Living history of medicine: vascular scaffolding, from dream to reality.

Following the launch of balloon angioplasty in 1977, its deficiencies-abrupt occlusion requiring emergency bypass surgery in one in twenty attempts and recurrence in one in three cases-became soon apparent. The attempts to eliminate the element of chance from this otherwise highly attractive technique resulted in the concept of intra-vascular scaffolding. Following the inception of self-expanding mesh stents made from stainless steel and extensive bench testing and animal experiments, the first clinical data were obtained in Switzerland almost 30 years ago in 1986 with promising, albeit not undisputed results. Technical improvements including potent platelet inhibitors have made the technique a cornerstone of catheter-treatment of vascular disease. This paper gives an account of the sometimes difficult beginnings of coronary and non-coronary stenting at the University of Lausanne in Switzerland.

Alcohol septal ablation in hypertrophic cardiomyopathy: For which patients?

Percutaneous and surgical therapies for septal reduction for hypertrophic cardiomyopathy have been going head-to-head for the past 20 years with similar outcomes and mortality rates, although contemporary myectomy seems to materialize its superiority. However, on closer analysis, the external validity of studies advocating myectomy does not translate to all centres. The aim of this review was to examine the most recent data on septal reduction therapy and to attempt to phenotype the appropriate patient for each of the two treatments. The key to similar low mortality rates between ventricular septal myectomy and alcohol septal ablation appears to be proper patient selection performed in high volume clinical environments. Furthermore, we analyse the role of mavacampten (the recently approved cardiac myosin inhibitor) in replacing or complementing the two septal reduction therapies.

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.

Controversies in cardiovascular medicine. Hypertrophic obstructive cardiomyopathy: alcohol septal ablation.

Alcohol septal ablation (ASA) was introduced in 1994 as an alternative to septal myectomy for patients with hypertrophic obstructive cardiomyopathy and symptoms refractory to medical therapy. This procedure alleviates symptoms by producing a targeted, limited infarction of the upper interventricular septum, resulting in an increase in left ventricular outflow tract (LVOT) diameter, a decrease in LVOT gradient, and regression of the component of LV hypertrophy that is due to pressure overload. Clinical success, with improvement in symptoms and reduction in gradient, is achieved in the great majority of patients with either resting or provocable LVOT obstruction. The principal morbidity of the procedure is complete heart block, resulting in some patients in the requirement for a permanent pacemaker. The introduction of myocardial contrast echocardiography as a component of the ASA procedure has contributed to the induction of smaller myocardial infarctions with lower dosages of alcohol and, in turn, fewer complications. Non-randomized comparisons of septal ablation and septal myectomy have shown similar mortality rates and post-procedure New York Heart Association class for the two procedures.

Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials.

BACKGROUND: Coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) are alternative treatments for multivessel coronary disease. Although the procedures have been compared in several randomised trials, their long-term effects on mortality in key clinical subgroups are uncertain. We undertook a collaborative analysis of data from randomised trials to assess whether the effects of the procedures on mortality are modified by patient characteristics. METHODS: We pooled individual patient data from ten randomised trials to compare the effectiveness of CABG with PCI according to patients' baseline clinical characteristics. We used stratified, random effects Cox proportional hazards models to test the effect on all-cause mortality of randomised treatment assignment and its interaction with clinical characteristics. All analyses were by intention to treat. FINDINGS: Ten participating trials provided data on 7812 patients. PCI was done with balloon angioplasty in six trials and with bare-metal stents in four trials. Over a median follow-up of 5.9 years (IQR 5.0-10.0), 575 (15%) of 3889 patients assigned to CABG died compared with 628 (16%) of 3923 patients assigned to PCI (hazard ratio [HR] 0.91, 95% CI 0.82-1.02; p=0.12). In patients with diabetes (CABG, n=615; PCI, n=618), mortality was substantially lower in the CABG group than in the PCI group (HR 0.70, 0.56-0.87); however, mortality was similar between groups in patients without diabetes (HR 0.98, 0.86-1.12; p=0.014 for interaction). Patient age modified the effect of treatment on mortality, with hazard ratios of 1.25 (0.94-1.66) in patients younger than 55 years, 0.90 (0.75-1.09) in patients aged 55-64 years, and 0.82 (0.70-0.97) in patients 65 years and older (p=0.002 for interaction). Treatment effect was not modified by the number of diseased vessels or other baseline characteristics. INTERPRETATION: Long-term mortality is similar after CABG and PCI in most patient subgroups with multivessel coronary artery disease, so choice of treatment should depend on patient preferences for other outcomes. CABG might be a better option for patients with diabetes and patients aged 65 years or older because we found mortality to be lower in these subgroups.

Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial (SoS).

BACKGROUND: The Stent or Surgery Trial is a randomized, controlled trial comparing percutaneous coronary intervention with coronary artery bypass grafting (CABG) for patients with multivessel disease. Initial results at a median follow-up of 2 years showed a survival advantage for patients randomized to CABG. This article reports survival outcome at a median follow-up of 6 years. METHODS AND RESULTS: A total of 988 (n=488 percutaneous coronary intervention, n=500 CABG) patients were randomized at 53 centers during the period from 1996 to 1999. Investigators established survival status from hospital or community medical records or national databases or by direct contact with patients and their relatives. All-cause mortality was compared with hazard ratios and confidence intervals calculated from Cox proportional hazards models. Prespecified subgroup analyses for diabetes mellitus, angina grade, and angiographic severity of coronary disease at baseline were performed with tests for interaction. At a median follow-up of 6 years, 53 patients (10.9%) died in the percutaneous coronary intervention group compared with 34 (6.8%) in the CABG group (hazard ratio 1.66, 95% confidence interval 1.08 to 2.55, P=0.022). Little evidence was found that the treatment effect on mortality differed between subgroups according to baseline angina grade (interaction test P=0.52), the severity of coronary disease (P=0.92), or diabetic status (P=0.15). CONCLUSIONS: At a median follow-up of 6 years, a continuing survival advantage was observed for patients managed with CABG, which is not consistent with results from other stent-versus-CABG studies.

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.

Nonsurgical reduction of the interventricular septum in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy and obstruction of the left ventricular outflow tract, nonsurgical reduction of the septum is a treatment option when medical therapy has failed. We investigated the long-term effects of nonsurgical reduction of the septum on functional capacity and electrocardiographic and echocardiographic characteristics. METHODS: Sixty-four consecutive patients with hypertrophic cardiomyopathy and a mean (+/-SD) age of 48.5+/-17.2 years underwent nonsurgical reduction of the septum by injection of ethanol into the septal perforator branch of the left anterior descending coronary artery. These patients were assessed by exercise testing, electrocardiography, and resting and dobutamine (stress-induced) echocardiography after a mean period of 3.0+/-1.3 years. RESULTS: At follow-up, patients had significant improvements in New York Heart Association class, peak oxygen consumption (from 18.4+/-5.8 to 30.0+/-4.4 ml per kilogram of body weight per minute, P<0.001), and left ventricular outflow tract gradients (resting gradient, from 64+/-36 to 16+/-15 mm Hg; P<0.001; stress-induced gradient, from 132+/-34 to 45+/-19 mm Hg; P<0.001). Procedure-related complications included right bundle-branch block in all patients, complete heart block in 31 patients (48 percent), and significant increases in QRS and corrected QT intervals. Seventeen patients (27 percent) required permanent pacing. R-wave amplitude was significantly decreased (from 32+/-8 to 17+/-7 mV, P<0.001). The dimensions of the left ventricular cavity increased, and the interventricular septal thickness was reduced. CONCLUSIONS: Nonsurgical septal reduction leads to sustained improvements in both subjective and objective measures of exercise capacity in association with a persistent reduction in resting and stress-induced left ventricular outflow tract gradients. It is also associated with a high incidence of procedure-related complete heart block, however, often requiring permanent pacing.

