Stephen M. Wildhirt

Surgical treatment of permanent atrial fibrillation using microwave energy ablation: a prospective randomized clinical trial

OBJECTIVE Radiofrequency or the use of microwave energy in combination with atrial size reduction during open heart surgery have been reported to be effective in up to 75% in the treatment of permanent atrial fibrillation. However, no data from prospective randomized trials using microwave energy are available. METHODS Forty-three patients with permanent atrial fibrillation undergoing open-heart surgery were randomly stratified into treatment group receiving microwave ablation and atrial size reduction (n=24) or control group (n=19). Patients in either group were treated with amiodarone or sotalol for 3 months if sinus rhythm or any atrioventricular rhythm was successfully restored. Follow-up time points were at 3, 6 and 12 month after surgery. RESULTS In the treatment group 22 out of 24 patients (91,7%) were successfully converted to sinus rhythm by using intraoperative microwave ablation therapy whereas only six out of 19 (31.5%) patients converted to sinus rhythm directly after surgery. At 12-month follow-up there were still a significantly higher percentage of patients in the treatment group free from atrial fibrillation when compared to control (80 vs. 33.3%, P=0.036). CONCLUSION The preliminary data from this first prospectively randomized trial indicate that microwave ablation combined with atrial size reduction is a safe and highly efficient treatment in permanent atrial fibrillation.

Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury

BACKGROUND Ischemia/reperfusion (I/R) leads to the induction of inducible nitric oxide synthase. The present study investigated the effects of selective and continuous inhibition of iNOS on myocardial performance, infarct size and histomorphological changes after I/R in rabbits. METHODS AND RESULTS Ischemia/reperfusion (I/R) was induced by occlusion of the circumflex coronary artery for 30 min followed by 48 h of reperfusion. Sham animals (group A) served as control. Three groups were subjected to I/R: (B) placebo; (C) aminoguanidine (AMG; 10 mg/kg bolus) given prior to and 48 h after I/R to test its acute effects; (D) AMG (300 mg/kg/day s.c.) to test effects of continuous treatment. Hemodynamics, myocardial blood flow, infarct size, iNOS activity, cGMP levels, immunohistochemical analysis of iNOS expression and AMG tissue levels were determined. Continuous AMG treatment improved myocardial performance (hemodynamics and blood flow) compared to placebo group. iNOS was highest in placebo-treated animals. AMG tissue levels were highest in tissues affected by I/R. Infarct size (% of the circumflex region) was significantly smaller in group D when compared to group B. CONCLUSIONS This is the first study showing that activation of myocardial iNOS isozyme during 48 h of reperfusion contributes to a late phase of I/R-induced injury in rabbits. Selective and continuous modulation of iNOS by AMG over this time period exerts protective effects with respect to myocardial performance, coronary blood flow, cellular infiltration and reduction of infarct size; this may be a novel therapeutic approach in the clinical situation to limit irreversible myocardial injury associated with ischemia and reperfusion.

Three-dimensional video and robot-assisted port-access mitral valve operation

BACKGROUND In order to minimize surgical trauma, video-assisted mitral valve operation has been started using the Port-Access technique with the addition of a three-dimensional visualization system (Vista Cardiothoracic Systems Inc, Westborough, MA) and a voice-controlled camera-holding robotic arm (Aesop; Computer Motion Inc, Goleta, CA). METHODS Port-Access mitral valve replacement or repair (PAMVR) was undertaken using an endovascular cardiopulmonary bypass (CPB) system. Fifty patients underwent Port-Access mitral valve replacement or repair. A three-dimensional thoracoscope was inserted allowing complete three-dimensional projection of the mitral valve (Vista). In the last 20 patients, the camera was attached to a robotic arm (Aesop), which allowed stabilization and voice-activated movement of the camera. Mitral valve repair was performed in 26 patients, and the valve was replaced in 24 patients with a mechanical valve prosthesis. RESULTS Median time of operation was 4.2 hours, aortic cross-clamp time 83 minutes, CPB time 125 minutes, intensive care unit stay 1.5 days and hospitalization 9.0 days. Three months follow-up was complete in 40 patients, with 34 patients (85%) in New York Heart Association class I and 6 patients in class II. Mortality was 0% and rate of reoperation was 2%, with a follow-up time up to 1.5 years postoperatively. CONCLUSIONS Using three-dimensional video and robotic assistance, it was possible to minimize the length of skin incision, but at the same time to optimally visualize the whole mitral valve apparatus in order to perform true Port-Access mitral valve operation, including various repair techniques.

