Marcel Kofflard

Hypertrophic cardiomyopathy in a large community-based population: Clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration

OBJECTIVES This study evaluates the clinical course and identifies risk factors for sudden cardiac death (SCD) and clinical deterioration in hypertrophic cardiomyopathy (HCM) in a large community-based population. Comparison was made with data from six tertiary referral and six nonreferral institutions. BACKGROUND Hypertrophic cardiomyopathy is a disease with marked heterogeneity in clinical presentation and prognosis. Risk factors for SCD are not well defined in patients free of referral bias. METHODS Between 1970 and 1999, 225 consecutive patients (mean age [+/-SD] 41+/-16 years) were examined and followed at yearly intervals. RESULTS Forty-four deaths were recorded of which 27 cases were cardiovascular. Fourteen patients died suddenly, six were successfully resuscitated, and seven patients died of congestive heart failure. The annual mortality, annual cardiac mortality, and annual mortality due to sudden death were 1.3%, 0.8%, and 0.6%, respectively. At least one New York Heart Association (NYHA) functional class deterioration was reported in 33% of the patients with a significant (> or =50 mm Hg) left ventricular outflow tract (LVOT) gradient in contrast to 7% without obstruction. The presence of syncope was related to SCD (p < 0.05). Younger age and more severe functional limitation distinguishes patients from in hospital-based centers from the ones in community-based centers. CONCLUSIONS Hypertrophic cardiomyopathy is a benign disease in an unselected population with a low incidence of cardiac death. Syncope was associated with a higher incidence of SCD and patients with a significant LVOT obstruction were more susceptible to clinical deterioration.

Decreased Coronary Flow Reserve in Hypertrophic Cardiomyopathy Is Related to Remodeling of the Coronary Microcirculation

BACKGROUND Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation. METHODS AND RESULTS End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8+/-2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4+/-3.0 mm; P<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0+/-0.8 versus 3.0+/-0.5 mm, P=NS), the coronary resistance reserve (CRR=CRRbasal/CRRhyperemic), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5+/-0.6 in HCM (P<.05; control, 2.6+/-0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21+/-5% versus 30+/-4%; P<.05), and capillary density tended to decrease (from 1824+/-424 to 1445+/-513 per mm2, P=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=O.1 AL-0.45 (r=.57; P<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy. CONCLUSIONS Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group.

Late Lumen Loss After Coronary Angioplasty Is Associated With the Activation Status of Circulating Phagocytes Before Treatment

BACKGROUND The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment. METHODS AND RESULTS To investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at 6-month follow-up. The plasma levels of interleukin (IL)-1 beta, tumor necrosis factor-alpha, IL-6, fibrinogen, C-reactive protein, and lipoprotein(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66, and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at 6 months after PTCA, while the production of IL-1 beta by stimulated monocytes was positively associated with the relative loss. Next, these univariate predictors were corrected for the established clinical risk factors of dilation of the left anterior descending coronary artery and current smoking, which were statistically significant classic predictors in our patient group. Only the expression of CD67 did not predict late lumen loss independent of these established clinical risk factors. Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (R2 = .65; P < .0001) in this patient group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, ie, the expression of CD66 by granulocytes and the production of IL-1 beta by stimulated monocytes. CONCLUSIONS The results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote late lumen loss. To validate this new finding, further study in an independent patient group is required.

Association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers

The plasma level of fibrinogen is associated with the risk of ischaemic heart disease (IHD) and the severity of atherosclerosis. It has been suggested that an increased plasma level of fibrinogen is a coronary risk indicator because it reflects the inflammatory condition of the vascular wall. An inflamed vascular wall may increase the production of the cytokines interleukin 6 (IL6), interleukin 1-beta (IL1-beta), and tumour necrosis factor alpha(TNF-alpha), which have a major role in the regulation of synthesis in the liver of acute phase proteins, including fibrinogen. Smoking has also been reported to increase the levels of fibrinogen and C-reactive protein (CRP). This may indicate that smoking induces an inflammatory reaction, probably of the pulmonary bronchi and alveolae. Therefore, we anticipated that with both types of inflammation the levels of acute phase proteins and cytokines would be related. We have investigated the contribution of inflammation to the plasma levels of fibrinogen in 34 patients with severe coronary artery disease (CAD) and 30 healthy controls comparable for age and smoking habits. We did not find a parallel in the effects of smoking and ischaemic heart disease on the plasma levels of fibrinogen, CRP, IL6, IL1-beta and TNF-alpha. Cardiovascular disease had its most important effect on the plasma fibrinogen level, while smoking appeared to increase the CRP levels, while both CAD and smoking seemed to affect the IL6 levels. Our results indicate that both smoking and CAD induce an inflammatory condition but that the increase of plasma levels of different inflammatory markers is complex. Although the acute phase reaction is the main regulatory mechanism of fibrinogen, the increase of fibrinogen in our group of CAD patients could not be fully explained by increased inflammation.

