Data_Sheet_1_Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction.pdf

BackgroundSkeletal muscle (SkM) phenotypic switching is associated with exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have decreased type-1 oxidative fibers and mitochondrial dysfunction, indicative of impaired oxidative capacity. The SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) mice are commonly used in HFpEF pre-clinical studies and demonstrate cardiac, lung, kidney, and white adipose tissue impairments. However, the SkM (specifically the oxidative-predominant, soleus muscle) has not been described in this preclinical HFpEF model. We sought to characterize the soleus skeletal muscle in the HFpEF SAUNA mice and investigate its translational potential.MethodsHFpEF was induced in mice by uninephrectomy, d-aldosterone or saline (Sham) infusion by osmotic pump implantation, and 1% NaCl drinking water was given for 4 weeks. Mice were euthanized, and the oxidative-predominant soleus muscle was collected. We examined fiber composition, fiber cross-sectional area, capillary density, and fibrosis. Molecular analyses were also performed. To investigate the clinical relevance of this model, the oxidative-predominant, vastus lateralis muscle from patients with HFpEF was biopsied and examined for molecular changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis, and inflammation.ResultsHistological analyses demonstrated a reduction in the abundance of oxidative fibers, type-2A fiber atrophy, decreased capillary density, and increased fibrotic area in the soleus muscle of HFpEF mice compared to Sham. Expression of targets of interest such as a reduction in mitochondrial oxidative-phosphorylation genes, increased VEGF-α and an elevated inflammatory response was also seen. The histological and molecular changes in HFpEF mice are consistent and comparable with changes seen in the oxidative-predominant SkM of patients with HFpEF.ConclusionThe HFpEF SAUNA model recapitulates the SkM phenotypic switching seen in HFpEF patients. This model is suitable and relevant to study SkM phenotypic switching in HFpEF.</p

Central Pulse Pressure in Chronic Kidney Disease A Chronic Renal Insufficiency Cohort Ancillary Study

Central pulse pressure (PP) can be noninvasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central PP cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort Study to determine correlates of the magnitude of central PP in the setting of chronic kidney disease. Tertiles of central PP were 51 mm Hg with an overall mean (+/-SD) of 46 +/- 19 mm Hg. Multivariable regression identified the following independent correlates of central PP: age, sex, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose, and parathyroid hormone parathyroid hormone concentrations. Additional adjustment for brachial mean arterial pressure and brachial PP showed associations for age, sex, diabetes mellitus, weight, and heart rate. Discrete intervals of brachial PP stratification showed substantial overlap within the associated central PP values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence. (Hypertension. 2010; 56: 518-524.