Free radical oxidation in patients with hypertrophic cardiomyopathy

As shown by the study of 27 patients with non-obstructive form of hypertrophic cardiomyopathy (HC), this disease is associated with a significant rise in the production of active oxygen forms by leukocytes, significant changes in the activity of enzyme antioxidant defense, unchanged lipid peroxidation, high total antioxidant activity of blood plasma. The patients received a complex of natural antioxidants varying by mechanism of action and glutaminic acid. Antioxidants produced a subjective clinical response, reduced incidence of cardiac arrhythmia, improved exercise tolerance. The response becomes still better in combination of antioxidants with conventional therapeutic tools.     

Prognosis of completely asymptomatic adult patients with hypertrophic cardiomyopathy

OBJECTIVES: We investigated the long-term prognosis of completely asymptomatic adult patients with hypertrophic cardiomyopathy (HC). Diagnosis of HC was suspected because of an abnormal electrocardiogram and/or cardiac murmur and confirmed by echocardiography and/or left ventricular angiography, and hemodynamic investigation. BACKGROUND: Hypertrophic cardiomyopathy shows marked heterogeneity in clinical expression and prognosis. The prognosis of asymptomatic patients with HC has not been fully defined. METHODS: Of 128 consecutive adult patients with HC, 58 asymptomatic patients (Group 1, mean age 42.8 years) and 70 symptomatic patients (Group 2, mean age 50.4 years) were studied to assess cardiac mortality. Mean follow-up periods were 11.0 years for Group 1 and 9.1 years for Group 2. RESULTS: At presentation, Group 1 patients were younger and had smaller left atrial dimensions than did Group 2 patients. The annual cardiac mortality rate and the rate for sudden death alone in Group 1 were significantly lower than in Group 2 (0.9% vs. 1.9%, p < 0.05, 0.1% vs. 1.4%, p < 0.05, respectively). Although about one-third of the survivors in Group 1 had cardiac symptoms at their most recent evaluation, only one patient died suddenly compared with eight in Group 2. The annual mortality rate due to heart failure was similar in each group. Only a syncopal episode was associated with both cardiac death and sudden death for both groups combined. CONCLUSIONS: The cardiac mortality rate for completely asymptomatic adult patients with HC was very low, significantly lower than that of symptomatic patients, and there was a disproportionately low incidence of sudden death.     

Is there increased sympathetic activity in patients with hypertrophic cardiomyopathy?

OBJECTIVES: This study aimed to assess autonomic nervous system activity in patients with hypertrophic cardiomyopathy. BACKGROUND: Patients with hypertrophic cardiomyopathy are traditionally thought to have increased sympathetic activity. However, convincing evidence is lacking. METHODS: Heart rate variability was assessed from 24-h ambulatory electrocardiographic (Holter) recordings in 31 patients with hypertrophic cardiomyopathy and 31 age- and gender-matched normal control subjects in a drug-free state. Spectral heart rate variability was calculated as total (0.01 to 1.00 Hz), low (0.04 to 0.15 Hz) and high (0.15 to 0.40 Hz) frequency components using fast Fourier transformation analysis. RESULTS: There was a nonsignificant decrease in the total frequency component of heart rate variability in patients with hypertrophic cardiomyopathy compared with that of normal subjects (mean +/- SD 7.24 +/- 0.88 versus 7.59 +/- 0.57 ln[ms2], p = 0.072). Although there was no significant difference in the high frequency component (5.31 +/- 1.14 versus 5.40 +/- 0.91 ln[ms2], p = 0.730), the low frequency component was significantly lower in patients than in normal subjects (6.25 +/- 1.00 versus 6.72 +/- 0.61 ln[ms2], p = 0.026). After normalization (i.e., division by the total frequency component values), the low frequency component was significantly decreased (38 +/- 8% versus 43 +/- 8%, p = 0.018) and the high frequency component significantly increased (16 +/- 6% versus 12 +/- 6%, p = 0.030) in patients with hypertrophic cardiomyopathy. The low/high frequency component ratio was significantly lower in these patients (0.94 +/- 0.64 versus 1.33 +/- 0.55, p = 0.013). In patients with hypertrophic cardiomyopathy, heart rate variability was significantly related to left ventricular end-systolic dimension and left atrial dimension but not to maximal left ventricular wall thickness. No significant difference in heart rate variability was found between 14 victims of sudden cardiac death and 10 age- and gender-matched low risk patients. CONCLUSIONS: Our observations suggest that during normal daily activities, patients with hypertrophic cardiomyopathy experience a significant autonomic alteration with decreased sympathetic tone.     

