Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy

An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alphaMHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using 31P nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alphaMHC403/+ mouse hearts. First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alphaMHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alphaMHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alphaMHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.     

Diastolic dysfunction in hypertrophic myocardiopathy: evaluation with radioisotopic ventriculography

Diastolic function was evaluated in 13 patients with hypertrophic cardiomyopathy and 10 normal subjects of comparable age. Time-activity curves were used to derive peak filling rate, time to peak filling rate and average filling velocity during the first third of diastole. Left ventricular ejection fraction was significantly higher in patients with hypertrophic cardiomyopathy. Time to peak filling rate and filling velocity during the first third of diastole were significantly lower in patients compared to controls. Thus, radionuclide techniques can be used to evaluate diastolic filling in clinical practice.     

Pregnancy-induced severe left ventricular systolic dysfunction in a patient with hypertrophic cardiomyopathy

This paper reports the first case of hypertrophic cardiomyopathy (HCM) that developed postpartum congestive heart failure (CHF) and severe left ventricular (LV) systolic dysfunction. Review of the literature and clinical implications are discussed.     

Familial hypertrophic cardiomyopathy

Investigating the family consisted of 8 members authors confirmed the diagnosis of hypertrophic cardiomyopathy in 5 cases. Secondly clinical features and echocardiographic data were compared. The clinical symptoms were not proportional to the pattern of hypertrophy revealed by echocardiography. The most significant pattern of hypertrophy was registered in youngest patients most likely due to increased expression and penetration of responsible genes. Considering cardiomyopathy as an inherited disease authors find family screening as a key in understanding and management of the disease.     

Coronary vasodilator reserve is impaired in patients with hypertrophic cardiomyopathy and left ventricular dysfunction

PURPOSE: To determine whether low concentrations of glutamate induce cell death in purified rat retinal ganglion cells (RGCs). METHODS: Rat retinal ganglion cells were purified from dissociated retinal cells by a modified two-step panning method and were cultured in serum-free medium containing neurotrophic factors and forskolin. Survival of RGCs after exposure to glutamate, with or without glutamate receptor antagonists, was measured by calcein-acetoxymethyl ester staining after 3 days in culture. To visualize calcium signals, RGCs were loaded with the calcium indicator dye, fluo-3 acetoxymethyl ester, and fluorescence was measured by laser scanning confocal microscope. Electrophysiological properties of RGCs were examined by using the whole-cell, patch-clamp technique. RESULTS: The application of increasing concentrations (5-500 microM) of glutamate caused a dose-dependent increase in RGC death after 3 days in culture. Neurotoxic effects of low doses of glutamate were totally blocked by a specific alpha-amino-3-dihydro-5-methyl-isoxazol-4-propionic acid-kainate (AMPA-KA) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but not by a specific N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovalerate (APV). In addition, calcium imaging and patch-clamp recordings showed that intracellular calcium accumulation and glutamate-evoked inward currents were completely blocked by DNQX but not by APV. CONCLUSIONS: Low doses of glutamate can activate AMPA-KA receptors in RGCs, which causes increases in intracellular calcium and decreases in cell survival. This is the first report to show the functional role of calcium-permeable AMPA-KA receptors in cultured RGCs.     

Iatrogenic neonatal hypertrophic cardiomyopathy

The expression of adhesion molecules and matrix proteins by human spermatozoa as well as their binding to and penetration of zona-free hamster eggs were investigated in 17 patients by means of flow cytometry. Both binding and penetration of hamster oocytes and expression of alpha- and beta-chains of beta 1, beta 3 and beta 4 integrins were determined before and after induction of the acrosome reaction. The expression of the integrin ligands, fibronectin and laminin were also analysed. Significant differences in the expression of very late antigen (VLA) integrins, VLA alpha 4-chain (CD49d), the classical fibronectin receptor VLA alpha 5-chain (CD49e), leukocyte function-associated molecule-3 (LFA-3; CD58) and fibronectin were observed between patients showing good (> 10%) or poor (< 10%) penetration in the sperm penetration assay (P = 0.0068). It is concluded that these adhesion molecules are intimately involved in the sperm-oolemma interaction. Since no differences were observed in either spermiogram parameters or the percentages of acrosome-reacted spermatozoa in the two groups, sperm-oolemma binding and penetration should be regarded as discrete parameters of sperm function.     

Treatment of hypertrophic cardiomyopathy

The medical management of hypertrophic cardiomyopathy is reviewed. Four cases of hypertrophic cardiomyopathy are presented, and serve to describe the currently available invasive treatment modalities, i.e. septal myectomy, dual chamber pacing, cardioverter defibrillator implantation and heart transplantation. These different invasive treatments all seem to be symptomatically effective in carefully selected patients, but studies of prognostic effects are not available. Finally, new experimental procedures are presented.     

Pathological analysis of hypertrophic cardiomyopathy simulating dilated cardiomyopathy

The pathomorphologic features of hypertrophic cardiomyopathy simulating dilated cardiomyopathy in the late stage (HCM-DCM) were compared with those of ordinary hypertrophic cardiomyopathy (HCM). Seven autopsied hearts with HCM-DCM and 11 with HCM were assessed quantitatively using an image analyzer. Unlike HCM, significant left ventricular enlargement and wall thinning were observed in HCM-DCM, and the percentage areas of massive fibrosis and disarray were significantly greater. In HCM-DCM, the disarray was distributed diffusely, whereas massive fibrosis was distributed more intensively in the ventricular septum and anterior wall than in the lateral and posterior wall. Narrowing of intramyocardial small arteries was observed more frequently in HCM-DCM, especially in the ventricular septum and anterior wall, than in HCM. These results suggest that the enlargement and wall thinning of the left ventricle in HCM-DCM are attributable to non-uniform progression of massive fibrosis, which is closely related to small-arterial lesions.     

