Clinically inapparent right heart dysfunction is associated with reduced myofilament force development in coronary artery disease

Background Right ventricular dysfunction after CABG is associated with poor peri- and postoperative outcomes. We aimed to identify clinical and experimental predictors for preoperative inapparent right ventricular dysfunction and therefore hypothesized that reduced myofilament force development as well as altered levels of biomarkers might predict inapparent right ventricular dysfunction. Methods From 08/2016 to 02/2018, 218 patients scheduled for CABG were divided into two groups (TAPSE ≥ 20 mm, n = 178; TAPSE < 20 mm, n = 40). Baseline serum samples for biomarkers (Galectin, TGFß1, N Acyl-SDMA, Arginine, ADMA and Pentraxin-3), clinical laboratory and transthoracic echocardiographic parameters were evaluated. To examine the myocardial apparatus of the right ventricle intraoperative right auricular tissue was harvested for stepwise skinned fiber force measurements. Results Patients with TAPSE < 20 mm had a higher incidence of DM (55 vs. 34%, p = 0.018), preoperative AFib (43 vs. 16%, p < 0.001), reduced GFR (67 ± 18 vs. 77 ± 24 ml/min/1.73 m2, p = 0.013), larger LA area (22 ± 6 vs. 20 ± 5 cm2, p = 0.005) and reduced LVEF (50 vs. 55%, p = 0.008). Furthermore, higher serum ADMA (0.70 ± 0.13 vs. 0.65 ± 0.15 µmol/l, p = 0.046) and higher serum Pentraxin-3 levels (3371 ± 1068 vs. 2681 ± 1353 pg/dl, p = 0.004) were observed in these patients. Skinned fiber force measurements showed significant lower values at almost every step of calcium concentration (pCa 4.52 to pCa 5.5, p < 0.01 and pCa 5.75–6.0, p < 0.05). Multivariable analysis revealed DM (OR 2.53, CI 1.12–5.73, Euro Score II (OR 1.34, CI 1.02–1.78), preoperative AF (OR 4.86, CI 2.06–11.47), GFR (OR 7.72, CI 1.87–31.96), albumin (OR 1.56, CI 0.52–2.60), Pentraxin-3 (OR 19.68, CI 14.13–25.24), depressed LVEF (OR 8.61, CI 6.37–10.86), lower force values: (pCa 5.4; OR 2.34, CI 0.40–4.29 and pCa 5.2; OR 2.00, CI 0.39–3.60) as predictors for clinical inapparent right heart dysfunction. Conclusions These preliminary data showed that inapparent right heart dysfunction in CAD is already associated with reduced force development of the contractile apparatus.

Treatment with EUK-134 improves sarcoplasmic reticulum Ca2+ release but not myofibrillar Ca2+ sensitivity after fatiguing contraction of rat fast-twitch muscle

Skeletal muscles undergoing vigorous activity can enter a state of prolonged low-frequency force depression (PLFFD). This study was conducted to examine whether antioxidant treatment is capable of accelerating the recovery from PLFFD, with a focus on the function of the sarcoplasmic reticulum (SR) and myofibril. One hour before fatiguing stimulation (FS) was administered, rats received an intraperitoneal injection of Eukarion (EUK-134), which mimics the activities of superoxide dismutase and catalase. Intact muscles of the hindlimbs were electrically stimulated via the sciatic nerve until the force was reduced to ~50% of the initial force (FS). Thirty minutes after cessation of FS, the superficial regions of gastrocnemius muscles were dissected and used for biochemical and skinned-fiber analyses. Whole muscle analyses revealed that antioxidant alleviated the FS-induced decrease in the reduced glutathione content. Skinned-fiber analyses showed that the antioxidant did not affect the FS-induced decrease in the ratio of force at 1 Hz to that at 50 Hz. However, the antioxidant partially inhibited the FS-mediated decrease in the ratio of depolarization-induced force to the maximum Ca2+-activated force. Furthermore, the antioxidant completely suppressed the FS-induced increase in myofibrillar Ca2+ sensitivity. These results suggest that antioxidant treatment is ineffective in facilitating the restoration of PLFFD, probably due to its negative effect on myofibrillar Ca2+ sensitivity, which supersedes its positive effect on SR Ca2+ release.

Peroxisome proliferator-activated receptor-α expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy

Although alterations in fatty acid (FA) metabolism have been shown to have a negative impact on contractility of the hypertrophied heart, the targets of action remain elusive. In this study we compared the function of skinned fiber bundles from transgenic (Tg) mice that overexpress a relatively low level of the peroxisome proliferator-activated receptor α (PPARα), and nontransgenic (NTg) littermates. The mice (NTg-T and Tg-T) were stressed by transverse aortic constriction (TAC) and compared with shams (NTg-S and Tg-S). There was an approximate 4-fold increase in PPARα expression in Tg-S compared with NTg-S, but Tg-T hearts showed the same PPARα expression as NTg-T. Expression of PPARα did not alter the hypertrophic response to TAC but did reduce ejection fraction (EF) in Tg-T hearts compared with other groups. The rate of actomyosin ATP hydrolysis was significantly higher in Tg-S skinned fiber bundles compared with all other groups. Tg-T hearts showed an increase in phosphorylation of specific sites on cardiac myosin binding protein-C (cMyBP-C) and β-myosin heavy chain isoform. These results advance our understanding of potential signaling to the myofilaments induced by altered FA metabolism under normal and pathological states. We demonstrate that chronic and transient PPARα activation during pathological stress alters myofilament response to Ca2+ through a mechanism that is possibly mediated by MyBP-C phosphorylation and myosin heavy chain isoforms. NEW & NOTEWORTHY Data presented here demonstrate novel signaling to sarcomeric proteins by chronic alterations in fatty acid metabolism induced by PPARα. The mechanism involves modifications of key myofilament regulatory proteins modifying cross-bridge dynamics with differential effects in controls and hearts stressed by pressure overload.