Patrick Ruchat

Cardiac Sodium Channel Nav1.5 Is Regulated by a Multiprotein Complex Composed of Syntrophins and Dystrophin

The cardiac sodium channel Nav1.5 plays a key role in cardiac excitability and conduction. The purpose of this study was to elucidate the role of the PDZ domain-binding motif formed by the last three residues (Ser-Ile-Val) of the Nav1.5 C-terminus. Pull-down experiments were performed using Nav1.5 C-terminus fusion proteins and human or mouse heart protein extracts, combined with mass spectrometry analysis. These experiments revealed that the C-terminus associates with dystrophin, and that this interaction was mediated by alpha- and beta-syntrophin proteins. Truncation of the PDZ domain-binding motif abolished the interaction. We used dystrophin-deficient mdx5cv mice to study the role of this protein complex in Nav1.5 function. Western blot experiments revealed a 50% decrease in the Nav1.5 protein levels in mdx5cv hearts, whereas Nav1.5 mRNA levels were unchanged. Patch-clamp experiments showed a 29% decrease of sodium current in isolated mdx5cv cardiomyocytes. Finally, ECG measurements of the mdx5cv mice exhibited a 19% reduction in the P wave amplitude, and an 18% increase of the QRS complex duration, compared with controls. These results indicate that the dystrophin protein complex is required for the proper expression and function of Nav1.5. In the absence of dystrophin, decreased sodium current may explain the alterations in cardiac conduction observed in patients with dystrophinopathies.

Prognosis after stroke followed by surgical closure of patent foramen ovale A prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound

Background: The risk of stroke and the long-term prognosis of recurrent strokes in young patients with patent foramen ovale (PFO) are not well known. For this reason, the treatment of these patients remains empirical. An alternative treatment to prolonged antithrombotic therapy may be surgical closure of the PFO. Methods: Thirty patients (20 men and 10 women) with stroke and PFO were prospectively selected among 138 patients with stroke and PFO for a study of surgical closure of PFO at our center. Eligible patients were <60 years old, had negative results of a systematic search for another cause of stroke (first criterion), and met two of the four following criteria: (1) recurrent clinical cerebrovascular events or multiple ischemic lesions on brain MR, (2) PFO associated with an atrial septal aneurysm, (3) >50 microbubbles counted in the left atrium on contrast transesophageal echocardiography (TEE), and (4) Valsalva maneuver or cough preceding the stroke. Patients selected in this manner for surgery were considered to be a subgroup with a higher risk of stroke recurrence. Results: All patients had a direct suture of PFO while under cardiopulmonary bypass without recorded early or delayed significant complication. All patients underwent a new brain MRI and TEE simultaneous with transcranial Doppler ultrasonography after contrast injection at 8 +/- 3 months after surgery. After a mean follow-up of 2 years without antithrombotic treatment, no recurrent cerebrovascular event (stroke or transient ischemic attack [TIA]) and no new lesion on MRI had developed. Postoperative contrast TEE and transcranial Doppler ultrasonography showed that two patients had residual interatrial right-to-left shunting, although much smaller than before surgery, associated with single versus double continuous suture. Conclusions: Our study of 30 selected stroke patients with surgical suture of PFO showed a stroke recurrence rate of 0% and no significant complication. Residual right-to-left shunting may be avoided by double continuous suture of the PFO. In the absence of controlled studies to guide individual therapeutic decisions, our findings show that PFO closure can be done safely and may be considered to avoid recurrence in selected patients with long life expectancy and presumed paradoxic embolism. NEUROLOGY 1996;47: 1162-1166

Five-Year Outcome in Patients With Isolated Proximal Left Anterior Descending Coronary Artery Stenosis Treated by Angioplasty or Left Internal Mammary Artery Grafting A Prospective Trial