Use of pulsed Doppler tissue imaging to assess regional left ventricular diastolic dysfunction in hypertrophic cardiomyopathy

In this study, regional diastolic patterns and their relations with transmitral Doppler inflow were investigated in hypertrophic cardiomyopathy (HC) by pulsed Doppler tissue imaging (DTI). Doppler echocardiography and DTI of basal septum and lateral wall (apical 4-chamber view) were performed in 20 patients (15 men and 5 women) with HC and in 10 healthy subjects (7 men and 3 women). Diabetes, hypertension, coronary artery and valvular disease, mitral regurgitation, New York Heart Association functional classes III to IV, sinus tachycardia, atrial fibrillation, and inadequate echocardiograms were exclusion criteria. Peak velocity and time-velocity integral of early and late waves and their ratios, and deceleration and isovolumic relaxation times were determined by standard Doppler and by DTI at the septal and lateral wall levels. The 2 groups were comparable for age, heart rate, blood pressure, and ejection fraction. Transmitral peak velocity and time-velocity integral E/A ratios were reduced (both p <0.05) and deceleration and isovolumic relaxation times prolonged (both p <0.00001) in HC. Septal DTI showed lower peak velocity and time-velocity integral e/a ratios (p <0.00001 and p <0.001, respectively) and lengthened regional deceleration (p <0.01) and isovolumic (p <0.001) relaxation times. DTI of the lateral wall showed a prolongation of deceleration and isovolumic relaxation times (both p <0.01). By dividing HC according to transmitral E/A, 8 patients with E/A <1 had lower DTI septal e/a ratio (p <0.01) and prolonged septal deceleration and isovolumic relaxation times (both p <0.01) but no changes in DTI pattern of lateral wall than 12 patients with E/A > 1. In conclusion, DTI is useful and complementary to standard Doppler imaging to characterize diastolic properties in HC, reflecting a typical pattern of intramyocardial impaired relaxation at the level of hypertrophied septum and also providing information about the degree of this regional impairment. The lateral wall presents minor changes in diastolic times, which indicate how diastolic asynchrony is not confined to the hypertrophied segment in HC.     

Brain natriuretic peptide in hypertrophic obstructive cardiomyopathy

The objective was to study potential bacterial virulence factors in S. aureus endocarditis. S. aureus strains isolated from patients with well-classified episodes of infective endocarditis (IE) (n=26) were compared with control S. aureus strains from consecutive patients with skin infections (n=30). The potential virulence factors studied were Staphylococcal enterotoxin A-D (SEA, SEB, SEC, SED) and toxic shock syndrome toxin-1 (TSST-1) production and binding capacity to the extracellular matrix proteins: fibronectin, collagen type I, collagen type II and bone sialoprotein (BSP). None of the potential virulence factors studied was more prevalent among the IE strains. BSP binding was more often found in the control group with skin infections. Endocarditis patients with previous damage of the heart valves were more often infected by strains not producing any enterotoxin. No correlation was found between the potential bacterial virulence factors studied and IE. Concerning the toxins known to act as superantigens (SEA-E and TSST-1), the tendencies in this and other studies indicate that a larger study group might identify them as pathogenic factors in a subgroup of staphylococcal endocarditis.     

Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy

BACKGROUND: In hypertrophic cardiomyopathy, ejection fraction is normal or increased, and force-length relations are reduced. However, three-dimensional (3D) motion and deformation in vivo have not been assessed in this condition. We have reconstructed the 3D motion of the left ventricle (LV) during systole in 7 patients with hypertrophic cardiomyopathy (HCM) and 12 normal volunteers by use of magnetic resonance tagging. METHODS AND RESULTS: Transmural tagging stripes were automatically tracked to subpixel resolution with an active contour model. A 3D finite-element model was used to interpolate displacement information between short- and long-axis slices and register data on a regional basis. Displacement and strain data were averaged into septal, posterior, lateral, and anterior regions at basal, midventricular, and apical levels. Radial motion (toward the central long axis) decreased slightly in patients with HCM, whereas longitudinal displacement (parallel to the long axis) of the base toward the apex was markedly reduced: 7.5 +/- 2.5mm (SD) versus 12.5 +/- 2.0 mm, P < .001. Circumferential and longitudinal shortening were both reduced in the septum (P < .01 at all levels). The principal strain associated with 3D maximal contraction was slightly depressed in many regions, significantly in the basal septum (-0.18 +/- 0.05 versus -0.22 +/- 0.02, P < .05) and anterior (-0.20 +/- 0.05 versus -0.23 +/- 0.02, P < .05) walls. In contrast, LV torsion (twist of the apex about the long axis relative to the base) was greater in HCM patients (19.9 +/- 2.4 degrees versus 14.6 +/- 2.7 degrees, P < .01). CONCLUSIONS: HCM patients had reduced 3D myocardial shortening on a regional basis; however, LV torsion was increased.     

Pacing in distal left ventricular hypertrophic cardiomyopathy

We report the case of an 85-year-old woman with distal LV hypertrophy resulting in an intraventricular pressure gradient and incomplete systolic emptying who benefited from permanent DDD pacing. Our experience based on this case suggests that permanent dual chamber pacing might be a safe and effective therapy also in symptomatic patients with the rare form of hypertrophic cardiomyopathy with left mid-ventricular obstruction resulting in incomplete emptying of the apical portion of the LV and a significant intraventricular pressure gradient that was not responding to pharmacological therapy.