Altered hetero- and homeometric autoregulation in the terminally failing human heart

Area of Science:

• Cardiology
• Physiology
• Molecular Biology

Background:

• The Frank-Starling mechanism is crucial for regulating cardiac output.
• Length-dependent force generation is a key aspect of cardiac muscle function.
• Dilated cardiomyopathy (DCM) is characterized by impaired cardiac contractility.

Purpose of the Study:

• To investigate length-dependent force generation in human nonfailing (NF) and failing (DCM) left ventricular myocardium.
• To explore the underlying mechanisms of impaired force generation in DCM.
• To assess the role of interstitial fibrosis in end-stage heart failure.

Main Methods:

• Studied human left ventricular myocardium from NF and DCM donors.
• Applied various preload and length conditions.
• Performed morphological studies including van Giesson Trichrome staining and electron microscopy.
• Measured force of contraction (FOC) and intracellular calcium transients (fura-2).

Main Results:

• Nonfailing myocardium showed a biphasic increase in FOC with increased preload (fast and slow components).
• Failing myocardium (DCM) exhibited blunted FOC components and increased diastolic tension.
• NF myocardium showed stretch-induced increase in diastolic calcium, absent in DCM.
• No significant interstitial fibrosis was observed in DCM myocardium.

Conclusions:

• Impaired length-dependent force generation in DCM results from dysregulation of both myofibrillar calcium sensitivity and intracellular calcium homeostasis.
• The Frank-Starling mechanism (fast FOC component) and calcium transient dynamics (slow FOC component) are both affected in heart failure.
• Interstitial fibrosis appears to have a minor role in force generation in human end-stage heart failure.