Cardiomyopathic Patients Research Articles

Long-Term Effect of Enhanced External Counterpulsation on Endothelial Function in the Patients with Intractable Angina

Enhanced external counterpulsation (EECP) is a noninvasive, pneumatic technique that provides favourable effects in patients with coronary artery disease. The objective of this study was to describe the long-term effect of EECP on endothelial function in patients with ischaemic cardiomyopathy. The study was performed in 15 patients with ischaemic cardiomyopathy. All subjects were treated with EECP 1-h per day, 5 days a week, over 7 weeks (totally 35h). Endothelium-dependent and -independent relaxation was assessed by flow-mediated dilation (FMD) and nitroglycerine-mediated dilatation (NMD). In each patient, FMD and NMD measurements were performed before, at midcourse (day 17th) and after completion of EECP course (day 35th). In addition, FMD index was assessed 1 month after completion of EECP therapy. Results showed that EECP was associated with a significant improvement in FMD index after 35 hours of EECP (10.95+/-4.1% vs. 7.40+/-4.9% for baseline, p<0.05). NMD index didn't significantly alter during the EECP therapy. Also, 1 month after completion of EECP, FMD index returned to baseline (7.51+/-4.4% vs. 7.40+/-4.9%, respectively, p<0.05). EECP acutely improved endothelial function in ischaemic cardiomyopathic patients. However, after 1 month completion of treatment, endothelium-dependent vasorelaxation returned to baseline. It seems that improvement of endothelial function is not the main mechanism of long-term EECP treatment and other mechanisms should be considered.

Abstract 1355: Determining Wavefront Size during Ventricular Fibrillation: Optical Mapping Study from Human Langendorff Hearts

Background: We had recently established a model for the study of VF in humans using an optical mapping technique in Langendorff perfused human hearts. The optical mapping technique allows for the unequivocal evaluation of wavefront identification, the origin of wavefronts and their directional spread. Objective: The objective of this study was to measure wavefront sizes from different regions during human VF to determine the minimal spatial resolution required to study human VF in-vitro. Methods: The hearts were explanted from seven cardiomyopathic patients who underwent transplantation. The hearts were Langendorff perfused with Tyrode’s solution (95%O 2 +5%CO 2 ) and the potentiometric dye (0.2 mg Di-4-ANEPPS dissolved in 20mg of perfusate) was injected as a bolus into the coronary circulation. The imaged region was physically immobilized to minimize motion. The fluorescence was excited at 530 nm with a HL 150 W halogen lamp, the emission signal was longpass filtered at 610 nm and recorded with a CCD and CMOS camera (MiCAM02, Ultima, BrainVision Inc., Japan). The spatial resolution depending on the mapping window was 0.65–0.85 mm and the temporal resolution was 1 kHz. The heart was paced at a cycle length of 600 ms and the VF was induced by briefly touching the heart with the two poles of a 9V battery. The changes in dye signal were recorded over 1887 ms and analyzed using BV-analyzer software (BrainVision Inc, Japan). Wavefronts were identified using high-pass filter (0.01 Hz) on the fluorescence data. Recordings were performed at 4 sites: LV Septum (LVS), Right Ventricle Endocardium (RV), Left Ventricle Endocardium (LVendo) and Left Ventricle Epicardium (LVepi). Results: 16 episodes of VF were recorded and a total of 54 wavefronts were identified. Average wavefront size was 23.6 mm. By region, the average wavefront sizes were: LVS = 26.3 mm; RV = 22.4 mm; LVendo = 29.7 mm; LVepi = 19.3 mm. Conclusion: These results show that different regions on the human ventricle during VF show different wavefront size suggesting that propensity for wavebreak maybe spatially differentially distributed. To study human VF with multi-electrode mapping tools using inter-electrode spacing of less than 1–2 cm should provide sufficient resolution.

