Identification of active components in Yixinshu Capsule with protective effects against myocardial dysfunction on human induced pluripotent stem cell-derived cardiomyocytes by an integrative approach.

Traditional Chinese medicine (TCM) preparations have significant effects on some refractory diseases; however, these compositions are complex and their mechanisms are unknown. Identification of the active components in these preparations is essential. The mortality rate for heart failure (HF) has been increasing in recent years, and myocardial dysfunction (MD) has been proved to be the pathological basis of HF. Yixinshu Capsule (YXSC) is a multi-component oral drug with therapeutic effects on HF. However, the key active components are still unclear. In this study, YXSC intestinal absorption liquid (IAL) was used and 62 compounds were identified by an analytical chemistry approach. Then, a compound - target - function network was established with a bioinformatics analysis tool. Finally, a cell model of MD on human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) was used to verify the therapeutic effects of the active components of YXSC. Schisandrin A (Sch A) and schisandrin B (Sch B) were demonstrated to be the active components of YXSC by attenuating endothelin-1 (ET-1)-induced contraction dysfunction, brain natriuretic peptide (BNP) content elevation, and the morphological changes of hiPS-CMs. For the first time, our data illustrate the potent protective effects of Sch A and Sch B on ET-1-induced dysfunctional hiPS-CMs and revealed their effective targets and pathways. The integrative approach used in our study was applied to identify active components in TCM preparations and excavate the possible mechanisms.

Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.

BACKGROUND: Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking. METHODS: A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention. The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan-Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied. RESULTS: During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P=0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P=0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group (P=0.03). CONCLUSION: Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.

Revisiting salt and water retention: new diuretics, aquaretics, and natriuretics.

Diuretics continue to be a mainstay in patients with CHF. Conventional diuretic therapy is associated, however, with potentially deleterious neurohumoral activation and renal impairment. It is not known to what extent these neurohumoral effects are offset by concurrent therapy with ACE-I, beta-blockers, and other agents. In the past, there was no alternative to conventional diuretic therapy, so their potential for adverse outcome in the long term could not be assessed. Enhancement of the natriuretic peptide system could provide us with a better strategy to treat sodium and water retention. In a unique way, the natriuretic peptides combine several of the beneficial actions of the other diuretics, but without the associated cost. Natriuretic peptides, like conventional diuretics, are natriuretic and diuretic. There are important differences, however. First, unlike conventional diuretics, NPs do not activate RAAS. Activation of this system is associated with progression of CHF. Second, NPs inhibit the sympathetic nervous system, the activation of which is associated with heart failure progression, myocyte necrosis and apoptosis, and arrhythmias. Third, unlike conventional diuretics that lead to a decrease in GFR by reflex mechanisms. NPs maintain or even improve GFR. We now appreciate that some "old" drugs may be beneficial to CHF patients in a new way, as is the case with spironolactone. The survival benefit of this aldosterone antagonist is clear: its usefulness, however, may be more a result of both its antifibrotic actions in addition to its tradional role as a potassium-sparing and natriuretic agent. It is hoped that the SARAs will provide the same survival benefit, but with fewer of the sex-steroid side effects. In addition, AVP-receptor antagonists may become useful tools in the treatment of patients with hyponatremia. Likewise, the A1 AR antagonists may find a role in the CHF armamentarium by providing good diuresis and natriuresis while at the same time maintaining GFR through inhibition of TGF. Many questions remain unanswered, and studies are needed to demonstrate that the positive results seen in basic research translate into improved morbidity and mortality.