Prognosis in hypertrophic cardiomyopathy observed in a large clinic population

Overall annual cardiac mortality in hypertrophic cardiomyopathy (HC) has been reported to be between 2 and 4%, although these numbers are primarily from retrospective studies of patients referred to large research institutions. A clinic population of 113 patients with HC was prospectively studied to assess cardiac mortality in the overall group and in selected subgroups commonly thought to be at high risk for sudden death. The mean age at diagnosis was 37 +/- 16 years. During follow-up, there were 11 cardiac and 2 noncardiac deaths. The annual cardiac mortality was 1% (95% confidence interval 0.2-1.8%). Because of the small number of deaths, relative risk for cardiac death was not significantly different in the presence of young age (< or = 30 years), family history of HC and sudden death, history of syncope or previous cardiac arrest, or both, ventricular tachycardia on 24-hour Holter monitoring, or septal myotomy/myectomy for refractory symptoms and outflow tract obstruction. It is concluded that HC has a relatively benign prognosis (1% annual cardiac mortality) that is 2 to 4 times less than that previously reported.

Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers

AIMS To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers. METHODS AND RESULTS Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers. CONCLUSION Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population.

Percutaneous Versus Surgical Treatment for Patients With Hypertrophic Obstructive Cardiomyopathy and Enlarged Anterior Mitral Valve Leaflets

Background—The purpose of this study was to compare percutaneous transluminal septal myocardial ablation (PTSMA) and septal myectomy combined with mitral leaflet extension (MLE) in symptomatic hypertrophic obstructive cardiomyopathy patients with an enlarged anterior mitral valve leaflet (AMVL). Both PTSMA and myectomy reduce septal thickness and left ventricular outflow tract (LVOT) gradient; however, an uncorrected enlarged AMVL may predispose to residual systolic anterior motion (SAM) after successful standard myectomy or PTSMA. Myectomy with MLE previously demonstrated superior hemodynamic results compared with standard myectomy, but its value relative to PTSMA is unknown. Methods and Results—Twenty-nine patients (aged 44±12 years) underwent myectomy with MLE, and 43 patients (aged 52±17 years) underwent PTSMA. Mitral leaflet area was similar in both groups (16.7±3.4 versus 15.9±2.7 cm2, respectively). After PTSMA, 2 patients died, 4 needed a reintervention, and 4 required a permanent pacemaker for complete heart block. After surgery, only 1 patient needed a reintervention. At 1-year follow-up, LVOT gradients did not differ between surgical and PTSMA patients (17±14 versus 23±19 mm Hg, respectively). Preinterventional mitral regurgitation grade was more severe in the surgical group, but with myectomy combined with MLE, the residual grade was similar to that of PTSMA. Mean SAM grade decreased significantly more after surgery (from 2.9±0.3 to 0.5±0.7 mm Hg versus from 2.8±0.5 to 1.3±0.9 mm Hg, P<0.05). Conclusions—PTSMA in these selected patients with hypertrophic obstructive cardiomyopathy had more periprocedural complications and resulted in more reinterventions. Hemodynamic results (SAM grade and reduction in mitral regurgitation) were better in surgical patients.

Minor elevations in troponin I are associated with mortality and adverse cardiac events in patients with atrial fibrillation

AIMS In patients with atrial fibrillation, minor troponin I elevation is regularly detected; however, the prognostic significance of this finding is unknown. We therefore sought to examine the prognostic value of elevated troponin I in patients with atrial fibrillation. METHODS AND RESULTS A prospective study was conducted analysing all consecutive patients admitted with atrial fibrillation in a 2-year period. Patients with an ST-elevation myocardial infarction (MI) were excluded. Minor troponin elevation was defined as a troponin I level between 0.15 and 0.65 ng/mL, which is still below the 99th percentile of the upper reference limit. A positive troponin I was defined as ≥ 0.65 ng/mL. Study outcomes were all-cause mortality (death), death and myocardial infarction (death/MI), or all major adverse cardiac events (MACE: death, MI, or revascularization). A total of 407 patients were eligible for inclusion. The median duration of follow-up was 688 days. A minor elevation occurred in 81 (20%) patients and 77 (19%) had a positive troponin I. In a multivariate model, minor troponin I elevation and a positive troponin I were independently associated with death [hazard ratio (HR): 2.36, 95% confidence interval (CI): 1.17-4.73 for minor elevation and HR: 3.77, 95% CI: 1.42-10.02 for positive troponin I]. Also, there was an independent correlation between the combined endpoints of death/MI and MACE and both a minor elevation and a positive troponin I. CONCLUSION Minor elevations in troponin I on hospital admission are associated with mortality and cardiac events in patients with atrial fibrillation and might be useful for risk stratification.