Abstract 2020: The Effect of Global Ischemia and Reperfusion on Long Duration of Human Ventricular Fibrillation: A Multi-Electrode Mapping Study

Introduction: The most significant change to the latest AHA CPR guidelines is the recommendation of CPR first followed by defibrillation, for un-witnessed arrests. We tested the hypothesis that global myocardial ischemia during ventricular fibrillation (VF) decreases activation rate and short duration of reperfusion would normalize activation rates. Methods: We studied 6 Langendorff perfused human hearts which were explanted from cardiomyopathic patients who underwent transplantation. Tyrode solution was used for perfusion and flow was maintained at 0.9 to 1.1 ml/g/min. Multi-electrode mapping was performed for the entire epicardium (112 electrodes sock array) and the LV endocardium (112 electrodes balloon array). VF was induced by applying a 9-volt battery on the epicardium. As soon as the VF episode was induced, perfusion was turned off for 200 seconds mimicking global ischemia. At the end of this period the perfusion system was turned back on at a flow similar to baseline for an additional 140 seconds, mimicking a state of reperfusion. The hearts were then defibrillated and this protocol was repeated twice after a rest period of 5 minutes. For the analysis, 20 s electrograms located on the LV freewall (both endo and epi) were recorded at t = 0, 90, 180, 260 and 320s, for a total of 11520 electrograms. Local Activation Rates (LAR) for each electrogram was determined as the dominant frequency (DF) corresponding to the highest value in the power spectrum between 1.5 and 8 Hz. Results: Activation rate decreased from 4.962±0.020 Hz to 3.704±0.022 Hz (p&lt;0.0001) during the 200 seconds of global ischemia. During the 140 seconds of reperfusion the activation rate increased to 4.882±0.024 Hz (p&lt;0.0001). This value was comparable to what was measured at the onset of VF (p = 0.011). These changes of rates were similar for both endocardium and epicardium data (p = 0.0236). Conclusions: During long episodes of human VF, global myocardial ischemia leads to slowing of activation rate on the epicardium and endocardium. Two minutes of re-perfusion leads to reversal of this effect. These findings may support the recent change in CPR guidelines.

A Comparison between QLAB and TomTec Full Volume Reconstruction for Real Time Three‐Dimensional Echocardiographic Quantification of Left Ventricular Volumes

To compare the interobserver variability and accuracy of two different real time three-dimensional echocardiography (RT3DE) analyzing programs. Forty-one patients (mean age 56 +/- 11 years, 28 men) in sinus rhythm with a cardiomyopathy and adequate 2D image quality underwent RT3DE and magnetic resonance imaging (MRI) within one day. Off-line left ventricular (LV) volume analysis was performed with QLAB V4.2 (semiautomated border detection with biplane projections) and TomTec 4D LV analysis V2.0 (primarily manual tracking with triplane projections and semiautomated border detection). Excellent correlations (R(2) > 0.98) were found between MRI and RT3DE. Bland-Altman analysis revealed an underestimated LV end-diastolic volume (LV-EDV) for both TomTec (-9.4 +/- 8.7 mL) and QLAB (-16.4 +/- 13.1 ml). Also, an underestimated LV end-systolic volume (LV-ESV) for both TomTec (-4.8 +/- 9.9 mL) and QLAB (-8.5 +/- 14.2 mL) was found. LV-EDV and LV-ESV were significantly more underestimated with QLAB software. Both programs accurately calculated LV ejection fraction (LV-EF) without a bias. Interobserver variability was 6.4 +/- 7.8% vs. 12.2 +/- 10.1% for LV-EDV, 7.8 +/- 9.7% vs. 13.6 +/- 11.2% for LV-ESV, and 7.1 +/- 6.9% vs. 9.7 +/- 8.8% for LV-EF for TomTec vs. QLAB, respectively. The analysis time was shorter with QLAB (4 +/- 2 minutes vs. 6 +/- 2 minutes, P < 0.05). RT3DE with TomTec or QLAB software analysis provides accurate LV-EF assessment in cardiomyopathic patients with distorted LV geometry and adequate 2D image quality. However, LV volumes may be somewhat more underestimated with the current QLAB software version.

