Charles Mady

Effect of Spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy

Epidemiologic studies have shown an important increase in the high mortality of patients with congestive heart failure (CHF) despite optimal medical management. Ventricular arrhythmia was recognized as the most common cause of death in this population. Electrolyte imbalance, myocardial fibrosis, left ventricular dysfunction, and inappropriate neurohumoral activation are presumed responsible for sudden cardiac death. In this study, we focused on the deleterious effects of the overproduction of aldosterone that occurs in patients with CHF. Secondary hyperaldersteronism can be part of several factors thought to be responsible for sudden cardiac death. We randomized 35 patients (32 men, aged 48 +/- 9 years) with systolic dysfunction (ejection fraction 33 +/- 5%) and New York Heart Association class III CHF secondary to dilated or ischemic cardiomyopathy into 2 groups. The treatment group received spironolactone, an aldosterone receptor antagonist, along with standard medical management using furosemide, angiotensin-converting enzyme inhibitors, and digoxin. The control group received only the standard medical treatment. Holter monitoring was used to assess the severity of ventricular arrhythmia. After 20 weeks, patients who received spironolactone had a reduced hourly frequency of ventricular premature complexes (VPCs) (65 +/- 18 VPCs/hour at week 0 and 17 +/- 9 VPCs/hour at week 16) and episodes of nonsustained ventricular tachycardia (VT) (3.0 +/- 0.8 episodes of VT/24-hour period at week 0, and 0.6 +/- 0.3 VT/24-hour period at week 16). During monitored treadmill exercise, a significant improvement in ventricular arrhythmia was found in the group receiving spironolactone (39 +/- 10 VPCs at week 0, and 6 +/- 2 VPCs at week 16). These findings suggest that aldosterone may contribute to the incidence of ventricular arrhythmia in patients with CHF, and spironolactone helps reduce this complication.

Value of Real Time Three-Dimensional Echocardiography in Patients with Hypertrophic Cardiomyopathy: Comparison with Two-Dimensional Echocardiography and Magnetic Resonance Imaging

Real time three‐dimensional echocardiography (RT3DE) has been demonstrated to be an accurate technique to quantify left ventricular (LV) volumes and function in different patient populations. We sought to determine the value of RT3DE for evaluating patients with hypertrophic cardiomyopathy (HCM), in comparison with cardiac magnetic resonance imaging (MRI). Methods: We studied 20 consecutive patients with HCM who underwent two‐dimensional echocardiography (2DE), RT3DE, and MRI. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, ejection fraction (LVEF), mass, geometric index, and dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland‐Altman model. Results: There was excellent agreement between 2DE and RT3DE (Rc = 0.92), 2DE and MRI (Rc = 0.85), and RT3DE and MRI (Rc = 0.90) for linear measurements. Agreement indexes for LV end‐diastolic and end‐systolic volumes were Rc = 0.91 and Rc = 0.91 between 2DE and RT3DE, Rc = 0.94 and Rc = 0.95 between RT3DE and MRI, and Rc = 0.89 and Rc = 0.88 between 2DE and MRI, respectively. Satisfactory agreement was observed between 2DE and RT3DE (Rc = 0.75), RT3DE and MRI (Rc = 0.83), and 2DE and MRI (Rc = 0.73) for determining LVEF, with a mild underestimation of LVEF by 2DE, and smaller variability between RT3DE and MRI. Regarding LV mass, excellent agreement was observed between RT3DE and MRI (Rc = 0.96), with bias of−6.3 g (limits of concordance = 42.22 to−54.73 g). Conclusion: In patients with HCM, RT3DE demonstrated superior performance than 2DE for the evaluation of myocardial hypertrophy, LV volumes, LVEF, and LV mass.

Obstructive Sleep Apnea Is Common and Independently Associated With Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy

BACKGROUND Hypertrophic cardiomyopathy (HCM) is associated with arrhythmias and cardiovascular death. Left atrial enlargement and atrial fibrillation (AF) are considered markers for death due to heart failure in patients with HCM. Obstructive sleep apnea (OSA) is independently associated with heart remodeling and arrhythmias in other populations. We hypothesized that OSA is common and is associated with heart remodeling and AF in patients with HCM. METHODS We evaluated 80 consecutive stable patients with a confirmed diagnosis of HCM by sleep questionnaire, blood tests, echocardiography, and sleep study (overnight respiratory monitoring). RESULTS OSA (apnea-hypopnea index [AHI] > 15 events/h) was present in 32 patients (40%). Patients with OSA were significantly older (56 [41-64] vs 38.5 [30-53] years, P < .001) and presented higher BMI (28.2 +/- 3.5 vs 25.2 +/- 5.2 kg/m(2), P < .01) and increased left atrial diameter (45 [42-52.8] vs 41 [39-47] mm, P = .01) and aorta diameter (34 [30-37] vs 29 [28-32] mm, P < .001), compared with patients without OSA. Stepwise multiple linear regression showed that the AHI (P = .05) and BMI (P = .06) were associated with left atrial diameter. The AHI was the only variable associated with aorta diameter (P = .01). AF was present in 31% vs 6% of patients with and without OSA, respectively (P < .01). OSA (P = .03) and left atrial diameter (P = .03) were the only factors independently associated with AF. CONCLUSIONS OSA is highly prevalent in patients with HCM and it is associated with left atrial and aortic enlargement. OSA is independently associated with AF, a risk factor for cardiovascular death in this population.

