Background-A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis. Methods and Results-To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress ( es ) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of es in pressure-overloaded wild-type mice (287Ϯ39 versus sham, 254Ϯ34 g/cm 2 ), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize es (415Ϯ81 g/cm 2 , PϽ0.05). Remarkably, despite inadequate normalization of es , cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure. Conclusions-These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.
BackgroundThe objective of this study was to investigate the impact of sodium glucose cotransporter type 2 (SGLT2) inhibitors on left ventricular (LV) diastolic function of type 2 diabetes mellitus (T2DM) patients with heart failure (HF).MethodsThis trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. The physical examinations, blood tests, and echocardiography were performed at baseline and 6 months after administration of dapagliflozin. The primary endpoint was defined as a change in mitral inflow E and mitral e′ annular velocities (E/e′) between baseline and 6 months after the administration of dapagliflozin. The secondary end points consisted of a change in brain natriuretic peptide (BNP), LV mass index (LVMI) and left atrial volume index (LAVI).ResultsE/e′ significantly decreased from 9.3 to 8.5 cm/s (p = 0.020) 6 months after administration of dapagliflozin. LAVI and LVMI significantly decreased from 31 to 26 mL/m2 (p = 0.001), and from 75.0 to 67.0 g/m2 (p < 0.001), respectively, 6 months after administration of dapagliflozin. No significant change was observed in BNP (from 27.9 to 28.9 pg/mL; p = 0.132) 6 months after administration of dapagliflozin, except for a significant decrease from 168.8 to 114.3 pg/mL (p = 0.012) in patients with BNP ≥ 100 pg/mL.ConclusionThis prospective multicenter trial showed the beneficial effect of SGLT2 inhibitors on LV diastolic functional parameters for T2DM patients with HF. Our findings may thus offer a new insight into the management of T2DM patients.Trial registration UMIN000019789, Registered 28 September 2014, Date of registration: 11/14/2015, Date of enrolment of the first participant to the trial: 6/15/2016, Date of enrolment of the last participant to the trial: 12/9/2017
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