Polymorphism in the 3′ UTR of the IL12B gene is associated with Chagas’ disease cardiomyopathy

The aim of this study was to investigate the possible influence of a 3′ untranslated region (3′ UTR) polymorphism of the IL12B gene in susceptibility to Trypanosoma cruzi infection or in the development to cardiomyopathy in Chagas’ disease (CD). We determined the IL12B 3′ UTR genotypes in a sample of 200 seronegative individuals and 260 serologically positive patients (130 with Chagasic cardiomyopathy and 130 asymptomatic). All individuals are from a Colombian region where T. cruzi infection is endemic. Genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. The overall distribution of the IL12B 3′ UTR alleles and genotypes in seronegative compared with seropositive individuals was not statistically significant. Interestingly, we found that the IL12B 3′ UTR CC genotype was significantly increased among cardiomyopathic patients when compared to asymptomatic individuals (16% versus 5%; P = 0.005; P c = 0.015; OR = 3.39; 95% CI 1.3–9.15). In addition, we observed that the IL12B 3′ UTR C allele was present at significantly higher frequency in cardiomyopathic (33% versus 22%; P = 0.008; P c = 0.016; OR = 1.69; 95% CI 1.12–2.55) as compared to asymptomatic. Our results suggest that IL12B 3′ UTR gene polymorphisms may influence the susceptibility to develop Chagasic cardiomyopathy.

Optical mapping of Langendorff-perfused human hearts: establishing a model for the study of ventricular fibrillation in humans

Our objective was to establish a novel model for the study of ventricular fibrillation (VF) in humans. We adopted the established techniques of optical mapping to human ventricles for the first time to determine whether human VF is the result of wave breaks and singularity point formation and is maintained by high-frequency rotors and fibrillatory conduction. We describe the technique of acquiring optical signals in human hearts during VF, their characteristics, and the feasibility of possible analyses that could be performed to elucidate mechanisms of human VF. We used explanted hearts from five cardiomyopathic patients who underwent transplantation. The hearts were Langendorff perfused with Tyrode solution (95% O(2)-5% CO(2)), and the potentiometric dye di-4-ANEPPS was injected as a bolus into the coronary circulation. Fluorescence was excited at 531 +/- 20 nm with a 150-W halogen light source; the emission signal was long-pass filtered at 610 nm and recorded with a mapping camera. Fractional change of fluorescence varied between 2% and 12%. Average signal-to-noise ratio was 40 dB. The mean velocity of VF wave fronts was 0.25 +/- 0.04 m/s. Submillimetric spatial resolution (0.65-0.85 mm), activation mapping, and transformation of the data to phase-based analysis revealed reentrant, colliding, and fractionating wave fronts in human VF. On many occasions the VF wave fronts were as large as the entire vertical length (8 cm) of the mapping field, suggesting that there are a limited number of wave fronts on the human heart during VF. Phase transformation of the optical signals allowed the first demonstration ever of phase singularity point, wave breaks, and rotor formation in human VF. This method provides opportunities for potential analyses toward elucidation of the mechanisms of VF and defibrillation in humans.

494: What is the prognostic value of a normal adenosine myocardial perfusion imaging in cardiac transplant patients?

epicardial CAV. For these 24 patients, 5-year survival after re-transplantation was 70.8%, which is comparable to survival of the 7 re-transplant patients with severe systolic dysfunction. Conclusions: Retransplantation in patients with severe heart failure symptoms but preserved systolic function (similar to restrictive cardiomyopathic patients) appears acceptable. These patients have comparable survival to patients re-transplanted due to systolic dysfunction and therefore, should be considered candidates for re-transplantation. 494

493: Re-transplantation for heart failure with preserved systolic function

Purpose: Re-transplantation has been considered for heart transplant patients with severe systolic dysfunction mainly due to underlying cardiac allograft vasculopathy (CAV) or severe rejection. However, some patients develop heart failure symptoms (shortness of breath, low cardiac output, fatigue, etc.) with preserved systolic function (defined as left ventricular ejection fraction (LVEF) >/= 40%). Similar to restrictive cardiomyopathic patients, these patients have symptoms refractory to medical therapy, which severely reduces their quality of life, necessitating re-transplantation.