Augmented exercise plasma noradrenaline with impaired chronotropic responsiveness in patients with hypertrophic cardiomyopathy

1. There is controversy regarding plasma catecholamine levels in patients with hypertrophic cardiomyopathy (HCM) and few data exist on serial plasma catecholamine measurements during exercise. The present study determined whether cardiovascular and plasma catecholamine responses to exercise were altered in patients with HCM. 2. Plasma noradrenaline (NA) and adrenaline were measured at rest, at the end of each stage during exercise and immediately and 5 min after submaximal treadmill exercise in 15 patients with non-obstructive HCM (13 males, two females; mean (+/- SEM) age 54 +/- 3 years) and in 15 age- and sex-matched controls. The ratio of the increment in heart rate (HR) divided by the increment in plasma NA during exercise (delta HR/delta NA) was used as an index of chronotropic sympathetic responsiveness to exercise. 3. Exercise duration was shorter (11.2 +/- 0.6 vs 8.7 +/- 0.6 min for control vs HCM, respectively; P < 0.01) and diastolic blood pressure was significantly higher at stages I and II of modified Bruce protocol HCM. 4. Resting plasma NA levels (149 +/- 17 vs 167 +/- 28 pg/mL for control vs HCM, respectively; NS) were not different, but plasma NA levels at stages I and II were significantly higher in HCM than in controls (243 +/- 26 vs 399 +/- 69 pg/mL (P < 0.05) and 308 +/- 30 vs 548 +/- 110 pg/mL (P < 0.05), respectively). 5. Peak plasma NA levels were not significantly higher in HCM than in controls (578 +/- 59 vs 918 +/- 184 pg/mL, respectively; NS). 6. The ratio delta HR/delta NA was significantly lower in HCM compared with control at stages I and II (0.49 +/- 0.10 vs 0.21 +/- 0.05 (P < 0.05) and 0.38 +/- 0.06 vs 0.20 +/- 0.05 (P < 0.05), respectively). There were no differences in plasma adrenaline responses during exercise between the two groups. 7. Patients with HCM had augmented plasma NA levels during submaximal exercise with a higher diastolic blood pressure response. Chronotropic sympathetic responsiveness was impaired during the early stages of exercise in patients with HCM.     

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.     

Ultrastructural changes of blood capillaries in patients with microvascular angina, hypertrophic cardiomyopathy, and dilated cardiomyopathy

The rat model has been used to present evidence of the effect of surgical damage on the immune system. Syngeneic small bowel transplantation (SBT) has been used to show an increased incidence of graft-versus-host disease (GVHD) as well as thymic atrophy and altered host T cell proliferative response. Syngeneic auxiliary SBT was carried out between (LEW x BN)F1 hybrids. Varying amounts of LEW mesenteric lymphocytes were injected into the last animals to induce GVHD. Results showed that in the SBT recipients the incidence of lethal GVHD was increased when compared with untreated or sham-laparotomy controls. Marked thymic atrophy was also observed, while the number of hepatic lymphocytes increased transiently. Lymphocyte proliferation in response to concanavalin A or interleukin-2 was impaired for up to 21 days postoperatively, whereas the mixed lymphocyte reaction reactivity was not affected. These results show that the number and proliferative activity of thymic T cells were impaired after major small bowel transplantation surgery and that extrathymic lymphocytes were developed in the liver.     

31P NMR spectroscopy detects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) often causes sudden, unexpected death in adolescents and young adults. Alterations in myocardial metabolism are considered to be causes for contractile dysfunction. We examined the question of whether metabolic abnormalities antedate the manifestation of symptoms in patients with HCM. METHODS AND RESULTS: Proton-decoupled 31P NMR spectroscopy of the anterior left ventricular wall of the heart of 14 young, asymptomatic patients with HCM was performed with a 1.5-T whole-body imager. Spectra of the phosphate metabolites were compared with those of normal control subjects. The patients exhibited a significantly reduced (P<0.02) ratio of phosphocreatine (PCr) to ATP of 1.98+/-0.37 (mean+/-SD), compared with 2.46+/-0.53 obtained in 11 normal control subjects. In addition, the group of patients with severe hypertrophy of the interventricular septum (n=8) showed a significantly increased (P<0.05) Pi-to-PCr ratio, with a Pi x 100/PCr of 20.0+/-8.3 versus 9.7+/-7.2 in control subjects. Both abnormalities are similar to those found in ischemic myocardium. This view is also supported by a significantly increased (P<0.01) phosphomonoester (PME)-to-PCr ratio, with a PME x 100/PCr of 20.7+/-11.2 compared with 8.4+/-6.7 in control subjects, indicating altered glucose metabolism. CONCLUSIONS: 31P NMR spectroscopy detects alterations of myocardial metabolism in asymptomatic patients with HCM. These alterations may contribute to the understanding of the pathophysiology and natural history of the disease.     