A randomized comparison of off-pump and on-pump multivessel coronary-artery bypass surgery.

BACKGROUND: The effect of the use of coronary-artery bypass surgery without cardiopulmonary bypass and cardiac arrest ("off pump") on graft patency remains uncertain. We undertook a prospective, randomized, controlled study to compare graft-patency rates and clinical outcomes in off-pump surgery with conventional, "on-pump" surgery. METHODS: We randomly assigned 50 patients to undergo on-pump coronary-artery bypass grafting and 54 to undergo off-pump surgery. Surgical and anesthetic techniques were standardized for both groups. Clinical outcomes and troponin T levels were measured. Three months later, the patients underwent coronary angiography, including quantitative analysis. RESULTS: The mean age of the patients was 63 years, and 87 percent were men. The on-pump group received a mean of 3.4 grafts, and the off-pump group 3.1 (P=0.41). There were no deaths. There was no significant difference in the median postoperative length of stay between the two groups (seven days in each group). The area under the curve of troponin T levels was higher during the first 72 hours in the on-pump group than in the off-pump group (30.96 hr x microg per liter vs. 19.33 hr x microg per liter, P=0.02). At three months, 127 of 130 grafts were patent in the on-pump group (98 percent), as compared with 114 of 130 in the off-pump group (88 percent, P=0.002). The patency rate was higher for all graft territories in the on-pump group than in the off-pump group. CONCLUSIONS: In this randomized study, off-pump coronary surgery was as safe as on-pump surgery and caused less myocardial damage. However, the graft-patency rate was lower at three months in the off-pump group than in the on-pump group, and this difference has implications with respect to the long-term outcome.

Computed tomography angiography planning identifies the target vessel for optimum infarct location and improves clinical outcome in alcohol septal ablation for hypertrophic obstructive cardiomyopathy.

AIMS: Alcohol septal ablation (ASA) is an established treatment option in hypertrophic obstructive cardiomyopathy (HOCM). ASA is ineffective in some: inaccurate infarct and inability to identify a vessel contribute. We aimed to improve accuracy of infarct using CT angiography guidance and provide a more predictable and satisfactory outcome. METHODS AND RESULTS: Twenty-one successive patients with symptomatic LVOT obstruction refractory to medication underwent CT angiography planning to guide ASA. CT was performed using a dual-source CT system. Alcohol was delivered to the artery identified from CT: in 17/21 this was a sub-branch of a septal artery, in 2/21 the septal vessel was identified from the circumflex artery. Peak gradient improved from 98 (IQR 89.50-111.50) mmHg to 14 (IQR 8.50-22) mmHg (p=0.003). Systolic anterior motion (SAM) improved in 18/20 patients. NYHA class improved by ≥1 in 18/20. Peak VO2 improved from 79.19% of predicted value (±14.01) to 91.62% (±12.02) predicted (p<0.0001). Success at the first procedure is greater with CT guidance, 17/20 vs. 50/75 with traditional methods (pre-CT guidance) (p=0.02); 9/20 had six-month CMR with target septum infarct in all. ASA-related RBBB reduced from 62% to 13% (p=0.0004). CONCLUSIONS: CT angiography planning improves localisation of infarct and procedural success at the first attempt in ASA when compared to traditional methods. Follow-up to six months suggests a symptomatic, functional and haemodynamic improvement.

Adverse events following percutaneous and surgical coronary revascularisation: Analysis of non-MACE outcomes in the Stent or Surgery (SoS) Trial.

