Pirk, Jan

PURPOSE: Experimental studies suggest that accumulation of triacylglyceroles (TAG) in myocardium and ensuing lipotoxicity may contribute to the progression of heart failure (HF), but relevance to human HF remains uncertain. We strived to quantify myocardial TAG in HF patients and controls and to identify their determinants. Methods: 49 myocardial samples from patients with terminal HF (52 yrs, 86% male, 45% CAD, 49% DCM, 6% other dg.) that underwent heart transplantation or LVAD implantation and 20 control samples from cadaverous organ donors without HF (42 years, 45% males) were analyzed. Myocardial TAG (determined chemically), reduced (GSH) and oxidized glutathione (GSSG) were determined. Results: Patients with HF had higher amount of myocardial TAG (8.07± 3.95 vs. 5.60±3.36 μmol/g wet tissue, p= 0.017) and lower levels of both GSH and GSSG (p< 0.05) with similar GSH/GSSG ratio. The amount of myocardial TAG was independent of age, gender, HF etiology, diabetes mellitus, BMI, mitral regurgitation grade and plasma lipids (total-, HDL-, LDL-cholesterol, TAG) but it correlated with plasmatic BNP level (p=0.049, r=0.28). In controls, a positive correlation between myocardial TAG and the myocardial redox state (GSH/GSSG ratio) was found (r=0.53, p=0.015). On the contrary, this correlation was negative (r= -0.31, p=0.02) in HF patients. Conclusion: Myocardial TAG in HF and controls have opposite relationship to redox state, indicating disparate mechanisms involved. Failing hearts display higher TAG accumulation, that is independent of comorbidities, but proportional to circulating BNP, supporting the role of natriuretic peptides in abnormal lipid homeostasis in HF.

Abstract Aims Iron replacement improves clinical status in iron-deficient patients with heart failure (HF), but the pathophysiology is poorly understood. Iron is essential not only for erythropoiesis, but also for cellular bioenergetics. The impact of myocardial iron deficiency (MID) on mitochondrial function, measured directly in the failing human heart, is unknown. Methods and results Left ventricular samples were obtained from 91 consecutive HF patients undergoing transplantation and 38 HF-free organ donors (controls). Total myocardial iron content, mitochondrial respiration, citric acid cycle and respiratory chain enzyme activities, respiratory chain components (complex I–V), and protein content of reactive oxygen species (ROS)-protective enzymes were measured in tissue homogenates to quantify mitochondrial function. Myocardial iron content was lower in HF compared with controls (156 ± 41 vs. 200 ± 38 µg·g−1 dry weight, P &lt; 0.001), independently of anaemia. MID (the lowest iron tercile in HF) was associated with more extensive coronary disease and less beta-blocker usage compared with non-MID HF patients. Compared with controls, HF patients displayed reduced myocardial oxygen2 respiration and reduced activity of all examined mitochondrial enzymes (all P &lt; 0.001). MID in HF was associated with preserved activity of respiratory chain enzymes but reduced activity of aconitase and citrate synthase (by –26% and –15%, P &lt; 0.05) and reduced expression of catalase, glutathione peroxidase, and superoxide dismutase 2. Conclusion Myocardial iron content is decreased and mitochondrial functions are impaired in advanced HF. MID in HF is associated with diminished citric acid cycle enzyme activities and decreased ROS-protecting enzymes. MID may contribute to altered myocardial substrate use and to worsening of mitochondrial dysfunction that exists in HF.