BACKGROUND Percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG) improve the clinical status of patients with isolated proximal left anterior descending coronary artery stenosis. At 2 years, only additional revascularization was more frequently required after PTCA. METHODS AND RESULTS We monitored 134 patients randomized to PTCA (n=68) or CABG (n=66) for </=5 years. End points were death, myocardial infarction, need for additional revascularization, clinical status, and medical treatment. At 5 years, 6 patients (9%) had died in the PTCA group versus 2 (3%) in the CABG group (P=0.12). One patient in each group died of a cardiac cause. Myocardial infarction was more frequent after PTCA (15% versus 4%; P=0.0001), but Q-wave infarction was not (6% in the PTCA group versus 3% in the CABG group; P=0.8). Additional revascularization was required in 38% of patients in the PTCA group versus 9% in the CABG group (P=0.0001). Functional status was comparable, with 6% of patients after PTCA and 3% after CABG in functional class III or IV. Finally, after PTCA or CABG, 62% and 91% of patients, respectively, were free of events (P=0.0001). CONCLUSIONS The 5-year prognosis of patients with isolated proximal left anterior descending coronary artery stenosis is good. Both PTCA and CABG improve clinical status, but revascularization was needed more frequently after PTCA. There is an excess incidence of non-Q-wave myocardial infarction in the PTCA group that does not affect the vital or symptomatic outcome.

Incidence of deep and superficial sternal infection after open heart surgery. A ten years retrospective study from 1981 to 1991.

Between January 1981 and December 1991, 4137 adult patients underwent various cardiac procedures via a median sternotomy under cardiopulmonary bypass. The overall infection rate was 1.33%, including superficial wound infections (SWI) (1.18%) and deep sternal infection (DSI) (0.145%). Pericardial and retrosternal suction drains with a vent allowed a better drainage of blood and serosities and probably contributed to our low DSI rate. Eleven factors predisposing to infection were evaluated by Fishers exact test. Only the operative urgency (P = 0.006), reexploration for bleeding (P = 0.00001) and preoperative renal failure (P = 0.0005) were statistically significant. Twenty of our infected patients had no risk factors for infection. When the risk factors described in the literature were applied to our infected patients, only one had no risk factor.

Long-term results of mitral-aortic valve operations

OBJECTIVE We analyzed the long-term morbidity and mortality of our experience with combined mitral-aortic surgery, as well as their determinants. METHODS Among 2109 consecutive patients undergoing valve operations, 200 had mitral-aortic valve procedures with at least implantation of a mechanical prosthesis: 163 of 200 (81.5%) patients had double valve replacement and 37 of 200 (18.5%) had mitral valve repair and aortic valve replacement. All mechanical valves were bileaflet prostheses. Preoperatively, 171 of 200 (85.5%) patients were in New York Heart Association class III-IV. Event-free survivals were determined by means of the Kaplan-Meier method and determinants of survivals with the Cox proportional hazards model (p < 0.05) entering 39 preoperative and perioperative factors. Follow-up was complete for 96% of the patients (192/200). RESULTS Overall survivals at 5, 10, and 15 years were 88.5% +/- 0.55%, 73.5% +/- 4%, and 53.3% +/- 8.9%, and rates of freedom from valve-related mortality were 92.9% +/- 1.5%, 85.8% +/- 3.5%, and 85.8% +/- 3.5%. The rates of freedom from permanent valve-related impairment were 91.5% +/- 1.7%, 85.4% +/- 3.5%, and 79.3% +/- 6.7%, and those from all valve-related mortality and morbidity were 74.1% +/- 2.3%, 53.8% +/- 5%, and 49% +/- 5.6%. At last follow-up, 90% (139/154) of the survivors were in New York Heart Association class I-II. Left ventricular ejection fraction less than 50%, age older than 70 years, and preoperative ventricular arrhythmias were independent risk factors for valve-related late deaths. Diabetes, ejection fraction less than 50%, and coronary artery disease were independent determinants of all valve-related events. CONCLUSIONS Functional results of survivors of combined mitral-aortic surgery are excellent. However long-term valve-related morbidity and mortality are substantial. In the patient population studied, the predictors are determined by patient-related factors, mainly myocardial factors, but not by valve-related factors.