Reduction of systemic and cardiac adhesion molecule expression after off-pump versus conventional coronary artery bypass grafting.

ABSTRACT Cardiopulmonary bypass (CPB) and operative trauma are associated with increased expression of pro‐ inflammatory mediators. We determined the relative contribution of CPB on activation of cytokines and adhesion molecules in patients undergoing coronary revascularization by comparing them with patients receiving off‐pump coronary artery bypass grafting (OPCAB). Twenty‐six patients were assigned to either the OPCAB procedure using a suction device and regular sternotomy (n = 13), or were treated conventionally using extracorporeal circulation, blood cardioplegia, and hypothermic arrest (29°C‐31°C; n = 13). Systemic levels of TNF‐&agr; and the soluble adhesion molecules P‐selectin and intracellular adhesion molecule 1 (ICAM‐1) were assayed. Immunohistochemistry was used to account for cardiac‐specific expression of adhesion molecules in interventricular endomyocardial sections. Both systemic and endomyocardial expres‐ sion of adhesion molecules were lower in the OPCAB group. Coronary revascularization with CPB resulted in a significant higher expression of TNF‐&agr;, which was associated with P‐selectin and ICAM‐1 expression. This was accompanied with higher catecholamine requirement in the CPB group in the early postoperative period. Despite comparable surgical trauma, the OPCAB procedure without the use of CPB and cardioplegic arrest significantly reduces systemic and cardiac adhesion molecule expression and catecholamine requirement. Since the clinical course in the early postoperative period was comparable, larger trials are required to select the appropria te patient who benefits most from one or the other treatment regime.

Minimally invasive coronary artery bypass grafting: port-access approach versus off-pump techniques

BACKGROUND Within the past 5 years several surgical techniques have been developed for less invasive surgical treatment of coronary artery disease. The aim of this study was to define specific indications for the various minimally invasive coronary artery surgical procedures. METHODS Minimally invasive direct coronary artery bypass grafting through a minithoracotomy was performed in 67 patients. The left internal mammary artery was anastomosed on the beating heart with the use of a pressure or suction stabilizer without the use of extracorporeal circulation. In 58 other patients with multivessel disease, the off-pump coronary artery bypass grafting technique through a sternotomy was applied with a left internal mammary artery to left anterior descending artery and additional vein grafts without extracorporeal circulation. In a third group, Port-Access (Heartport Inc, Redwood City, CA) coronary artery bypass grafting was performed through a left minithoracotomy with the use of an endovascular extracorporeal circulation system and cardioplegic arrest. Angiographic follow-up was complete in 64% of the patients. RESULTS There was minimal perioperative or postoperative mortality (0.5%). The medium surgical procedure time for all minimally invasive and off-pump procedures was 2.5 hours; it was 4.5 hours for Port-Access procedures. The median postoperative intensive care unit stay was 1.0 days, and the median hospitalization was 5.0 days. Overall graft patency was 97.3%; in 8 patients (4.1%) a stenosis either at or distal to the graft anastomosis was dilated with coronary angioplasty. CONCLUSIONS For single-vessel disease of the left anterior descending artery, the minimally invasive coronary artery bypass grafting procedure can be performed safely without the use of extracorporeal circulation. In case of hemodynamic instability or anatomic variation, the Port-Access procedure can be applied without additional necessity for sternotomy. For multivessel disease, the off-pump bypass grafting procedure with sternotomy can be recommended depending on the coronary arteries involved. In case of necessary grafts to the lateral marginal or circumflex branches, Port-Access grafting can be recommended and may play an important role in the future for the development of fully endoscopic robot-assisted coronary artery bypass grafting.

