Autophagic vacuoles in cardiomyocytes of dilated cardiomyopathy with initially decompensated heart failure predict improved prognosis

Abstract

Autophagy is a process of bulk protein degradation and organelle turnover, and is a current therapeutic target in several diseases. The present study aimed to clarify the significance of myocardial autophagy of patients with dilated cardiomyopathy (DCM). Left ventricular endomyocardial biopsy was performed in 250 consecutive patients with DCM (54.9±13.9 years; male, 79%), initially presenting with decompensated heart failure (HF). The association of these findings with HF mortality or recurrence was examined. Myofilament changes, which are apparent in the degenerated cardiomyocytes of DCM, were recognized in 164 patients (66%), and autophagic vacuoles in cardiomyocytes were identified in or near the area of myofilament changes in 86 patients (34%). Morphometrically, fibrosis (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93 to 0.99) and mitochondrial abnormality (OR, 2.24; 95% CI, 1.23 to 4.08) were independently related with autophagic vacuoles. During the follow-up period of 4.9±3.9 y, 24 patients (10%) died, including 10 (4%) who died of HF, and 67 (27%) were readmitted for HF recurrence. Multivariate analysis identified a family history of DCM (hazard ratio [HR], 2.117; 95% CI, 1.199 to 3.738), hemoglobin level (HR, 0.845; 95% CI, 0.749 to 0.953), myofilament changes (HR, 13.525; 95% CI, 5.340 to 34.255), and autophagic vacuoles (HR, 0.214; 95% CI, 0.114 to 0.400) as independent predictors of death or readmission due to HF recurrence. In conclusion, autophagic vacuoles in cardiomyocytes are associated with a better HF prognosis in patients with DCM, suggesting autophagy may play a role in the prevention of myocardial degeneration.

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

“…There is ongoing debate about whether autophagy plays a beneficial or detrimental role in cardiac diseases . Excessive autophagy contributed to age‐related cardiac disease development, including heart failure, hypertension‐induced cardiac diseases, mitral regurgitation, and diabetic cardiomyopathy . Interestingly, all these cardiac diseases are recognized to represent a substrate for AF, suggesting a role for autophagic activation in AF development.…”

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…By using Kaplan-Meier survival curves, the authors concluded that the presence of autophagosomes was associated with a better CHF prognosis in patients with DCM, i.e. a longer event-free period (death or readmission due to CHF) compared with those who did not have autophagic vacuoles in their cardiomyocytes [55]. Moreover, genetic approaches have been helpful in understanding the role of autophagy in cardiac diseases.…”

“…Currently, the real contribution of autophagy to CHF is still a matter of controversy [33]. In a recent study, the hearts from 250 DCM patients with initially decompensated CHF (systolic dysfunction with an LV ejection fraction of less than 50%) were analyzed in terms of content of autophagic vacuoles in cardiomyocytes with or without myofilament changes [55]. By using Kaplan-Meier survival curves, the authors concluded that the presence of autophagosomes was associated with a better CHF prognosis in patients with DCM, i.e.…”

Myocardial stress and autophagy: mechanisms and potential therapies

“…Cardiomyocyte autophagy disturbance has been reported in chronic conditions of heart failure, 78 hypertrophic and dilated cardiomyopathy (genetic and non-genetic forms), 79, 80 cardiac aging, 81, 82 and diabetes; 83, 84 and in acute conditions of sepsis 85, 86 and ischemia-reperfusion injury. 87, 88 Cardiomyopathy associated with chemotherapeutic agents such as doxorubicin also involves autophagy disruption with impaired cardiomyocyte autophagosome clearance.…”

“…91 Conversely, in vivo activation of autophagy (by rapamycin treatment) immediately after aortic banding surgery 97 or thyroid hormone treatment, 98 prevents hypertrophic remodeling (functional outcomes not evaluated). In patients with dilated cardiomyopathy, the presence of autophagic vacuoles in left ventricular biopsies predict better outcomes over a 12 year follow-up period, 79 suggesting that an autophagy response is beneficial for long-term myocyte integrity in pathological settings.…”