Ventricular fibrillation in myopathic human hearts: mechanistic insights from in vivo global endocardial and epicardial mapping

Ventricular fibrillation (VF) is an important cause of sudden cardiac death and cardiovascular mortality in patients with cardiomyopathy. Although it was generally believed that chaotic reentrant wavefronts underlie VF in humans, there is emerging evidence of spatiotemporal organization during early VF. The mechanism of this organization of electrical activity in early VF is unknown in myopathic hearts. We studied early VF in vivo, intraoperatively in five cardiomyopathic patients. Simultaneous electrograms were obtained from the epicardium and endocardium in left ventricular cardiomyopathy and from the endocardium in right ventricular myopathy. The Hilbert transform was used to derive the phase of the electrograms. Rotors were identified by isolating phase singularity points. Rotors were present in all of the myopathic hearts studied during VF and cumulatively lasted a mean of 3.2 +/- 2.0 s of the 7.0 +/- 4.0 s of the VF segments analyzed. For each surface mapped, 3.6 +/- 2.9 rotors were identified for the duration mapped. The average number of cycles completed by these rotors was 4.9 +/- 4.9. The longest rotor lasted 10.2 +/- 6.2 rotations and lasted 2.0 +/- 1.2 s. The rotors on the endocardium had a cycle length of 192 +/- 33 ms compared with 220 +/- 15 ms on the epicardium (P=0.08). There is centrifugal activation of electrical activity from these rotors, and they give rise to domains that activate at faster rates with evidence of conduction block at the border with slower domains. These rotors frequently localized to border regions of myocardium with bipolar electrogram amplitude of <0.5 mV. The organization of electrical activity during early VF in myopathic human hearts is characterized by wavefronts emanating from a few rotors.

Steeper restitution slopes across right ventricular endocardium in patients with cardiomyopathy at high risk of ventricular arrhythmias

Steep action potential duration (APD) restitution slopes (>1) and spatial APD restitution heterogeneity provide the substrate for ventricular fibrillation in computational models and experimental studies. Their relationship to ventricular arrhythmia vulnerability in human cardiomyopathy has not been defined. Patients with cardiomyopathy [left ventricular (LV) ejection fraction <40%] and no history of ventricular arrhythmias underwent risk stratification with programmed electrical stimulation or T wave alternans (TWA). Low-risk patients (n = 10) had no inducible ventricular tachycardia (VT) or negative TWA, while high-risk patients (n = 8) had inducible VT or positive TWA. Activation recovery interval (ARI) restitution slopes were measured simultaneously from 10 right ventricular (RV) endocardial sites during an S1-S2 pacing protocol. ARI restitution slope heterogeneity was defined as the coefficient of variation of slopes. Mean ARI restitution slope was significantly steeper in the high-risk group compared with the low-risk group [1.16 (SD 0.31) vs. 0.59 (SD 0.19), P = 0.0002]. The proportion of endocardial recording sites with a slope >1 was significantly larger in the high-risk patients [47% (SD 35) vs. 13% (SD 21), P = 0.022]. Spatial heterogeneity of ARI restitution slopes was similar between the two groups [29% (SD 16) vs. 39% (SD 34), P = 0.48]. There was an inverse linear relationship between the ARI restitution slope and the minimum diastolic interval (P < 0.001). In cardiomyopathic patients at high risk of ventricular arrhythmias, ARI restitution slopes along the RV endocardium are steeper, but restitution slope heterogeneity is similar compared with those at low risk. Steeper ARI restitution slopes may increase the propensity for ventricular arrhythmias in patients with impaired left ventricular function.

Interleukin-1 Gene Cluster Polymorphism in Chagas Disease in a Colombian Case-Control Study