Nitric oxide and endothelin in the development of cardiac allograft vasculopathy. Potential targets for therapeutic interventions

Extensive research has been carried out in recent years to discover the potential risk factors contributing to cardiac allograft atherogenesis. Injury to endothelial cells has been regarded as an important early mechanism in the development of transplant atherosclerosis; it leads to the manifestation of epicardial and microvascular endothelial dysfunction and development of intimal hyperplasia. Moreover, continuous minor endothelial cell damage contributes to endothelial dysfunction which reflects one of the first measurable steps in the cascade of atherogenesis without macroscopic evidence of vascular lesions. The discovery of two important vasoactive substances nitric oxide (NO) and endothelin (ET) has brought new insights but also new unsolved questions regarding the mechanisms leading to atherosclerosis. To date it is known that both substances play a major role in both prevention and development of atherosclerosis. NO appears to be protective in low concentrations by inhibiting leukocyte and platelet activation/adherence and smooth muscle cell proliferation. Impaired endothelial NO production, as one cause of endothelial dysfunction may occur in early stages of atherosclerosis before macroscopic lesions are evident. In addition, increased endothelin release also results in endothelial dysfunction by inducing vasoconstriction; it promotes vascular lesion formation due to endothelial- and vascular smooth muscle cell proliferation. Direct and indirect manipulation of both the NO and ET signal transduction systems may provide novel preventive and therapeutic approaches for limiting transplant atherogenesis and to treat native atherosclerosis. This review summarizes important experimental and clinical evidence which points to nitric oxide and endothelin as potential therapeutic targets in the process of cardiac allograft vasculopathy.

Effects of Celsior and University of Wisconsin preservation solutions on hemodynamics and endothelial function after cardiac transplantation in humans: a single-center, prospective, randomized trial.

Abstract Optimal preservation of the myocardium remains a major concern in clinical and experimental heart transplantation. The present study compared the efficacy of University of Wisconsin (UW) and Celsior preservation solution with respect to myocardial performance, epicardial and microvascular endothelial vasomotor function and myocardial expression of endothelin and nitric oxide synthases in humans. Forty‐one cardiac transplant recipients received either UW (n = 20) or Celsior (n = 21) preserved hearts. Catecholamine and vasodilator requirements were assessed within the first 5 postoperative days. Left ventricular performance and endothelial function was assessed 1 month after transplantation. Endothelin and nitric oxide synthase gene expression were detected in myocardial biopsy samples. Celsior preserved hearts required significantly more catecholamines and vasodilators within the first 5 postoperative days. Myocardial performance and endothelial function were comparable 1 month after transplantation. Total ischemic time correlated with impaired endothelial function in the Celsior but not in the UW group. Endothelin and inducible nitric oxide synthase gene expression were significantly higher in the Celsior group. The results of the study show that both solutions provide myocardial protection with regard to left ventricular performance and endothelial function 1 month after cardiac transplantation. The necessity for higher vasodilator and catecholamine therapy in Celsior preserved hearts suggests post‐ischemic myocardial stunning within the first 5 postoperative days. The positive correlation between impaired endothelial function and total ischemic time in the Celsior group requires longitudinal investigation in particular with regard to the development of allograft vasculopathy.

Coronary vasomotor dysfunction in the cardiac allograft: impact of different immunosuppressive regimens.

