Predictors of coronary in-stent restenosis: importance of angiotensin-converting enzyme gene polymorphism and treatment with angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study aimed to clarify the role of the angiotensin-converting enzyme (ACE) gene polymorphism in the development of in-stent restenosis. BACKGROUND: In-stent restenosis occurs after treatment of coronary artery stenosis in 12% to 32% of coronary interventions with stents. Experimental and clinical studies have suggested that the deletion/insertion (D/I) polymorphism of the ACE gene plays a role in this. METHODS: Quantitative coronary angiography before, immediately after and six months after stent implantation were compared in 369 patients, in whom D/I typing of the ACE gene was performed. RESULTS: At follow-up we found no differences between the three genotypes in minimal lumen diameter (homozygotes with two deletion alleles in the ACE gene [DD], 2.20 mm; heterozygotes with one deletion and one insertion allele in the ACE gene [DI], 2.19 mm; and homozygotes with two insertion alleles in the ACE gene [II], 2.25 mm). The corresponding diameter stenoses were: DD: 25%, DI: 27%, II: 27% (p = NS), and the frequency of restenosis (>50% diameter stenosis) was: DD: 15.7%, DI: 11.0% and II: 16.4% (p = NS). Logistic regression analysis identified diabetes (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.0 to 8.7), lesion length (OR: 1.1, 95% CI: 1.01 to 1.30) and minimal lumen diameter immediately after the intervention (OR: 0.3, 95% CI: 0.14 to 0.85) as predictors of in-stent restenosis. In a post hoc analysis of patients treated versus those not treated with an ACE-inhibitor antagonist or an angiotensin receptor antagonist, we found an increased frequency of in-stent restenosis in the DD genotypes (40% vs. 12%, p = 0.006). CONCLUSIONS: The D/I polymorphism is not an independent predictor of coronary in-stent restenosis in general, but it may be of clinical importance in patients treated with ACE inhibitors or angiotensin receptor antagonists.

A novel missense mutation, Leu390Val, in the cardiac beta-myosin heavy chain associated with pronounced septal hypertrophy in two families with hypertrophic cardiomyopathy.

OBJECTIVE: An examination of the genetic background and phenotypic presentation of familial hypertrophic cardiomyopathy (FHC) with respect to specific mutations in the MYH7-gene encoding the cardiac beta-myosin heavy chain. SETTINGS: Two families (n = 22) from a cohort of 67 families with FHC were studied at the National University Hospital, Rigshospitalet, Copenhagen. METHODS: Clinical, non-invasive examinations of all included family members followed by molecular genetic analysis including PCR-single strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and sequencing of exon 3-23 of the MYH7-gene. RESULTS: We found FHC associated with a missense mutation in two families, i.e. a C > G transversion at position g10124 and a G > T transversion at position g10126 causing the change of a leucine residue at codon 390 to a valine residue. The mutation is located in the actin-binding region of the beta-myosin heavy chain. The leucine residue is evolutionarily conserved in vertebrate myosins. In the two families, the phenotypic presentations in the clinically affected were characterized by asymmetric septal hypertrophy (septum diameter 18.8 (5.0) mm (mean (SD)) with only minor involvement of the left ventricular free wall (posterior wall diameter 11.0 (2.2) mm). Furthermore, the left ventricular systolic and diastolic functions were well preserved, even at a high age. The symptomatic status of the clinically affected patients depended on the presence or absence of a concomitant left ventricular outflow tract gradient. CONCLUSIONS: We report a novel missense mutation associated with FHC caused by a double nucleotide transversion. The penetrance of the mutation was not complete, but in clinically affected patients the mutation gives rise to an echocardiographic phenotype, predominantly characterized by pronounced septal hypertrophy.

Outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: To study the outcome of septal myectomy in patients with hypertrophic obstructive cardiomyopathy. DESIGN: Septal myectomy in patients with hypertrophic cardiomyopathy with obstruction of the left ventricular outflow tract (HOCM) is symptomatically effective, and complication rates have been found to be low in large centres performing the procedure routinely. Representing a small centre we studied the outcome after septal myectomy in 11 consecutive patients, aged 44 +/- 21 (mean +/- SD) years with HOCM myectomized at our institution from 1991 to 1998. The patients were evaluated preoperatively using echocardiography and left-sided heart catheterization. RESULTS: Eight patients were operated on after medical treatment had failed and three after sudden deterioration of cardiac function. A Morrow myectomy was performed in 10 patients and a modified Konno procedure in one. Significant reductions were observed in left ventricular outflow tract gradients (77 +/- 29 to 10 +/- 7 mmHg, p < 0.01; n = 11), the degree of mitral valve regurgitation (grades 0-3) (1.7 +/- 1.0 to 0.8 +/- 0.7, p < 0.01; n = 11), NYHA functional classification score (2.4 +/- 1.0 to 1.5 +/- 0.7, p < 0.01; n = 11) and all five patients with angina preoperatively had an improved CCS angina classification score. There were no operative or early postoperative (30 days) deaths. One patient operated on with the modified Konno procedure was reoperated for a septal patch suture leak. During follow-up (43 +/- 24 months, range 11-83), the linearized mortality rate was 3.6% per year. One patient died from a pancreas cancer, one probably from coronary artery disease and one suddenly of unknown cause. CONCLUSION: We conclude that septal myectomy efficiently relieves symptoms in HOCM patients, possibly reflecting the direct as well as secondary effects of left ventricular outflow tract gradient reduction. The present results, obtained at a smaller centre for this procedure, should be considered when choosing from available therapeutic alternatives when medical therapy fails: dual chamber pacemaker implantation, percutaneous transluminal septal myocardial ablation or myectomy.

Familial hypertrophic cardiomyopathy associated with a novel missense mutation affecting the ATP-binding region of the cardiac beta-myosin heavy chain.

Mutations in the cardiac beta -myosin heavy chain gene (MYH7), and other genes encoding cardiac sarcomere proteins may cause familial hypertrophic cardiomyopathy (F-HCM), an autosomal dominant disease, characterized by myocardial hypertrophy. We analysed the MYH7 gene in three generations of a family with one borderline and four clinically verified cases of hypertrophic cardiomyopathy, and identified a mutation in exon 7 changing the 190 arginine residue into a threonine residue. The mutation is located in the ATP-binding region of the myosin head and alters the charge in the F-helix close to the phosphate-binding P-loop. The mutation may thus interfere with the coupling between ATP-hydrolysis and the transition into mechanical energy. In conclusion, the novel Arg190Thr mutation in exon 7 of the MYH7 gene is associated with the development of symptomatic myocardial hypertrophy in adults.

[Hypertrophic cardiomyopathy]. / Hypertrofisk kardiomyopati.

Hypertrophic cardiomyopathy is a heterogeneous, progressive disease with a variable age of debut. Hypertrophic cardiomyopathy is characterized by myocardial hypertrophy with a bizarre fibre disarray. Angina pectoris, dyspnoea and syncope are the most frequent symptoms. Hypertrophic cardiomyopathy is an important cause of sudden death, especially in children and young adults. The aetiology is genetic in more than 60% of the cases, with an autosomal dominant mode of inheritance. More than 50 different mutations involving six genes have so far been associated with the development of hypertrophic cardiomyopathy. These mutations are located to genes coding for several of the proteins in the cardiac sarcomere. The protein changes seem to compromise contractility as well as sarcomere assembly, thereby secondarily causing compensatory hypertrophy. The management of hypertrophic cardiomyopathy has been markedly improved within the last few years. This emphasizes the importance of determining prognostic markers in each patient. A specific genetic diagnosis may prove to be of major importance.

[Treatment of hypertrophic cardiomyopathy]. / Behandling af hypertrofisk kardiomyopati.

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.

Mutation Detection by Cleavase in Combination With Capillary Electrophoresis Analysis: Application to Mutations Causing Hypertrophic Cardiomyopathy and Long-QT Syndrome.

Background: Genetic screening requires methods for mutation detection that are sensitive, precise, and robust. In population screening for complex genetic diseases in which large genes and/or several genes may be affected, automation of the mutation detection analysis is desirable. Methods and Results: The combined use of Cleavase nuclease and analysis of the DNA cleavage pattern by capillary electrophoresis was evaluated with respect to sensitivity, reproducibility, and dependency of experimental conditions in detecting mutations in the human genes MYH7 and KVLQT1 (KCNA9). The cleavage patterns obtained by capillary electrophoresis were very reproducible and robust. Conclusions: The combination of a sensitive enzymatic mutation detection method capillary electrophoresis may prove to be a useful system for automated, large-scale genetic screening.