10-Year Follow-Up of a Prospective Randomized Trial Comparing Bare-Metal Stenting With Internal Mammary Artery Grafting for Proximal, Isolated De Novo Left Anterior Coronary Artery Stenosis The SIMA (Stenting versus Internal Mammary Artery grafting) Trial

OBJECTIVES This study was designed to compare the long-term clinical outcome of coronary artery bypass grafting (CABG) with intracoronary stenting of patients with isolated proximal left anterior descending coronary artery. BACKGROUND Although numerous trials have compared coronary angioplasty with bypass surgery, none assessed the clinical evaluation in the long term. METHODS We evaluated the 10-year clinical outcome in the SIMA (Stent versus Internal Mammary Artery grafting) trial. Patients were randomly assigned to stent implantation versus CABG. RESULTS Of 123 randomized patients, 59 underwent CABG and 62 received a stent (2 patients were excluded). Follow-up after 10 years was obtained for 98% of the randomized patients. Twenty-six patients (42%) in the percutaneous coronary intervention group and 10 patients (17%) in the CABG group reached an end point (p < 0.001). This difference was due to a higher need for additional revascularization. The incidences of death and myocardial infarction were identical at 10%. Progression of the disease requiring additional revascularization was rare (5%) and was similar for the 2 groups. Stent thrombosis occurred in 2 patients (3%). Angina functional class showed no significant differences between the 2 groups. CONCLUSIONS Both stent implantation and CABG are safe and highly effective in relieving symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Stenting with bare-metal stents is associated with a higher need for repeat interventions. The long-term prognosis for these patients is excellent with either mode of revascularization.

Drawback of aortoplasty for aneurysm of the ascending aorta associated with aortic valve disease.

BACKGROUND Aortoplasty has been advocated for moderate dilatation of the ascending aorta associated with aortic valve disease. We report our results with this conservative approach. METHODS Seventeen consecutive patients with unsupported aortoplasty were reviewed. Twelve patients had aortic valve regurgitation and 5 had stenosis. The aortic wall was analyzed histologically in 14 patients. Follow-up was complete, with a mean time of 6 years (range, 2.3 to 10.5 years). RESULTS Two patients among the 15 hospital survivors died during follow-up of causes unrelated to aortic pathology. Survival at 7 years was 86.7% (+/- 8.8%). Recurring aortic aneurysms developed in 4 patients after a mean time of 63 months, with an event-free survival at 7 years of 41% (+/- 21%). All of these 4 patients had aortic valve regurgitation and cystic medial necrosis. CONCLUSIONS The recurrence rate of aneurysms after unsupported aortoplasty and aortic valve replacement is high in patients with aortic regurgitation. This strongly suggests that in these patients, the aortic dilatation is related to an underlying wall deficiency, associated with the aortic valve pathology, rather than to the hemodynamic stress imposed by the aortic valve disease.

Gastrointestinal disease following heart transplantation.

Abstract. With advances in heart transplantation, a growing number of recipients are at risk of developing gastrointestinal disease. We reviewed our experience with gastrointestinal disease in 92 patients undergoing 93 heart transplants. All had follow-up, with the median time 4.8 years (range 0.5–9.6 years). During the period of the study we progressively adopted a policy of low immunosuppression aiming toward monotherapy with cyclosporine. Nineteen patients (20.6%) developed 28 diseases related to the gastrointestinal tract. Thirteen patients required 18 surgical interventions, five as emergencies: closure of a duodenal ulcer, five cholecystectomies (one with biliary tract drainage), a sigmoid resection for a diverticulitis with a colovesical fistula, a colostomy followed by a colostomy takedown for an iatrogenic colon perforation, appendectomy, two anorectal procedures, and six abdominal wall herniorrhaphies. At the onset of gastrointestinal disease, 8 patients were on standard triple-drug immunosuppression, all of them within 6 months of transplantation; 13 were on double-drug immunosuppression; and 7 were on cyclosporine alone. All the patients with perforations/fistulas were on steroids. Among the 11 infectious or potentially infectious diseases, 10 were on triple- or double-drug immunosuppression. One death, a patient who was on triple-drug immunosuppression, had a postmortem diagnosis of necrotic and hemorrhagic pancreatitis. Except for an incisional hernia following a laparoscopic cholecystectomy, there was no morbidity and, importantly, no septic complications. We concluded that a low immunosuppression policy is likely to be responsible for the low morbidity and mortality of posttransplant gastrointestinal disease, with a lower incidence of viscous perforation/fistula and infectious gastrointestinal disease.

