Ulrich Sigwart

A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high‐throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice. We developed a custom DNA resequencing array that contains both strands of all coding exons (160), splice‐site junctions, and 5′UTR regions of 12 genes that have been clearly implicated in HCM (MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2). We analyzed a first series of 38 unrelated patients with HCM (17 familial, 21 sporadic). A total of 953,306 bp across the 38 patients were sequenced with a mean nucleotide call rate of 96.92% (range: 93–99.9%). Pathogenic mutations (single nucleotide substitutions) in MYH7, MYBPC3, TNNI3, and MYL3 (six known and six novel) were identified in 60% (10/17) of familial HCM and 10% of sporadic cases (2/21). The high‐throughput HCM resequencing array is the most rapid and cost‐effective tool for molecular testing of HCM to date; it thus has considerable potential in diagnostic and predictive testing, and prognostic stratification. Hum Mutat 29(6), 879–885, 2008.

Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice

Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. Method and results The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5′-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. Conclusions Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.

Incidence of atrial fibrillation after percutaneous closure of patent foramen ovale and small atrial septal defects in patients presenting with cryptogenic stroke

Objective The occurrence of atrial fibrillation after percutaneous closure of a patent foramen ovale for cryptogenic stroke has been reported in a variable percentage of patients. However, its precise incidence and mechanism are presently unclear and remain to be elucidated. Design Prospective follow-up study. Patients Ninety-two patients undergoing a percutaneous patent foramen ovale closure procedure (closure group) for cryptogenic stroke were compared with a similar group of 51 patients, who were medically treated. Methods A systematic arrhythmia follow-up protocol to assess the incidence of AF was performed including a 7-day event-loop recording at day 1, after 6 and 12 months in patients of the closure group and compared with those of the medically treated group. Results The incidence of AF was similar in both study groups during a follow-up of 12 months, including 7·6% (95% CI: 3·1–15·0%) in the closure and 7·8% (95% CI: 2·18–18·9%) in the medically treated group (P = 1·0). The presence of a large patent foramen ovale was the only significant risk factor for the occurrence of AF as demonstrated by a multivariate Cox regression analysis (95% CI, 1·275–20·018; P = 0·021). Conclusions Our findings indicate that patients with cryptogenic stroke and patent foramen ovale have a rather high incidence of AF during a follow-up of 12 months. Atrial fibrillation occurred with a similar frequency whether the patent foramen ovale/atrial septal defect was successfully percutaneously closed or was medically managed. The presence of a large patent foramen ovale was the only significant predictor of AF occurrence during follow-up.

Interatrial septum rupture during balloon measurement of a patent foramen ovale in a young patient presenting cryptogenic stroke

We report the case of a 36‐year‐old woman admitted for cryptogenic stroke, in whom the Patent Foramen Ovale (PFO) diameter measurement, with a purpose built sizing balloon, performed before the closure procedure, was complicated with the rupture of the inter‐atrial septum generating an Atrial Septal Defect (ASD) with a significant left‐to‐right shunt. This kind of complication may not be easy to handle, changing the initial procedural strategy from PFO to ASD closure technique requiring specific material and operators technical skill.

Coronary myocardial bridge: an innocent bystander?

AbstractMyocardial bridge (MB) or tunneled coronary artery is an inborn abnormality, which implicates a systolic vessel compression with a persistent mid-late diastolic diameter reduction. Myocardial bridges are often observed during coronary angiography with an incidence of 0.5%-5.5%. The most involved coronary artery is the left anterior descending artery followed by the diagonal branches, the right coronary artery, and the left circumflex. The overall long-term prognosis is generally benign. However, several risk or precipitating factors (e.g., high heart rate, left ventricular hypertrophy, decreased peripheral vascular resistance) may trigger symptoms (most frequently angina). Herein, we describe two cases of symptomatic myocardial bridge, where medical treatment (i.e., inotropic negative drug) and coronary stenting were successfully utilized to treat this pathology. We also focus on the clinical presentation, and the diagnostic and therapeutic modalities to correctly manage this frequently observed congenital coronary abnormality, underlining the fact that in cases of typical angina symptoms without any significant coronary artery disease, MB should be considered as a possible differential diagnosis.

