Left Ventricular Atrophy Research Articles

Myocardial mechanics and cardiac biomarkers in adults with severe anorexia nervosa.

Anorexia nervosa (AN) is associated with left ventricular (LV) atrophy and unexplained sudden death. Myocardial mechanics have not been well studied in adults with AN. Whether LV mass or illness duration, markers of AN severity, correlate with abnormal strain imaging is unknown. We performed a prospective study among patients hospitalized with severe AN (n = 29) [body mass index (BMI) < 14.5 kg/m2] and sex/age-matched controls (n = 16) (BMI > 18.5 kg/m2). LV ejection fraction (LVEF) was calculated via modified-biplane method and LV mass was derived using the truncated ellipsoid formula. Apical 2-, 3-, and 4-chamber images were used to generate regional strain mapping and global longitudinal strain (GLS). N-terminal brain natriuretic peptide (NT-proBNP) levels were measured and linear regression was used to determine independent predictors of strain. Mean LVEF did not differ (65% ± 6.0 vs. 62% ± 4.4, p = 0.06), but LV mass was substantially reduced (61.6 ± 16.8 vs. 97.6 ± 19.1 g, p < .0001). GLS was similar (-20.6 ± 3.8 vs. -20.9 ± 2.8, p = 0.82), however, the basal strain was worse (-18.7 ± 4.8 vs. -21.9 ± 4.1, p = 0.03). Lower LV mass was associated with worsening GLS (r = -0.40, p = 0.003), but not among controls (p = 0.89). Median (IQR) NT-proBNP (pg/ml) was higher in patients with AN [141 (59-257) vs. 35.5 (21-56.5) p = 0.0007]. Both increasing NT-proBNP and illness duration were associated with worsening strain patterns in AN (both p = .001). While LVEF and GLS did not differ, regional strain variation was noted among patients with AN. Elevated NT-proBNP may reflect increased wall tension from LV atrophy. Whether strain heterogeneity can identify patients with AN, at risk for sudden death, requires further study.

Novel left ventricular mechanical index in pulmonary arterial hypertension.

Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N-terminal pro B-type natriuretic peptide(r = 0.73, p < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions.

Determinants of Left Ventricular Dysfunction and Remodeling in Patients With Corrected Tetralogy of Fallot.

BackgroundThe aim of this study was to identify in asymptomatic patients with repaired tetralogy of Fallot the prevalence and determinants of impaired left‐sided cardiac function and adverse ventricular remodeling and the relation of left ventricular (LV) dysfunction and remodeling with cardiopulmonary exercise capacity.Methods and ResultsIn a cross‐sectional study, 103 patients with tetralogy of Fallot (median age, 16.3 years) in New York Heart Association class 1, with surgical repair at a median age of 1.1 years, and 63 age‐matched controls were studied. LV, right ventricular function and geometry, LV myocardial extracellular volume (n=57), and left atrial function were quantified with cardiac magnetic resonance. Peak oxygen consumption was measured by a standardized cardiopulmonary exercise test (n=70). Patients with tetralogy of Fallot had lower LV ejection fraction (P=0.001; 49% below age‐adjusted fifth percentile for controls), lower LV mass index (P=0.003), lower LV mass/volume ratio (P<0.01), and impaired left atrial function. Right ventricular mass/volume ratio was the best predictor for LV systolic dysfunction and for a lower LV mass/volume ratio. Compared with controls, LV extracellular volume was higher (P<0.001), particularly in female patients, and associated with subnormal peak oxygen consumption (P=0.037). A peak oxygen consumption below the third percentile reference level was more likely with decreasing LV ejection fraction (P=0.008), and lower LV mass index (P=0.024), but independent of right ventricular ejection fraction.ConclusionsIn New York Heart Association class 1 patients with tetralogy of Fallot, frequent impaired systolic and diastolic LV function, LV adverse remodeling with LV atrophy, a decreased mass/volume ratio, and extracellular matrix expansion suggest cardiomyopathic changes. The best predictor for LV systolic dysfunction was the right ventricular mass/volume ratio. The subnormal peak oxygen consumption indicates that monitoring of LV status may be important for long‐term prognosis.

