Spinal Cord Injury Causes Systolic Dysfunction and Cardiomyocyte Atrophy

Ventricular pressure-volume relationships have become well established as the most rigorous and comprehensive ways to assess intact heart function. Thanks to advances in miniature sensor technology, this approach has been successfully translated to small rodents, allowing for detailed characterization of cardiovascular function in genetically engineered mice, testing effects of pharmacotherapies and studying disease conditions. This method is unique for providing measures of left ventricular (LV) performance that are more specific to the heart and less affected by vascular loading conditions. Here we present descriptions and movies for procedures employing this method (anesthesia, intubation and surgical techniques, calibrations). We also provide examples of hemodynamics measurements obtained from normal mice/rats, and from animals with cardiac hypertrophy/heart failure, and describe values for various useful load-dependent and load-independent indexes of LV function obtained using different types of anesthesia. The completion of the protocol takes 1-4 h (depending on the experimental design/end points).

The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of alpha- and beta-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membrane-associated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, alpha-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material. (2) Further accumulation of microtubules and desmin to compensate for the increasing loss of myofilaments and titin represents the late clinical and irreversible state. We suggest, based on a structural basis for heart failure, an integrative view which closes the gap between changes within cardiac myocytes and the involvement of the extracellular matrix, including the development of fibrosis. These factors contribute significantly to structural ventricular remodeling and dilatation finally resulting in reduced cardiac function.

The aim of the present study was to diagnose heart failure with preserved ejection fraction (HFPEF) in outpatients with unexplained chronic dyspnea and to elucidate its underlying mechanisms in this population using invasive pressure-volume loop analysis. The diagnosis of HFPEF in stable outpatients with unexplained dyspnea is difficult. Thirty patients (age 67 +/- 8.6 years, 27% males) with preserved left ventricular (LV) ejection fraction (>50%) and unexplained chronic New York Heart Association functional class II to III dyspnea underwent heart catheterization. Patients with significant coronary artery stenosis (>50%) were excluded. Pressure-volume loops were assessed using a conductance catheter at rest, hand-grip exercise, leg lifting, and nitroprusside and dobutamine infusion. Twenty (66%) patients showed LV end-diastolic pressure >16 mm Hg (HFPEF), whereas the remaining 10 patients served as controls. Patients with HFPEF had significantly higher end-diastolic stiffness (0.205 +/- 0.074 vs. 0.102 +/- 0.017, p < 0.001) at rest, and their end-diastolic pressure-volume relationship showed a consistent upward and leftward shift during all hemodynamic interventions compared with controls. Regarding the underlying mechanism of HFPEF, 14 (70%) patients had markedly increased end-diastolic stiffness, which was considered a sufficient single pathology to induce increased LV end-diastolic pressure. Four (20%) patients showed a concomitant presence of moderately increased stiffness and severe LV dyssynchrony, and the remaining 2 (10%) patients, with normal stiffness, showed significant exercise-induced mitral regurgitation at hand-grip exercise. If the invasive pressure measurements were absent, only 5 (25%) of the outpatients with HFPEF fulfilled the European Society of Cardiology definition of HFPEF. A significant proportion of stable outpatients with unexplained chronic dyspnea may have HFPEF. In the patients whom we studied, increased LV stiffness, dyssynchrony, and dynamic mitral regurgitation were the major mechanisms underlying development of HFPEF. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.