Impaired heart rate variability in patients with symptomatic NYHA class II-III hypertrophic cardiomyopathy

Power spectral analysis of heart rate variability was performed to assess cardiac autonomic function using Holter monitoring in 19 hospitalized patients with symptomatic NYHA class II-III hypertrophic cardiomyopathy (sHCM), 20 ambulatory patients with asymptomatic NYHA class I hypertrophic cardiomyopathy (asHCM) and 20 normal control subjects. Power spectral analysis decomposed the heart rate variability into high-frequency power (HF: 0.15-0.40 Hz) and low-frequency power (LF: 0.04-0.15 Hz). HF was corrected by mean RR intervals (CCVHF). CCVHF values and LF/HF ratios were used as indices of vagal and sympathetic modulations, respectively. The sHCM group demonstrated no significant elevation in CCVHF during the nighttime as compared to the daytime, while asHCM and control groups showed significant CCVHF elevation during the nighttime (p < 0.05-0.01). The nighttime CCVHF, therefore, was significantly lower in the sHCM group than in the control or asHCM group (sHCM, 1.08 +/- 0.36%; control, 1.60 +/- 0.57%; asHCM 1.82 +/- 0.77%; sHCM vs. control or sHCM vs. asHCM, p < 0.01). All of these three groups showed significant reduction in LF/HF ratio during the nighttime as compared to the daytime (p < 0.01). However, the reduction in the sHCM group was not as great as that in the control group and there was a significant difference between the sHCM and control group (2.01 +/- 1.58 vs. 1.08 +/- 0.65, p < 0.05). Two patients in the sHCM group, who later died suddenly, demonstrated very low CCVHF throughout a 24-hour period (0.2-0.8%). Both vagal and sympathetic impairment with a predominance of vagal abnormalities is suggested in patients with symptomatic NYHA class II or III hypertrophic cardiomyopathy.     

Effects of postural changes on left atrial function in patients with hypertrophic cardiomyopathy

BACKGROUND: We assessed left atrial function in normal subjects and in patients with hypertrophic cardiomyopathy (HCM) by using Doppler echocardiography at the supine position and after sudden standing. METHODS AND RESULTS: Twenty-seven patients with hypertrophic obstructive cardiomyopathy (HOCM), 17 patients with HCM, and 35 normal subjects were studied. From the transmitral Doppler flow velocities, peak early and late (E and A) waves, E/A ratio, and time velocity integrals (Ei and Ai) were calculated. Left atrial active contribution (LAAC) was assessed as the ratio Ei/(Ei + Ai). Furthermore, isovolumetric relaxation time (IVRT) was estimated by means of Doppler echocardiography. In the supine position, the E/A ratio was similar in the 3 groups. Conversely, LAAC was significantly higher in patients with HOCM (24.4 +/- 2.0) and in patients with HCM (23.3 +/- 3.3) compared with normal subjects (20.3 +/- 2.3, P <.001 and P <.05, respectively). After sudden standing, LAAC increased significantly in normal subjects by 11%, in patients with HOCM by 24%, and in patients with HCM by 13% (P <.001). Similarly, IVRT increased significantly in all study groups (P <. 001). By using stepwise forward multiple linear regression analysis, we found that LAAC was associated with age, IVRT, and body mass index in the supine position and with diastolic blood pressure and IVRT in the standing position. CONCLUSIONS: Left atrial contribution to left ventricular filling was increased after sudden changes of posture in normal subjects and in patients with HOCM or HCM.     

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.     

Hypercalcemic cardiomyopathy associated with primary hyperparathyroidism mimicking primary obstructive hypertrophic cardiomyopathy

A 72-year-old woman presented to hospital with rapidly progressive dyspnea and chest pain on exertion. Physical findings included a grade 3/6 systolic murmur increased by the Valsalva manoeuvre. Transthoracic echocardiography revealed concentric left ventricular hypertrophy, systolic anterior motion of the mitral valve and critical dynamic outflow tract obstruction. The myocardium was strikingly heterogeneous with hyperdynamic left ventricular systolic function. Laboratory findings included severe hypercalcemia secondary to primary hyperparathyroidism. The patient's outcome was unfavourable with nephrogenic diabetes insipidus, pancreatitis, shock, severe acidosis and death. Postmortem examination confirmed the presence of severe concentric left ventricular hypertrophy, a narrowed left ventricular outflow tract and localized endocardial fibrosis of the left interventricular septum. Microscopic findings showed diffuse calcium deposits of the myocardium, coronary arteries, kidneys and lungs. This appears to be the first report of two-dimensional and Doppler echocardiographic findings in hypercalcemic cardiomyopathy mimicking obstructive hypertrophic cardiomyopathy.     