OBJECTIVES: To analyse adverse events requiring or prolonging hospitalisation in the Stent or Surgery (SoS) trial. BACKGROUND: Many adverse events following coronary revascularisation are non-major adverse cardiovascular events (non-MACE). Trials comparing percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) have reported rates of mortality and MACE only. MATERIAL AND METHODS: Comparisons between PCI and CABG groups in the SOS trial were by intention to treat. For patients with non-fatal/non-MACE, number of events per 100 patient years follow-up and duration of hospital stay were assessed. Competing risk analysis was used to illustrate temporal pattern of adverse outcomes. RESULTS: During 2 y median follow up, 1 one or more adverse event occurred in 47.3% (231) of the PCI group and 53% (265) of the CABG group (p=0.086). Non-fatal/non-MACE occurred in 11.9% of the PCI group and 38.6% of the CABG group (p<0.001). Non-fatal/non-MACE per 100 patient years follow-up was 17.49 (PCI) and 35.04 (CABG), rate ratio 2.0, 95% CI 1.7 to 2.4, p<0.001. Cumulative non-fatal/non-MACE associated hospital stays were 1387 and 3287 days in PCI and CABG groups respectively. Median duration of hospitalisation per non-fatal/non-MACE was 5 days (interquartile range 2 to 11.75 days) in the PCI group and 6 days (interquartile range 2 to 12 days) in the CABG group, p=0.245. CONCLUSIONS: CABG had lower cumulative incidence of fatal or MACE outcomes, higher cumulative incidence of non-fatal/non-MACE outcomes, and longer cumulative hospitalisation periods compared to the PCI group.

Neuropsychological outcome after percutaneous coronary intervention or coronary artery bypass grafting: results from the Stent or Surgery (SoS) Trial.

BACKGROUND: Coronary artery bypass surgery (CABG) has been associated with a range of neurological and neuropsychological complications from stroke to cognitive problems such as memory and problem solving disturbance. However, little is known about the impact of percutaneous coronary intervention (PCI) on neuropsychological outcome. METHODS AND RESULTS: In the Stent or Surgery Trial (SoS), 988 patients were randomized in equal proportions between PCI supported by stent implantation and CABG. As a substudy of this trial, we undertook an evaluation of neurological and neuropsychological outcomes after intervention. A clinical examination and neuropsychological assessment consisting of 5 tests (Digit Span Forwards and Backwards, Visual Reproduction, Bourdon, and Block Design) were performed at baseline and 6 and 12 months after the procedure. A total of 145 patients were included in the substudy analysis: 77 in the PCI group and 68 in the CABG group. One patient in the PCI arm had a stroke. There was no significant difference between treatment groups at 6 and 12 months for any of the 5 tests. The mean change from baseline was also similar in both groups. CONCLUSIONS: We were not able to demonstrate an important and significant difference in neuropsychological outcome in patients treated with different revascularization strategies. This important finding needs to be examined in further research.

New treatment strategies for hypertrophic obstructive cardiomyopathy: alcohol ablation of the septum: the new gold standard?

Hypertrophic cardiomyopathy is a primary myocardial disorder with an autosomal pattern of inheritance characterized by inappropriate myocardial hypertrophy. Annual mortality has been reported to be 1% to 2% and sudden death represents the most common cause. Treatment strategies are 1) medical therapy in patients with mild to moderate symptoms, 2) reduction of septal hypertrophy by surgical myectomy or alcohol ablation, and 3) implantation of an automatic cardioverter-defibrillator in the presence of non-sustained ventricular tachyarrhythmias. A debate has been started on whether surgical myectomy or alcohol ablation of the septum is the appropriate treatment for hypertrophic obstructive cardiomyopathy. Surgical (transaortic) myectomy has been the gold standard in the past 20 to 30 years for treatment of symptomatic patients with significant hemodynamic outflow tract obstruction. However, modern interventional technologies allow reduction of the myocardial septum by injection of alcohol into the first or second septal branch under guidance of two-dimensional (2D)-contrast echocardiography. This percutaneous technique not only has a lower morbidity than surgical myectomy but can be guided precisely by 2D echocardiography. One potential complication is transient (<30%) or permanent (<10%) atrioventricular block III; however, this complication is relatively rare. A randomized trial comparing the two treatment modalities is lacking, and the chance is small that such a trial will be performed because alcohol ablation can be done with high success and low complication rates, leaving only complex interventions (with valvular reconstructions and so on) for surgical myectomy.