Heterozygosity for the S180L Variant of MAL/TIRAP, a Gene Expressing an Adaptor Protein in the Toll‐Like Receptor Pathway, Is Associated with Lower Risk of Developing Chronic Chagas Cardiomyopathy

BACKGROUND Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Among T. cruzi-infected individuals, only a subgroup develops severe chronic Chagas cardiomyopathy (CCC); the majority remain asymptomatic. T. cruzi displays numerous ligands for the Toll-like receptors (TLRs), which are an important component of innate immunity that lead to the transcription of proinflammatory cytokines by nuclear factor-kappaB. Because proinflammatory cytokines play an important role in CCC, we hypothesized that single-nucleotide polymorphisms (SNPs) in the genes that encode proteins in the TLR pathway could explain differential susceptibility to CCC among T. cruzi-infected individuals. METHODS For 169 patients with CCC and 76 T. cruzi-infected, asymptomatic individuals, we analyzed SNPs by use of polymerase chain reaction-restriction fragment length polymorphism analysis for the genes TLR1, TLR2, TLR4, TLR5, TLR9, and MAL/TIRAP, which encodes an adaptor protein. RESULTS Heterozygous carriers of the MAL/TIRAP variant S180L were more prevalent in the asymptomatic group (24 [32%] of 76 subjects) than in the CCC group (21 [12%] of 169) (chi2=12.6; P=.0004 [adjusted P (Pc)=.0084]; odds ratio [OR], 0.31 [95% confidence interval {CI}, 0.16-0.60]). Subgroup analysis showed a stronger association when asymptomatic patients were compared with patients who had severe CCC (i.e., patients with left-ventricular ejection fraction<or=40%) (chi2=11.3; P=.0008 [Pc=.017]; OR, 0.22 [95% CI, 0.09-0.56]) than when asymptomatic patients were compared with patients who had mild CCC (i.e., patients with left-ventricular ejection fraction>40%) (chi2=7.7; P=.005 [Pc=.11]; OR, 0.33 [95% CI, 0.15-0.73]). CONCLUSION T. cruzi-infected individuals who are heterozygous for the MAL/TIRAP S180L variant that leads to a decrease in signal transduction upon ligation of TLR2 or TLR4 to their respective ligand may have a lower risk of developing CCC.

Myocardial Chemokine Expression and Intensity of Myocarditis in Chagas Cardiomyopathy Are Controlled by Polymorphisms in CXCL9 and CXCL10

Background Chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium. Methods and Results Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2–6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes. Conclusions Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC.

Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

ABSTRACT Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

The Monocyte Chemoattractant Protein–1 Gene Polymorphism Is Associated with Cardiomyopathy in Human Chagas Disease

BACKGROUND Only a subset of individuals infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC). Familial aggregation of CCC in areas of endemicity indicates that susceptibility may be genetic, which may be a plausible explanation for why only one-third of T. cruzi-infected individuals develop CCC. The monocyte chemoattractant protein-1 (CCL2/MCP-1) has been shown to enhance the uptake of T. cruzi in murine macrophages and to up-regulate the inducible nitric oxide synthase/nitric oxide system, with a consequent increased production of nitric oxide that controls the replication of the parasite. METHODS We assessed CCL2 variants at position -2518A/G, which are known to influence transcriptional activity, by polymerase chain reaction and restriction fragment-length polymorphism in 245 individuals, all of whom were infected with T. cruzi. One hundred sixty-nine patients had CCC, and 76 were asymptomatic. RESULTS Genotype distributions differed between the CCC and asymptomatic groups (chi2 = 9.4; P = .009), with an excess of genotypes with the A allele (AA + AG) in the CCC group. Among patients with CCC, 5% were homozygous for the G allele, compared with 16% of the asymptomatic subjects (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.7-11; P = .001). A similar trend was observed when individuals heterozygous for the G allele were compared with individuals homozygous for the G allele between the CCC and asymptomatic groups (OR, 2.7; 95% CI, 0.97-7.2; P = .026). The A allele seems to confer susceptibility to CCC (OR, 1.9; 95% CI, 1.3-2.9; P = .001). CONCLUSIONS The CCL2 variant correlated with a low transcriptional level behaves as a genetic modifier of clinical outcome for T. cruzi infection, and subjects with the CCL2 -2518AA genotype have a 4-fold greater risk of developing CCC than do those without this genotype.