Percutaneous closure of a residual ventricular septal defect in a challenging patient

Percutaneous transcatheter closure of congenital or acquired cardiac ventricular septal defects has emerged as a valid alternative to surgical closure in selected cases. It avoids the considerable morbidity and mortality related to open heart surgical procedures. The choice of the device is determined by the particular VSD morphology and thanks to considerable material and technical improvements procedural success rates of over 90% are nowadays achievable. We discuss the case of a young woman who required VSD closure, and in whom re‐open‐heart surgery was avoided by a successful percutaneous closure using an Amplatzer Patent Ductus Arteriosus OccluderTM.

Feasibility and safety of intra‐coronary Beta irradiation with 144Ce/Pr for prevention of restenosis after percutaneous transluminal coronary angioplasty of in‐stent restenotic lesions

Background: Endovascular brachytherapy is a proven and efficacious treatment of coronary in‐stent restenosis with established long‐term benefit. Owing to its complexity and logistic inconveniences, brachytherapy did not find wide acceptance, especially in the current drug‐eluting stents era. We conducted a single center, non‐randomized pilot trial with 144Ce/Pr, utilizing a new high‐energy Beta emitting source, for prevention of restenosis after percutaneous treatment of in‐stent restenotic lesions. Methods and Results: Thirty consecutive patients presenting in‐stent restenosis were enrolled in the study. After conventional balloon angioplasty, 144Ce/Pr was applied to the dilated coronary segment at a dose of 21Gy. Technical feasibility, safety and efficacy of 144Ce/Pr at 9 months clinical and angiographic follow‐up were tested. Thirty‐seven arterial segments were irradiated with 100% technical success and no in‐hospital major adverse cardiac events (MACE). Five MACE were observed (13.5% of the treated segments) during 9 months follow‐up, including four target lesion revascularizations and one episode of acute coronary syndrome secondary to sudden late thrombotic occlusion of the irradiated segment. Conclusions: The study confirmed the safety and the feasibility of the intra‐coronary Beta irradiation utilizing the 144Ce/Pr source. It also shows some practical advantages compared to traditional Gamma or other Beta sources. Considering the high‐risk restenosis profile of the selected patients (i.e. diffuse in‐stent restenosis, bifurcation lesions, small vessels) these results are encouraging in terms of restenosis prevention. Late acute thrombosis remains a problem requiring further improvement.

The SoS Acronym.

The term “acronym” has been used since World War II. It refers to an abbreviation created from the first letters of each word in a series of words. Typical examples are NATO ( North Atlantic Treaty Organization ) and SOS ( Save our Souls ). Acronyms are frequently being used to refer to

Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy

About 25% of patients with hypertrophic cardiomyopathy (HCM) have left ventricular outflow obstruction under resting conditions (1,2). Medical therapy with negative inotropic drugs might alleviate symptoms in many of these patients; however, a certain number might remain refractory to drug therapy. This subset of patients could represent 5–10% of the total population with this disease (3). Surgical myectomy has been shown to reduce outflow gradients and has been practiced since the 1960s. However, some patients might not be regarded as favorable candidates for this major intervention because of advanced age, concomitant medical conditions, or previous cardiac surgery (4). In 1994, a catheter treatment (known as a variety of terms listed in Table 1) using absolute alcohol to induce a myocardial infarction localized to the interventricular septum has been introduced as an alternative to surgery. An alcohol-induced septal branch ablation procedure was first described as therapy for ventricular tachycardia (5). This technique was applied to HCM after noting clinical improvement in a patient with septal hypertrophy who suffered an anterior myocardial infarction, as well as the transient reduction in left ventricular outflow pressure gradients observed with temporary septal artery balloon occlusion. Since the first series of three patients reported in 1995 (6), there has been growing enthusiasm in this technique. During the first 5 yr, over 800 cases had been performed (7); the number is probably several thousand now. Although initially confined to Europe and North America, this technique is now being practiced worldwide.