Erythropoietin in heart failure:Pathology and protection

Anemia is common in chronic heart failure (CHF) patients and related to impaired survival. The etiology of anemia in CHF-patients is often unknown. We hypothesized that dysregulation of erythropoietin (EPO) synthesis by the kidney or an altered sensitivity of the bone marrow to EPO might represent causes specific for CHF. In addition, recombinant human EPO (rhEPO) has been shown to improve cardiac function in heart failure. We hypothesized that EPO-induced improvement of cardiac function is mediated through mechanisms that are unrelated to increases in hematocrit levels. In the present thesis we explored EPO as a pahthophysiological factor in anemia and the mechanisms of its ancillary beneficial cardiac effects in heart failure.

Sodium-glucose co-transporter 2 inhibition as a mitochondrial therapy for atrial fibrillation in patients with diabetes?

While patients with type 2 diabetes mellitus (T2DM) are at increased risk to develop atrial fibrillation (AF), the mechanistic link between T2DM and AF-susceptibility remains unclear. Common co-morbidities of T2DM, particularly hypertension, may drive AF in the setting of T2DM. But direct mechanisms may also explain this relation, at least in part. In this regard, recent evidence suggests that mitochondrial dysfunction drives structural, electrical and contractile remodelling of atrial tissue in patients T2DM. Mitochondrial dysfunction may therefore be the mechanistic link between T2DM and AF and could also serve as a therapeutic target. An elegant series of experiments published in Cardiovascular Diabetology provide compelling new evidence to support this hypothesis. Using a model of high fat diet (HFD) and low-dose streptozotocin (STZ) injection, Shao et al. provide data that demonstrate a direct association between mitochondrial dysfunction and the susceptibility to develop AF. But the authors also demonstrated that the sodium-glucose co-transporter 2 inhibitors (SGLT2i) empagliflozin has the capacity to restore mitochondrial function, ameliorate electrical and structural remodelling and prevent AF. These findings provide a new horizon in which mitochondrial targeted therapies could serve as a new class of antiarrhythmic drugs

Short-Chain Fatty Acids in the Metabolism of Heart Failure - Rethinking the Fat Stigma

Heart failure (HF) remains a disease with immense global health burden. During the development of HF, the myocardium and therefore cardiac metabolism undergoes specific changes, with decreased long-chain fatty acid oxidation and increased anaerobic glycolysis, diminishing the overall energy yield. Based on the dogma that the failing heart is oxygen-deprived and on the fact that carbohydrates are more oxygen-efficient than FA, metabolic HF drugs have so far aimed to stimulate glucose oxidation or inhibit FA oxidation. Unfortunately, these treatments have failed to provide meaningful clinical benefits. We believe it is time to rethink the concept that fat is harmful to the failing heart. In this review we discuss accumulating evidence that short-chain fatty acids (SCFAs) may be an effective fuel for the failing heart. In contrast to long-chain fatty acids, SCFAs are readily taken up and oxidized by the heart and could serve as a nutraceutical treatment strategy. In addition, we discuss how SCFAs activate pathways that increase long chain fatty acid oxidation, which could help increase the overall energy availability. Another potential beneficial effect we discuss lies within the anti-inflammatory effect of SCFAs, which has shown to inhibit cardiac fibrosis - a key pathological process in the development of HF

Exercising heart failure patients:cardiac protection through preservation of mitochondrial function and substrate utilization?

Current heart failure (HF) therapy remains unable to substantially improve exercise capacity. Studies have shown that exercise training has beneficial effects on the heart in both health and disease. How mitochondria respond to exercise in this setting has, however, received less attention in literature. These beneficial effects may include protective changes in mitochondrial function and adaptations in substrate utilization. This review describes exercise-induced changes in cardiac metabolism, including changes in mitochondrial function and substrate utilization and their effects on cardiac function. We conclude that exercising HF patients can improve mitochondrial function and optimize substrate utilization, eventually improving or restoring cardiac function. This suggests that exercise itself should be incorporated in the HF treatment plan, to improve cardiac function and in term exercise capacity. Extending knowledge on mechanisms by which exercise exerts protective effects could potentially lead to development of therapies directed at improving mitochondrial function and substrate utilization in HF.</p