The aim of this study was to assess the possible association between the IL1A, IL1B and IL1RN gene polymorphisms and Chagas disease. Our study population consisted of 130 serologically positive cardiomyopathic patients and 130 seropositive and asymptomatic individuals from a Colombian population where Trypanosoma cruzi infection is endemic. Genotyping of the IL1A (−889C/T, +4845G/T), IL1B (−511C/T, −31T/C, +3954T/C, +5810G/A) and IL1RN (+8006T/C, +8061C/T, +11100T/C) polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism and polymerase chain reaction sequence-specific primer methods. Statistically significant differences in the distribution of the IL1B +5810 genotypes were observed comparing cardiomyopathic patients and asymptomatic individuals ( p = 0.036). Frequency of the GG genotype was higher in the cardiomyopathic patient group than in the asymptomatic group (13% versus 5%, p = 0.03, odds ratio [OR] = 2.64, 95% confidence interval [CI] = 0.99–7.33). Differences in the distribution of the allele frequencies were also observed, being the +5810G allele overrepresented in patients with cardiomyopathy (37% versus 27%, p = 0.014, OR = 1.59, 95% CI = 1.08–2.36). Examination of markers in the IL1A (−889 and +4845), IL1B (−511, −31, and +3954) and IL1RN (+11100) genes revealed that the overall distribution of alleles and genotypes in patients with chagasic cardiomyopathy and asymptomatic were not significantly different. Our results show that in Colombian population the IL1B+5810G allele was associated with an increased risk chagasic cardiomyopathy. In addition, we demonstrated that homozygosity for the IL1B +5810G risk allele increased significantly the susceptibility to cardiomyopathy. This implies that the effect of IL1B gene on chagasic cardiomyopathy predisposition is dose dependent. We found that the haplotype CT of IL1B −31 and +3954 polymorphisms showed higher association with risk to chagasic cardiomyopathy ( p c = 0.008, OR = 12.53) and the extended haplotype (CCTCATT) was significantly more frequent in asymptomatic than in cardiomyopathic patients ( p = 0.0014, p c = 0.011, OR = 0.17). Therefore this study suggests that IL1 gene cluster polymorphisms may play a relevant role in the susceptibility to development of chagasic chronic cardiomyopathy.

Ca2+-ATPases in non-failing and failing heart: evidence for a novel cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2 isoform (SERCA2c).

We recently documented the expression of a novel human mRNA variant encoding a yet uncharacterized SERCA [SR (sarcoplasmic reticulum)/ER (endoplasmic reticulum) Ca2+-ATPase] protein, SERCA2c [Gélébart, Martin, Enouf and Papp (2003) Biochem. Biophys. Res. Commun. 303, 676-684]. In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. In microsomes prepared from transfected cells, SERCA2c showed a lower apparent affinity for cytosolic Ca2+ than SERCA2a and a catalytic turnover rate similar to SERCA2b. We further demonstrated the expression of the endogenous SERCA2c protein in protein lysates isolated from heart left ventricles using a newly generated SERCA2c-specific antibody. Relative to the known uniform distribution of SERCA2a and SERCA2b in cardiomyocytes of the left ventricle tissue, SERCA2c was only detected in a confined area of cardiomyocytes, in close proximity to the sarcolemma. This finding led us to explore the expression of the presently known cardiac Ca2+-ATPase isoforms in heart failure. Comparative expression of SERCAs and PMCAs (plasma-membrane Ca2+-ATPases) was performed in four nonfailing hearts and five failing hearts displaying mixed cardiomyopathy and idiopathic dilated cardiomyopathies. Relative to normal subjects, cardiomyopathic patients express more PMCAs than SERCA2 proteins. Interestingly, SERCA2c expression was significantly increased (166+/-26%) in one patient. Taken together, these results demonstrate the expression of the novel SERCA2c isoform in the heart and may point to a still unrecognized role of PMCAs in cardiomyopathies.

Cardiac and peripheral actions of growth hormone and its releasing peptides: Relevance for the treatment of cardiomyopathies

Ischemic and nonischemic cardiomyopathies are associated with significant morbidity and mortality in industrialized countries. Cardiomyopathies of primary origin, and more specifically the dilated form of the disease, have been associated with a number of gene defects in cytoskeletal, membrane, and sarcomeric proteins. Cardiomyopathies of secondary origin such as ischemic cardiomyopathy remain the leading cause of left ventricular systolic dysfunction and heart failure. Among novel strategies to improve cardiac function in heart failure, treatment with growth hormone, insulin growth factor-1 (IGF-1), and natural and synthetic growth hormone-releasing peptides such as ghrelin and hexarelin have been explored. The present review focuses on the issues involved in the use of exogenous growth hormone and its releasing peptides in experimental animal models of chronic heart failure and in clinical studies on cardiomyopathic patients as potential releasing peptides for the treatment of chronic heart failure developing as a consequence of cardiomyopathy.