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.     

QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy

Growth hormone (GH) treatment is associated with a reduction in fat mass in healthy and GH-deficient (GHD) subjects. This is mainly mediated via a direct GH action on adipose cells and stimulation of lipolysis. Leptin is secreted from adipose tissue and may be involved in signaling information about adipose tissue stores to the brain. Hormonal regulation of leptin is still not fully elucidated, and in the present study, we investigated both the long-term (4-month) and short-term (28-hour) GH effects on serum leptin and leptin gene expression in subcutaneous adipose tissue. In GHD adults (n = 24), leptin correlated with most estimates of adiposity (r = .62 to .86), as previously found in healthy subjects. However, no correlation was observed with intraabdominal fat determined by computed tomographic (CT) scan (INTRA-CT). GH treatment for 4 months had no independent effect on either serum leptin or leptin gene expression. In a short-term study, we found that fasting gradually reduced leptin levels in both healthy men and GHD adults, with a maximum reduction of 58% to 60% (P < .01) after 31 hours. No independent effect of GH suppression or GH substitution on serum leptin was found during fasting. Adipose tissue leptin mRNA correlated with serum leptin (r = .51, P < .01) and the body mass index ([BMI] r = .55, P < .05). Serum leptin levels and gene expression were significantly higher in women compared with men (26.6 +/- 5.8 v 10.0 +/- 1.30 ng/mL, P < .05). However, in regression analysis accounting for the gender differences in subcutaneous femoral adipose tissue (FEM-CT), the difference in serum leptin disappeared, indicating that subcutaneous femoral fat or factors closely related to femoral fat (eg, sex hormones) may be causal factors for the gender difference in leptin.     

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.     

Effects of diltiazem on myocardial perfusion abnormalities during exercise in patients with hypertrophic cardiomyopathy

We developed a novel chemiluminescent assay of beta-D-galactosidase (beta-gal) based on the chemiluminescence of indole. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) was used as a substrate for beta-gal and also as a light emitter. X-gal was hydrolysed by beta-gal to liberate free indoxyl, followed by oxidation to indigo dye, and simultaneously produces hydrogen peroxide (H2O2). H2O2 reacts with the residual X-gal in the presence of horseradish peroxidase (HRP) to emit light. The measurable range of beta-gal obtained by this method was 6 x 10(-14) mol/L to 6 x 10(-11) mol/L; the detection limit was 3 amol/assay. This chemiluminescent assay could be applied to an enzyme immunoassay of thyroxine using beta-gal as the enzyme label.     

Nocturnal variation in human sympathetic baroreflex sensitivity

INTRODUCTION: The differential diagnosis of malignancy in small foci of microcalcifications or in extremely small nodes can be difficult. We carried out a retrospective analysis of integrated mammographic and US results, correlated with histologic data, to assess the limitations of each method and to optimize and benign/malignant ratio. MATERIALS AND METHODS: Our series consisted of 485 nonpalpable breast lesions submitted to histologic examination after vegetable charcoal marking. We gave each lesion an 0-5 score according to the degree of diagnostic doubt/suspicion after mammography and US, which results were correlated with histologic data to assess the carcinoma frequency in the various groups identified. RESULTS: The analysis of mammographic and US images showed that the most frequent mammographic alteration in the lesions submitted to biopsy was an isolated cluster of microcalcifications (40.99%): of these, 36.86% were neoplastic. The nodules submitted to biopsy, which were 29.81% of the total, showed a cancer rate (36.80%) very similar to that of the microcalcifications. The carcinoma rate rose to 37.93% when the microcalcifications were associated with nodes. The highest carcinoma rates, i.e., 52.94% and 66.66%, respectively, were found in parenchymal distortions, either isolated or associated with microcalcifications, which however were only 7.03% and 3.10%, respectively, of the total number of cases. DISCUSSION AND CONCLUSIONS: Our study showed that: 1) a highly suspicious US result must be seriously considered when a negative mammography has poor intrinsic contrast; 2) a highly suspicious US image with a little suspicious good contrast mammography requires further confirmation before surgery is planned; 3) when the mammographic finding is mid-to-highly suspicious, further investigations are needed even if US is negative. To conclude, even though the histologic examination of nonpalpable breast lesions involves performing a biopsy, we believe this is acceptable when performed on an outpatient basis, under local anesthesia and removing a limited amount of tissue only. The benign/malignant ratio ranges 2 to 1.5: if it is further reduced (below 1.5), there will be the risk of missing some early neoplastic lesions.