Abstract 17263: Pre-Clinical Left Ventricular Myocardial Remodeling in Patients With Friedreich’s Ataxia: A Cardiac MRI Study

Background: Heart Failure (HF) is the most common cause of death in Friedreich’s ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis is a well-documented histopathological feature among FRDA patients with HF. Objectives: In this study we will investigate the myocardial extracellular volume fraction (ECV) and intracellular water lifetime (τ ic ), using T1-weighted CMR imaging, in a cohort of patients with FRDA without signs of heart failure. We will also investigate whether myocardial tissue phenotyping by CMR can highlight particular characteristics of LV remodeling in FRDA’s cardiomyopathy, beyond those currently assessed with imaging-based classification of disease severity. Methods: Twenty-six FRDA’s patients (age 26.6±9.3 years, 15 women) without signs of HF, and 10 healthy controls (32.6±7.3 years, 5 women) underwent cardiac magnetic resonance (CMR) studies for assessment of left ventricular (LV) function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τ ic ) as marker of cardiomyocyte size. Neurological decline was determined using the FRDA rating scale (FARS 3). Results: FRDA patients had normal LV ejection fraction (LVEF: 67.66±11.4 vs. 63.9±9.0, P=0.311), larger LV mass index (LVMASSi: 61.03±22.1 vs. 45±4.2g/m 2 , P&lt;0.001), and decreased LV end-diastolic volume index (LVEDVi 53.42±12 vs. 75.7±16.1, P=0.002), compared with controls. ECV and τ ic , were increased in FRDA patients (ECV: 0.36±0.05 vs. 0.25±0.02, P&lt;0.0001; τ ic : 0.13±0.07 vs. 0.06±0.03, P=0.001). ECV was positively associated with LV mass-to-volume ratio (r=0.628, P&lt;0.001). FARS 3 correlated positively with disease duration (r=0.669, P&lt;0.001), and negatively with τ ic , (r=0.478, P=0.039). LVMASSi and cardiomyocyte mass-index [(1–ECV)LVMASSi] declined with age, indicating that LV hypertrophy may transition to a “burn-out” phase with LV atrophy. Conclusions: LV hypertrophy in FRDA reflects an expansion of the myocardial interstitium and an increase in cardiomyocyte size. In contrast, the neurological decline was more likely with decreasing cardiomyocyte size, possibly an early sign of myocardial “burn-out” in FRDA.

Experimental Spinal Cord Injury Causes Left-Ventricular Atrophy and Is Associated with an Upregulation of Proteolytic Pathways.

Spinal cord injury (SCI) causes autonomic dysfunction, altered neurohumoral control, profound hemodynamic changes, and an increased risk of heart disease. In this prospective study, we investigated the cardiac consequences of chronic experimental SCI in rats by combining cutting edge in vivo techniques (magnetic resonance imaging [MRI] and left-ventricular [LV] pressure-volume catheterization) with histological and molecular assessments. Twelve weeks post-SCI, MRI-derived structural indices and in vivo LV catheterization-derived functional indices indicated the presence of LV atrophy (LV mass in Control vs. SCI = 525 ± 38.8 vs. 413 ± 28.6 mg, respectively; p = 0.0009), reduced ventricular volumes (left-ventricular end-diastolic volume in Control vs. SCI = 364 ± 44 vs. 221 ± 35 μL, respectively; p = 0.0004), and contractile dysfunction (end-systolic pressure-volume relationship in Control vs. SCI = 1.31 ± 0.31 vs. 0.76 ± 0.11 mm Hg/μL, respectively; p = 0.0045). Cardiac atrophy and contractile dysfunction in SCI were accompanied by significantly lower blood pressure, reduced circulatory norepinephrine, and increased angiotensin II. At the cellular level, we found the presence of reduced cardiomyocyte size and increased expression of angiotensin II type 1 receptors and transforming growth factor-beta receptors (TGF-β receptor 1 and 2) post-SCI. Importantly, we found more than a two-fold increase in muscle ring finger-1 and Beclin-1 protein level following SCI, indicating the upregulation of the ubiquitin-proteasome system and autophagy-lysosomal machinery. Our data provide novel evidence that SCI-induced cardiomyocyte atrophy and systolic cardiac dysfunction are accompanied by an upregulation of proteolytic pathways, the activation of which is likely due to loss of trophic support from the sympathetic nervous system, neuromechanical unloading, and altered neurohumoral pathways.