Plasma Monitoring of the Myocardial Specific Tissue Inhibitor of Metalloproteinase-4 After Alcohol Septal Ablation in Hypertrophic Obstructive Cardiomyopathy

Background The overall goal of this study was to develop an assay procedure for measuring the relative abundance of tissue inhibitor of metalloproteinase (TIMP)-4 in plasma, and then use this approach to determine dynamic changes of TIMP-4 levels in hypertrophic obstructive cardiomyopathic (HOCM) patients after an acute myocardial infarction (MI). Matrix metalloproteinases (MMPs) contribute to tissue remodeling and are regulated by the endogenous TIMPs. TIMP-4 is observed to be expressed in higher abundance in the myocardium when compared with other types of tissues. Recent clinical studies have measured changes in TIMP-4 levels; however, these studies have been limited to measuring this protein from myocardial tissue samples. To date, no studies have monitored TIMP-4 levels in plasma samples. Methods and Results Plasma TIMP-4 levels were examined (by semiquantitative immunoblotting) in normal (n = 18) and HOCM (n = 16) patients after alcohol-induced MI. Serial measurements of plasma TIMP-4 levels were examined up to 60 hours after alcohol-induced MI in patients with HOCM. Unglycosylated plasma TIMP-4 levels increased 250% in the HOCM patients when compared with normal controls. Total plasma TIMP-4 levels decreased by 20% at 30 hours after alcohol-induced MI. Conclusions The unique results demonstrated that an induction of a controlled MI, specifically through alcohol ablation, caused a reduction in plasma TIMP-4 levels in HOCM patients after alcohol-induced MI that would facilitate myocardial remodeling in the early post-MI setting.

Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits

ObjectivesWe sought to define the electrophysiologic property of the rabbit heart associated with autoimmunity against the second extracellular loop of the beta1-adrenergic receptor. BackgroundSudden death of patients with cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted by the presence of autoantibodies against the second extracellular loop of the beta1-adrenergic receptor. MethodsRabbits were immunized by repetitive subcutaneous administration of a synthetic peptide corresponding to the second extracellular loop of beta1-adrenergic receptors (beta group; n = 30) for a mean of 4.2 months. Control rabbits received only vehicle (control group; n = 30). ResultsOne of the rabbits in the beta group died suddenly during the observation period, but none of the control animals died. The prevalence of sustained ventricular tachycardia was significantly higher in the beta group (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment revealed prolongation of the action potential duration (APD) in the right ventricular papillary muscle (beta: 156 ± 5 ms vs. control: 131 ± 4 ms; p < 0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta group (1 of 26), but not in any animals in the control group (0 of 17). A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp experiment on left ventricular M cells showed significant decreases in transient outward current (Ito1) (−43%) and slowly activated delayed rectifier current (IKs) densities (−33%), whereas the inward-rectifying K current (IK1) and rapidly activated delayed rectifier current (IKr) densities remained unchanged. ConclusionsLong-term immunization against the second extracellular loop of the beta1-adrenergic receptor caused EAD and APD prolongation and decreased the K-channel density, suggesting that an arrhythmic substrate via autoimmune mechanisms is present in cardiomyopathic patients who have autoantibodies directed against the receptors.

