Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10–20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DC

Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice

Background —The activation of B 2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure. Methods and Results —To test whether the absence of bradykinin B 2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B 2 receptor gene knockout (B 2 −/− ), heterozygous (B 2 +/− ), and wild-type (B 2 +/+ ) mice. The BP of B 2 −/− mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B 2 +/+ , P &lt;0.01). In B 2 +/− mice, BP elevation was delayed. At 40 days, the heart rate was higher ( P &lt;0.01) in B 2 −/− and B 2 +/− than in B 2 +/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B 2 −/− and B 2 +/− mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B 2 +/+ mice. In B 2 −/− mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B 2 +/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B 2 +/+ mice, P &lt;0.01), and reparative fibrosis. Conclusions —The disruption of the bradykinin B 2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart. </jats:p