Quantification of Regional Left and Right Ventricular Deformation Indices in Healthy Neonates by Using Strain Rate and Strain Imaging

BACKGROUND Color Doppler myocardial imaging (CDMI) allows the calculation of local longitudinal or radial strain rate (SR) and strain (epsilon). The aims of this study were to determine the feasibility and reproducibility of longitudinal and radial SR and epsilon in neonates during the first hours of life and to establish reference values. METHODS Data were obtained from 55 healthy neonates (29 male; mean age, 20 +/- 14 hours; mean birth weight, 3,174 +/- 374 g). Apical and parasternal views quantified regional longitudinal and radial SR and epsilon in differing ventricular wall segments. Values at peak systole, early diastole, and late diastole were calculated from the extracted curves. CDMI data acquired at 300 +/- 50 frames/s were analyzed offline. Three consecutive cardiac cycles were measured during normal respiration. The timing of specific systolic or diastolic regional events was determined. Multiple comparisons between walls and segments were made. RESULTS Left ventricular (LV) longitudinal deformation showed basal differences compared with apical segments within one specific wall. Right ventricular (RV) longitudinal deformation was not homogeneous, with significant differences between basal and apical segments. Longitudinal epsilon values were higher in the RV free basal and middle wall segments compared with the left ventricle. In the RV free wall apical segment, longitudinal SR and epsilon were maximal. LV systolic SR and epsilon values were higher radially compared with longitudinally (radial peak systolic SR midportion, 2.9 +/- 0.6 s(-1); radial peak systolic epsilon, 53.8 +/- 19%; longitudinal peak systolic SR midportion, -1.8 +/- 0.5 s(-1); longitudinal peak systolic epsilon, -24.8 +/- 3%; P < .01). Longitudinal systolic epsilon and SR interobserver variability values were 1.2% and 0.7%, respectively. CONCLUSION Ultrasound-based SR and epsilon imaging is a practical and reproducible clinical technique in neonates, allowing the calculation of regional longitudinal and radial deformation in RV and LV segments. These regional SR and epsilon indices represent new, noninvasive parameters that can quantify normal neonate regional cardiac function. Independent from visual interpretation, they can be used as reference values for diagnosis in ill neonates.

BAT1, a Putative Anti-Inflammatory Gene, Is Associated with Chronic Chagas Cardiomyopathy

BACKGROUND It is not understood why only a subset of individuals infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC). Patients with CCC display high levels of circulating proinflammatory cytokines. Heart-infiltrating lymphocytes from patients with CCC also express proinflammatory cytokines (tumor necrosis factor- alpha and interferon- gamma ) that are detectable in biopsy samples and surgical heart-tissue samples. BAT1, a putative anti-inflammatory gene, presents functional polymorphisms in its promoter region that influence its transcriptional level. METHODS We assessed, by polymerase chain reaction restriction fragment-length polymorphism analysis, BAT1 variants in the promoter region at positions -22C/G and -348C/T in 154 patients with CCC and in 76 T. cruzi-infected but asymptomatic (ASY) patients. RESULTS Of the patients with CCC, 16% were homozygous for the -22C allele, compared with 4% of the ASY patients (P=.004; odds ratio [OR], 4.7 [95% confidence interval {CI}, 1.4-16]). A similar trend was observed for the -348C homozygotes (P=.01; OR, 1.9 [95% CI, 1.0-3.5]). Susceptibility to CCC was conferred by the C variants at nt -22 (P=.003; OR, 1.8 [95% CI, 1.2-2.8]) and at nt -348 (P=.02; OR, 1.7 [95% CI, 1.0-2.8]). CONCLUSIONS BAT1 variants previously associated with reduced expression of HLA-B-associated transcript 1 are predictive of the development of CCC. These variants may be less efficient in down-regulating inflammatory responses and may contribute to the elevated production of proinflammatory cytokines in patients with CCC.

Late Gadolinium Enhancement Magnetic Resonance Imaging in the Diagnosis and Prognosis of Endomyocardial Fibrosis Patients

Background— Endocardial fibrous tissue (FT) deposition is a hallmark of endomyocardial fibrosis (EMF). Echocardiography is a first-line and the standard technique for the diagnosis of this disease. Although late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) allows FT characterization, its role in the diagnosis and prognosis of EMF has not been investigated. Methods and Results— Thirty-six patients (29 women; age, 54±12 years) with EMF diagnosis after clinical evaluation and comprehensive 2-dimensional Doppler echocardiography underwent cine-CMR for assessing ventricular volumes, ejection fraction and mass, and LGE-CMR for FT characterization and quantification. Indexed FT volume (FT/body surface area) was calculated after planimetry of the 8 to 12 slices obtained in the short-axis view at end-diastole (mL/m2). Surgical resection of FT was performed in 16 patients. In all patients, areas of LGE were confined to the endocardium, frequently as a continuous streak from the inflow tract extending to the apex, where it was usually most prominent. There was a relation between increased FT/body surface area and worse New York Heart Association functional class and with increased probability of surgery (P<0.05). The histopathologic examination of resected FT showed typical features of EMF with extensive endocardial fibrous thickening, proliferation of small vessels, and scarce inflammatory infiltrate. In multivariate analysis, the patients with FT/body surface area >19 mL/m2 had an increased mortality rate, with a relative risk of 10.8. Conclusions— Our study provides evidence that LGE-CMR is useful in the diagnosis and prognosis of EMF through quantification of the typical pattern of FT deposition.