One-year outcomes of coronary artery bypass graft surgery versus percutaneous coronary intervention with multiple stenting for multisystem disease: a meta-analysis of individual patient data from randomized clinical trials.

BACKGROUND: We aimed to provide a quantitative analysis of the 1-year clinical outcomes of patients with multisystem coronary artery disease who were included in recent randomized trials of percutaneous coronary intervention with multiple stenting versus coronary artery bypass graft surgery. METHODS: An individual patient database was composed of 4 trials (Arterial Revascularization Therapies Study, Stent or Surgery Trial, Argentine Randomized Trial of Percutaneous Transluminal Coronary Angioplasty Versus Coronary Artery Bypass Surgery in Multivessel Disease 2, and Medicine, Angioplasty, or Surgery Study 2) that compared percutaneous coronary intervention with multiple stenting (N = 1518) versus coronary artery bypass graft surgery (N = 1533). The primary clinical end point of this study was the combined incidence of death, myocardial infarction, and stroke at 1 year after randomization. Secondary combined end points included the incidence of repeat revascularization at 1 year. All analyses were based on the intention-to-treat principle. RESULTS: After 1 year of follow-up, 8.7% of patients randomized to percutaneous coronary intervention with multiple stenting versus 9.1% of patients randomized to coronary artery bypass graft surgery reached the primary clinical end point (hazard ratio 0.95 and 95% confidence interval 0.74-1.2). Repeat revascularization procedures occurred more frequently in patients allocated to percutaneous coronary intervention with multiple stenting compared with coronary artery bypass graft surgery (18% vs 4.4%; hazard ratio 4.4 and 95% confidence interval 3.3-5.9). The percentage of patients who were free from angina was slightly lower after percutaneous coronary intervention with multiple stenting than after coronary artery bypass graft surgery (77% vs 82%; P = .002). CONCLUSIONS: One year after the initial procedure, percutaneous coronary intervention with multiple stenting and coronary artery bypass graft surgery provided a similar degree of protection against death, myocardial infarction, or stroke for patients with multisystem disease. Repeat revascularization procedures remain high after percutaneous coronary intervention, but the difference with coronary artery bypass graft surgery has narrowed in the era of stenting.

Technology insight: transcoronary ablation of septal hypertrophy.

Among patients with hypertrophic cardiomyopathy, 5-10% have outflow tract obstruction that results in symptoms refractory to medical therapy. Surgical myectomy has been the gold standard for treating these patients since the 1960s. In the past 10 years, however, alcohol septal ablation has emerged as an alternative procedure. There is growing evidence to indicate that this technique is comparable to surgical myectomy with respect to hemodynamic and functional improvement, although no randomized comparative studies exist to date. The procedure consists of injecting as mall volume of alcohol into a septal perforator under balloon occlusion,preferably after localization of the target septal branch by myocardial contrast echocardiography. Relief of the gradient is instantaneous in about 90% of patients, and further decreases might occur over time. Functional class, exercise capacity and quality of life have been shown to be improved during follow-up. The main risk of the technique is atrioventricular block, which occurs in about 10% of patients. Because of this side-effect and a steep learning curve, the technique should be performed only by experienced operators and on carefully selected patients.

Late recurrence of outflow tract obstruction seven years after septal ablation in hypertrophic cardiomyopathy.

We present a case of late recurrence of outflow tract obstruction 7 years after successful septal ablation in hypertrophic cardiomyopathy. In addition the debate over maximal versus minimal treatment is discussed.