Pressure overload-induced impairment in fatty acid oxidation precedes the onset of congestive heart failure but mitochondrial respiratory capacity is maintained until the EF decreases in vivo. These temporal relations suggest a tight link between impaired substrate oxidation capacity in the development of heart failure and contractile dysfunction and may imply therapeutic and prognostic value.
Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 micromol/(kg day)] or with NVP-LAB121 [60 micromol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of alpha- and beta-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 +/- 0.26 to 4.14 +/- 0.48 after 1 week and from 2.80 +/- 0.21 to 6.54 +/- 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 +/- 11 vs. 73 +/- 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased alpha and beta-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.
Kurdziel, Marta, Jarosław Wasilewski, Karolina Gierszewska, Anna Kazik, Gracjan Pytel, Jacek Wacławski, Adam Krajewski, Anna Kurek, Lech Poloński, and Mariusz Gąsior. Echocardiographic assessment of right ventricle dimensions and function after exposure to extreme altitude: Is an expedition to 8000 m hazardous for right ventricular function? High Alt Med Biol 18:330-337, 2017.-Although the right ventricle (RV) is under great hypoxic stress at altitude, still little is known what happens to the RV after descent. The aim of this study was to evaluate RV dimensions and function after exposure to extreme altitude. Therefore, echocardiographic examination was performed according to a protocol that focused on the RV in 11 healthy subjects participating in an expedition to K2 (8611 m) or Broad Peak (BP, 8051 m). In comparison to measurements before the expedition, after 7-8 weeks of sojourn above 2300 meters with the aim of climbing K2 and BP, the RV Tei index increased (0.5 ± 0.1 vs. 0.4 ± 0.1; p = 0.028), and RV free wall longitudinal systolic strain (RVFWLSS) decreased (-23.1% ± 2.7% vs. -25.9% ± 2.4%; p = 0.043). Decrease in peak systolic strain and strain rate was observed in the basal and mid segments of the RV free wall (respectively: -24.4% ± 4.4% vs. -30.9% ± 6.5%; -1.4 ± 0.3 s vs. -1.8 ± 0.3 s; -28.7% ± 3.9% vs. -34% ± 3.3%; -1.5 ± 0.2 s vs. -1.9 ± 0.3 s; p for all <0.05). The linear RV dimensions, the proximal and distal RV outflow tracks, increased (respectively: 31.3 ± 4 mm vs. 29.2 ± 3 mm, p = 0.025; 27 ± 2.7 mm vs. 24.8 ± 3 mm, p = 0.012). We found that exposure to extreme altitude may cause RV dilatation and a decrease in RV performance. The Tei index and RVFWLSS are sensitive performance indices to detect changes in RV function after the exposure to hypoxic stress. The observed alterations seem to be a manifestation of physiological adaptation to high-altitude condition in healthy individuals.
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