Mitochondrial Therapies in Heart Failure.

The current therapy for patients with stable systolic heart failure is largely limited to treatments that interfere with neurohormonal activation. Critical pathophysiological hallmarks of heart failure are an energetic deficit and oxidative stress, and both may be the result of mitochondrial dysfunction. This dysfunction is not (only) the result of defect within mitochondria per se, but is in particular traced to defects in intermediary metabolism and of the regulatory interplay between excitation-contraction coupling and mitochondrial energetics, where defects of cytosolic calcium and sodium handling in failing hearts may play important roles. In the past years, several therapies targeting mitochondria have emerged with promising results in preclinical models. Here, we discuss the mechanisms and results of these mitochondria-targeted therapies, but also of interventions that were not primarily thought to target mitochondria but may have important impact on mitochondrial biology as well, such as iron and exercise. Future research should be directed at further delineating the details of mitochondrial dysfunction in patients with heart failure to further optimize these treatments.

[Cardiopulmonary Comorbidities]. / Kardiopulmonale Komorbiditäten.

Cardiac and pulmonary diseases are primary causes of global morbidity and mortality. Since the prevalence of both cardiac and pulmonary diseases increases with age, cardiopulmonary comorbidities inflict especially the elderly. Due to the tight physiological connection of the heart and the lung, diseases of both organs affect each other beyond a mere coincidence. At the same time, due to the similarity of their respective symptoms, their differentiation is challenging in clinical practice and therefore, comorbidities can be easily overlooked. This article provides an overview on the characteristics of cardiopulmonary comorbidities and their specific-, but also mutual pathophysiology.

Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure.

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.