Swimming exercise in infancy has beneficial effect on the hearts in cardiomyopathic Syrian hamsters

The phenotypic expression of cardiomyopathy is greatly influenced by extrinsic factors other than intrinsic genetic defects, such as environmental stress. Exercise is assumed to be an important extrinsic factor, since sudden death is sometimes seen during exercise in young patients with hypertrophic cardiomyopathy (HCM). However, the long-term effects of mild exercise on phenotypic expression in cardiomyopathy remain unclear. To evaluate the effects of exercise performed during infancy or adolescence in cardiomyopathic patients, cardiomyopathic Syrian hamsters (BIO14.6) were subjected to swimming. BIO14.6 and age-matched congenic normal hamsters (CN) as controls were divided into three groups: sedentary (Sed), and trained during infancy (Inf) and during adolescence (Ado). Histological and biochemical analysis of 41-week-old hamsters revealed that (1) the relative level of beta-myosin heavy chain mRNA was significantly lower in the Inf group than in the Sed and Ado groups of BIO14.6. The level in the Inf group of BIO14.6 was compatible with that in the age-matched Sed group of the CN strain; (2) in BIO14.6, degenerative mitochondrial change in the cardiomyocytes was not seen in the Inf group while it was common in the Sed and Ado groups; (3) calcineurin phosphatase activity in the swimming group in 10-week-old CN was significantly higher than that of the age-matched sedentary group, and was as much as that of the swimming and sedentary groups in 10- and 41-week-old BIO14.6.

Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy

Phospholamban is an endogenous inhibitor of sarcoplasmic reticulum calcium ATPase and plays a prime role in cardiac contractility and relaxation. Phospholamban may be a candidate gene responsible for cardiomyopathy. We investigated genome sequence of phospholamban in patients with cardiomyopathy. PCR-based direct sequence was performed for the promoter region and the whole coding region of phospholamban in 87 hypertrophic, 10 dilated, and 2 restricted cardiomyopathic patients. We found a heterozygous single nucleotide transition from A to G at −77-bp upstream of the transcription start site in the phospholamban promoter region of one patient with familial hypertrophic cardiomyopathy. This nucleotide change was not found in 296 control subjects. Using neonatal rat cardiomyocytes, the mutation, −77A→G, increased the phospholamban promoter activity. No nucleotide change in the phospholamban coding region was found in 99 patients with cardiomyopathy. We suspect that the mutation plays an important role in the development of hypertrophic cardiomyopathy.

HLA haplotypes are associated with differential susceptibility to Trypanosoma cruzi infection.

We explored a possible role of HLA class II genes in determining the susceptibility to Trypanosoma cruzi infection as well as in the development of chagasic heart disease in a rural mestizo population from Arequipa (Southern Peru). HLA-DRB1 and DQB1 polymorphisms were determined in 85 seropositive (asymptomatic, n=52; cardiomyopathic, n=33) and 87 seronegative individuals. We observed that the DRB1*14-DQB1*0301 haplotype correlates with not having T. cruzi infection in a highly endemic area (OR= 0.26 (0.124.63); Pc=0.01). This protective association is a dominant trait. We found no differences in the allelic or haplotypic distributions we examined between asymptomatic and cardiomyopathic patients in this population. Our data offer indirect but compelling evidence that polymorphism in HLA region is involved in a differential susceptibility to T. cruzi chronic infection.

GTN Induced Change of Radial Pressure Pulse Contour in Cardiomyopathic Patients.

GTN Induced Change of Radial Pressure Pulse Contour in Cardiomyopathic Patients.

Effect of doubutamine-induced mild work load on high-energy phosphate metabolism in myopathic myocardium

In general, caridiac work load is not recommended in patients with heart failure, but they often experience mild work load in their daily life and it may have deleterious effect. We measured phosphocreatine (PCr) to beta-ATP ratio before and during 5mmg/kg/min infusion of dobutamine in 7 patients with dilated cardio myopathy (DCM) and in 8 normal subjects by MR-spectroscopy. Dobutarnine infusion was kept constant for 50 minutes. Myocardial contractility and ventricular size were determined by echocardiography with the same protocol. The ratio of myocardial PCr to ATP slightly increased from 1.7+/0.4 to 2.2 + /0 .6 in normal subjects but was unchanged from 1.5+/0.4 to 1.8+/-0.6 in patients with DCM. The heart rate and the mean rate of circumferential fiber shortening increased dose dependently both in patients with DCM and normal subjects. These results demonstrate that constant loading of dobutamine for hours had no deleterious effect on high energy phosphate metabolism in the myopathic myocardium. We concluded that the high-energy phosphate metabolism of stable cardiomyopathic patients is stable if the work load is temporary and weak. 206