Initial results of combined anterior mitral leaflet extension and myectomy in patients with obstructive hypertrophic cardiomyopathy

OBJECTIVES The purpose of this study was to describe the clinical and functional results of combined anterior mitral leaflet extension and myectomy in patients with hypertrophic obstructive cardiomyopathy. BACKGROUND Septal myectomy is the most commonly performed surgical procedure in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. Because of the role of the mitral valve in creating the outflow tract gradient, mitral valve replacement or plication is performed in selected cases in combination with myectomy, often with better hemodynamic results than those of myectomy alone. Mitral valve leaflet extension, in which a glutaraldehyde-preserved autologous pericardial patch is used to enlarge the mitral valve along its horizontal axis, is a novel surgical approach in patients with hypertrophic obstructive cardiomyopathy. METHODS Eight patients with hypertrophic obstructive cardiomyopathy were treated with mitral leaflet extension and myectomy. Preoperative and postoperative data (New York Heart Association functional class, number of drugs prescribed, width of the interventricular septum, severity of mitral valve regurgitation severity of systolic anterior motion of the mitral valve and outflow tract gradient) were compared with those of 12 patients undergoing myectomy alone. RESULTS Preoperative evaluation demonstrated that mitral regurgitation and systolic anterior motion of the mitral valve were more severe in the group undergoing mitral valve extension (p < 0.001 and p < 0.05, respectively). There were no deaths associated with either surgical procedure. Two patients, both treated by myectomy alone, died during the follow-up period. Postoperatively, patients treated with mitral valve extension had less mitral regurgitation (p < 0.005), less residual systolic anterior motion (p < 0.001), greater improvement in functional class (p = 0.05) and greater reduction in the number of drugs (p < 0.005) and in septal thickness (p < 0.05). CONCLUSIONS Mitral leaflet extension in combination with myectomy is a promising new surgical approach that may provide superior results to those of myectomy alone. Further studies are needed to determine the clinical value of this procedure.

Diastolic abnormalities as the first feature of hypertrophic cardiomyopathy in Dutch myosin-binding protein C founder mutations.

OBJECTIVES To test the hypothesis that carriers of Dutch founder mutations in cardiac myosin-binding protein C (MYBPC3), without left ventricular hypertrophy (LVH) or electrocardiographic abnormalities, have diastolic dysfunction on tissue Doppler imaging (TDI), which can be used for the screening of family members in the hypertrophic cardiomyopathy (HCM) population. BACKGROUND TDI is a more sensitive technique for the assessment of left ventricular contraction and relaxation abnormalities than is conventional echocardiography. METHODS Echocardiographic studies including TDI were performed in genotyped hypertrophic cardiomyopathy patients (genotype-positive, G+/LVH+; n = 27), mutation carriers without LVH (G+/LVH-; n = 27), and healthy controls (n = 55). The identified mutations in MYBPC3 in the G+/LVH+ subjects were c.2864_2865delCT (12 subjects), c.2373dupG (n = 8), and p. Arg943X (n = 7). In the G+/LVH- subjects, the following mutations were identified: c.2864_2865delCT (n = 11), c.2373dupG (n = 8), and p. Arg943X (n = 8). RESULTS Mean TDI-derived systolic and early and late diastolic mitral annular velocities were significantly lower in the G+/LVH+ subjects compared with the other groups. However, there was no difference between controls and G+/LVH- subjects. Mean TDI-derived late mitral annular diastolic velocities were significantly higher in the G+/LVH- subjects compared with controls and G+/LVH+ subjects. Using a cut-off value of mean +/- 2 SD, an abnormal late mitral annular diastolic velocity was found in 14 (51%) of G+/LVH- patients. There was no difference among the 3 different mutations. CONCLUSIONS In contrast to earlier reports, mean mitral annular systolic velocity and early mitral annular diastolic velocity velocities were not reduced in G+/LVH- subjects, and TDI velocities were not sufficiently sensitive for determination of the affected status of an individual subject. Our findings, however, support the theory that diastolic dysfunction is a primary component of pre-clinical HCM.