Low body mass index correlates with low left ventricular mass index in patients with severe anorexia nervosa.

The patients with anorexia nervosa (AN) are known to be associated with high mortality, but the actual causes of death are still undefined. We tested the hypothesis that AN patients had cardiac disorders, including left ventricular (LV) dysfunction and LV atrophy. This study is a cross-sectional study at St. Luke's International Hospital, Tokyo. We analyzed 13 female inpatients with AN. We assessed cardiac function and heart volume in AN by echocardiography, LV ejection fraction (LVEF), LV mass, and LV mass index (LVMI). We assessed the correlations between body mass index (BMI) and heart volume (LV mass and LVMI). The mean age and BMI were 34.8±11.2years and 15.5±3.1kg/m2, respectively. There was no patient with mitral valve prolapse, but 3 patients had trivial to small amount of pericardial effusion. The mean LVEF was 67.7±6.5%, and 12 out of 13 patients had normal LVEF. Their LV mass (89.0±27.3g) and LVMI (66.3±16.4g/m2) were small. BMI positively correlated with LVMI (r=0.58, p=0.040), as well as LV mass (r=0.74, p=0.004). Lower BMI reflects lower LVMI, as well as smaller LV mass. These issues suggest that heart volume is initially decreased in severe AN conditions. Low LVMI could be a good marker of severity of AN.

Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism.

Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.

Myocardial remodelling in left ventricular atrophy induced by caloric restriction

Changes in body weight due to changes in food intake are reflected by corresponding changes in the cardiac phenotype. Despite a growing body of literature on cardiac hypertrophy associated with obesity, little is known on the atrophic remodelling of the heart associated with calorie restriction. We hypothesized that, besides the cardiomyocyte compartment, capillaries and nerve fibres are involved in the atrophic process. C57Bl6 mice were kept on normal diet (control group) or at a calorie-restricted diet for 3 or 7 days (n = 5 each). At the end of the protocol, mice were killed and the hearts were processed for light and electron microscopic stereological analysis of cardiomyocytes, capillaries and nerve fibres. Body, heart and left ventricular weight were significantly reduced in the calorie-restricted animals at 7 days. Most morphological parameters were not significantly different at 3 days compared with the control group, but at 7 days most of them were significantly reduced. Specifically, the total length of capillaries, the volume of cardiomyocytes as well as their subcellular compartments and the interstitium were proportionally reduced during caloric restriction. No differences were observed in the total length or the mean diameter of axons between the cardiomyocytes. Our data indicate that diet-induced left ventricular atrophy leads to a proportional atrophic process of cardiomyocytes and capillaries. The innervation is not involved in the atrophic process.

Right Ventricular Failure Following Chronic Pressure Overload Is Associated With Reduction in Left Ventricular Mass: Evidence for Atrophic Remodeling

We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy.The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction.We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization.At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV.RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.

