaired T cell IRE1α-XBP1 signaling directs inflammation in experimental Heart Failure with Preserved Ejection Fraction. Journal of Clinical Investigation (2023).
5. Animal models of heart failure with preserved ejection fraction. Netherlands Heart Journal (2016).
6. Chronic low‐grade inflammation in heart failure with preserved ejection fraction. Aging Cell (2021).