Ultrasound Measurement of the Fibrous Cap in Symptomatic and Asymptomatic Atheromatous Carotid Plaques

Background—Fibrous cap thickness (FCT) is an important determinant of atheroma stability. We evaluated the feasibility and potential clinical implications of measuring the FCT of internal carotid artery plaques with a new ultrasound system based on boundary detection by dynamic programming. Methods and Results—We assessed agreement between ultrasound-obtained FCT values and those measured histologically in 20 patients (symptomatic [S]=9, asymptomatic [AS]=11) who underwent carotid endarterectomy for stenosing (>70%) carotid atheromas. We subsequently measured in vivo the FCT of 58 stenosing internal carotid artery plaques (S=22, AS=36) in 54 patients. The accuracy in discriminating symptomatic from asymptomatic plaques was assessed by receiver operating characteristic curves for the minimal, mean, and maximal FCT. Decision FCT thresholds that provided the best correct classification rates were identified. Agreement between ultrasound and histology was excellent, and interobserver variability was small. Ultrasound showed that symptomatic atheromas had thinner fibrous caps (S versus AS, median [95% CI]: minimal FCT=0.42 [0.34 to 0.48] versus 0.50 [0.44 to 0.53] mm, P=0.024; mean FCT=0.58 [0.52 to 0.63] versus 0.79 [0.69 to 0.85] mm, P<0.0001; maximal FCT=0.73 [0.66 to 0.92] versus 1.04 [0.94 to 1.20] mm, P<0.0001). Mean FCT measurement demonstrated the best discriminatory accuracy (area under the curve [95% CI]: minimal 0.74 [0.61 to 0.87]; mean 0.88 [0.79 to 0.97]; maximal 0.82 [0.71 to 0.93]). The decision threshold of 0.65 mm (mean FTC) demonstrated the best correct classification rate (82.8%; positive predictive value 75%, negative predictive value 88.2%). Conclusions—FCT measurement of carotid atheroma with ultrasound is feasible. Discrimination of symptomatic from asymptomatic plaques with mean FCT values is good. Prospective studies should determine whether this ultrasound marker is reliable.

Solid or Gaseous Circulating Brain Emboli: Are They Separable by Transcranial Ultrasound?:

High-intensity transient signals (HITS) detected by transcranial Doppler (TCD) ultrasound may correspond to artifacts or to microembolic signals, the latter being either solid or gaseous emboli. The goal of this study was to assess what can be achieved with an automatic signal processing system for artifact/microembolic signals and solid/gas differentiation in different clinical situations. The authors studied 3,428 HITS in vivo in a multicenter study, i.e., 1,608 artifacts in healthy subjects, 649 solid emboli in stroke patients with a carotid stenosis, and 1,171 gaseous emboli in stroke patients with patent foramen ovale. They worked with the dual-gate TCD combined to three types of statistical classifiers: binary decision trees (BDT), artificial neural networks (ANN), and support vector machines (SVM). The sensitivity and specificity to separate artifacts from microembolic signals by BDT reached was 94% and 97%, respectively. For the discrimination between solid and gaseous emboli, the classifier achieved a sensitivity and specificity of 81% and 81% for BDT, 84% and 84% for ANN, and 86% and 86% for SVM, respectively. The current results for artifact elimination and solid/gas differentiation are already useful to extract data for future prospective clinical studies.