Increased Cardiac Alpha-Myosin Heavy Chain in Left Atria and Decreased Myocardial Insulin-Like Growth Factor (IGF-I) Expression Accompany Low Heart Rate in Hibernating Grizzly Bears

Grizzly bears (Ursus arctos horribilis) tolerate extended periods of extremely low heart rate during hibernation without developing congestive heart failure or cardiac chamber dilation. Left ventricular atrophy and decreased left ventricular compliance have been reported in this species during hibernation. We evaluated the myocardial response to significantly reduced heart rate during hibernation by measuring relative myosin heavy-chain (MyHC) isoform expression and expression of a set of genes important to muscle plasticity and mass regulation in the left atria and left ventricles of active and hibernating bears. We supplemented these data with measurements of systolic and diastolic function via echocardiography in unanesthetized grizzly bears. Atrial strain imaging revealed decreased atrial contractility, decreased expansion/reservoir function (increased atrial stiffness), and decreased passive-filling function (increased ventricular stiffness) in hibernating bears. Relative MyHC-α protein expression increased significantly in the atrium during hibernation. The left ventricle expressed 100% MyHC-β protein in both groups. Insulin-like growth factor (IGF-I) mRNA expression was reduced by ∼50% in both chambers during hibernation, consistent with the ventricular atrophy observed in these bears. Interestingly, mRNA expression of the atrophy-related ubiquitin ligases Muscle Atrophy F-box (MAFBx) and Muscle Ring Finger 1 did not increase, nor did expression of myostatin or hypoxia-inducible factor 1α (HIF-1α). We report atrium-specific decreases of 40% and 50%, respectively, in MAFBx and creatine kinase mRNA expression during hibernation. Decreased creatine kinase expression is consistent with lowered energy requirements and could relate to reduced atrial emptying function during hibernation. Taken together with our hemodynamic assessment, these data suggest a potential downregulation of atrial chamber function during hibernation to prevent fatigue and dilation due to excessive work against an optimally filled ventricle, a response unpredicted by the Frank-Starling mechanism.

Does the β 2 -Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading?

Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a beta2-adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, beta2-AR stimulation is reported to improve Ca2+ handling and contribute to antiapoptosis. However, there is little information on the effects of clenbuterol during LV unloading. We investigated LV atrophy and function after LV unloading produced by heterotopic heart transplantation in isogenic rats. After transplantation, rats were randomized to 1 of 2 groups (n=10 each). The clenbuterol group received 2 mg.kg(-1).d(-1) of the drug for 2 weeks; the control group received normal saline. The weight of unloaded control hearts was 48% less than that of host hearts after 2 weeks of unloading. Clenbuterol significantly increased the weight of the host hearts but did not prevent unloading-induced LV atrophy. Papillary muscles were isolated and stimulated, and there was no difference in developed tension between the 2 groups. However, the inotropic response to the beta-AR agonist isoproterenol significantly improved in the clenbuterol group. The mRNA expression of myocardial sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) and fetal gene shift (myosin heavy chain [MHC] mRNA isozyme) was also significantly improved by clenbuterol treatment. There was no difference in beta1-AR mRNA expression between the 2 groups. In contrast, beta2-AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate beta2-ARs. In the evaluation of apoptosis, mRNA expression of caspase-3, which is the central pathway for apoptosis, tended to be better in the clenbuterol group. During complete LV unloading, clenbuterol did not prevent myocardial atrophy but improved gene expression (SERCA2a, beta-MHC) and beta-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of beta2-ARs.

Bethesda conference: conference for the design of clinical trials to study circulatory support devices for chronic heart failure

James M. Anderson, MD Eugene H. Blackstone, MD Harvey S. Boroevetz, PhD Arthur Ciarkowski, MD Jack G. Copeland III, MD Maria Rosa Costanzo-Nordin, MD Kurt Daase, MD Mary Amanda Dew, PhD Michael J. Domanski, MD Benjamin H. Eidleman, MD Roger W. Evans, PhD David J. Farrar, PhD O. H. Frazier, MD Bartley P. Griffith, MD Charles-Julien Hahn, MD J. Donald Hill, MD Sharon Hunt, MD Kay Kendell, RN Robert L. Kormos, MD Howard R. Levin, MD Donna M. Mancini, MD Patrick M. McCarthy, MD Dennis McNamara, MD Fr Kevin O’Rourke, PhD Lisa Parker, PhD D. Glenn Pennington, MD Victor L. Poirier, PhD Peer M. Portner, PhD Eric A. Rose, MD Wolf Sapirstein, MD Eleanor Schron, MD Rhona Shanker, MD Ramiah Subramanian, MD John Wallwork, MD Lynne Warner Stevenson, MD

Role of protein turnover in Lisinopril (an ace-inhibitor) induced left ventricular atrophy

Role of protein turnover in Lisinopril (an ace-inhibitor) induced left ventricular atrophy

Reversal of adaptive left ventricular atrophy following electrically-stimulated exercise training in human tetraplegics

Left ventricular (LV) myocardial atrophy and diminished cardiac function have been shown to accompany chronic human tetraplegia. These changes are attributable both to physical immobilisation and abnormal autonomic circulatory regulation imposed by a spinal cord injury (SCI). To test whether exercise training increases LV mass following chronic SCI, 8 neurologically complete quadriplegic males at 2 SCI rehabilitation and research centres underwent one month of electrically-stimulated quadriceps strengthening followed by 6 months of electrically-stimulated cycling exercise. Resting M-mode and 2-D echocardiograms were measured before and after exercise training to quantify the interventricular septal and posterior wall thicknesses at end-diastole (IVSTED and PWTED, respectively), and the LV internal dimension at end-diastole (LVIDED). LV mass was computed from these measurements using standard cube function geometry. Results showed a 6.5% increase in LVIDED following exercise training (p less than 0.02), with increases in IVSTED and PWTED of 17.8 (p less than 0.002) and 20.3% (p less than 0.01), respectively. Computed LV mass increased by 35% following exercise training (p = 0.002). These data indicate that myocardial atrophy is reversed in tetraplegics following electrically-stimulated exercise training, and that the changes in cardiac architecture are likely to be the result of both pressure and volume challenge to the heart imposed by exercise.

Evolution of human cardiac myocyte dimension during prolonged mechanical support

In animal models using left ventricular assist systems over long time periods, myocardial cellular atrophy has been reported, raising concern that prolonged clinical use of such systems might lead to deterioration in left ventricular function. At the University of Pittsburgh, long-term clinical use of the Novacor (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.) left ventricular support system for patients awaiting heart transplants has allowed study of the effects of long-term mechanical support on human subjects. This study determined that cardiac myocyte dimension is initially greater in patients with end-stage cardiac disease who require support rather than in patients with the same disease who do not require such support. Although myocyte dimension does decrease within a few days of the inception of support, this decrease merely brings cell size closer to the values usual in patients with chronic end-stage cardiac disease, and no further shrinkage is observed. Thus the Novacor left ventricular assist system does not appear associated with left ventricular atrophy, and its long-term use may not be detrimental to left ventricular function.

Protein synthesis and degradation during starvation-induced cardiac atrophy in rabbits.

To determine the relative importance of protein degradation in the development of starvation-induced cardiac atrophy, in vivo fractional synthetic rates of total cardiac protein, myosin heavy chain, actin, light chain 1, and light chain 2 were measured in fed and fasted rabbits by continuous infusion of [3H] leucine. In addition, the rate of left ventricular protein accumulation and loss were assessed in weight-matched control and fasted rabbits. Rates of total cardiac protein degradation were then estimated as the difference between rates of synthesis and growth. Fasting produced left ventricular atrophy by decreasing the rate of left ventricular protein synthesis (34.8 +/- 1.4, 27.3 +/- 3.0, and 19.3 +/- 1.2 mg/day of left ventricular protein synthesized for 0-, 3-, and 7-day fasted rabbits, respectively). Inhibition of contractile protein synthesis was evident by significant reductions in the fractional synthetic rates of all myofibrillar protein subunits. Although fractional rates of protein degradation increased significantly within 7 days of fasting, actual amounts of left ventricular protein degraded per day were unaffected. Thus, prolonged fasting profoundly inhibits the synthesis of new cardiac protein, including the major protein constituents of the myofibril. Both this inhibition in new protein synthesis as well as a smaller but significant reduction in the average half-lives of cardiac proteins are responsible for atrophy of the heart in response to fasting.