Immunosuppression may have an important impact on early graft coronary endothelial injury. We investigated functional and morphologic coronary alterations, myocardial expression, and cardiac release of possible mediators of allograft vasculopathy within 6 months after cardiac transplantation with respect to different immunosuppressive regimens. Epicardial and microvascular endothelium-dependent and endothelium-independent vasomotor function and epicardial intimal thickening were measured in 8 transplant recipients treated with cyclosporin A (CyA), azathioprine, and prednisone (group 1), 9 transplant recipients treated with tacrolimus (TKL), azathioprine, and prednisone (group 2), and 14 patients treated with TKL, mycophenolate mofetil (MMF), and prednisone (group 3). The gene expressions of inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1, prostacyclinsynthase, and thromboxansynthase were analyzed in endomyocardial biopsy specimens using semiquantitative reverse transcription polymerase chain reaction. Transcardiac cytokine release, endothelin-1, and nitrate-release were determined from plasma samples. Epicardial endothelial dysfunction (vasoconstriction to acetylcholine > 10%) and microvascular smooth muscle cell dysfunction (flow velocity increase to adenosine and nifedipine < 2.0) were enhanced in heart transplant recipients immunosuppressed with TKL, azathioprine, and prednisone. The prevalence of epicardial dysfunction was 78% in group 2 versus 44% and 46% in group 1 and 3 (p < 0.05), respectively. The prevalence of microvascular dysfunction was 56% in group 2 versus 13% and 7% in group 1 and 3 (p < 0.02), respectively. Coronary vasomotor dysfunction was associated with increased myocardial iNOS expression (p < 0.05), decreased eNOS expression (p < 0.05), and enhanced cardiac immunoreactive interleukin-6 (p < 0.01). Coronary intimal thickening was not different between the groups. The combination of TKL and MMF appears to be superior to TKL and azathioprine (and comparable to CyA and azathioprine) concerning preservation of early coronary vasomotor function, eNOS expression, iNOS suppression as well as cardiac interleukin-6 release. This may have an important impact on subsequent development of transplant coronary atherosclerosis.

Leaflet escape in Omnicarbon monoleaflet valve

In almost every type of artificial valve, mechanical disruption has been described. We present the first case of leaflet fracture with aortic embolization in an Omnicarbon monoleaflet valve 42 months after implantation. The 22-year-old male patient suffered of acute respiratory insufficiency and was referred to our hospital as an emergency case. Until a few days before presentation, he was in good condition without clinical complaints. By means of transesophageal echocardiography (TEE) and abdominal sonography the diagnosis of leaflet fracture with embolization to the abdominal aorta could be made. The patient underwent consecutive operative valve replacement and foreign body extraction that resulted in a complete recovery.

An association between microvascular endothelial dysfunction, transcardiac nitric oxide production and pro-inflammatory cytokines after heart transplantation in humans

Abstract Endothelial dysfunction anticipates the development of transplant coronary artery disease (TxCAD) observed more than 1 year after transplantation (HTx). We investigated whether in patients early after HTx myocardial inducible and constitutive nitric oxide synthases (iNOS; cNOS) are expressed and cardiac nitric oxide production occurs. Moreover, a possible relationship to alterations in endothelium dependent and independent vasomotor function was assessed. Forty‐two transplant recipients were studied 37 ± 5 days after HTx. Microvascular coronary flow velocity reserve (CFVR) was tested endothelium dependent (acetylcholine; 30 μg/min × 5 min/i.c.) and independent (adenosine; 160 μg/min × 5 min/i.c.) by Doppler flow wire. Flow velocity increase by a factor greater than 2 was considered normal. Quantitative coronary angiography was used to assess epicardial vasomotor function in response to the same stimuli. Myocardial iNOS and cNOS gene expression were detected by semiquantitative reversed transcriptase polymerase chain reaction. Plasma nitrite levels (μM) were measured by spectrophotometry. Cytokines (TNF‐a, IL‐6; pg/ml) were measured by enzyme linked immunosorbent assay. In 26.1% of patients (n = 11; group A) an impaired endothelium dependent CFVR (1.65 ± 0.23 increase) was observed; in 73.9 % (n = 31, group B) a normal endothelium dependent CFVR (3.0 ± 0.7 increase; P = 0.003) was observed. Myocardial iNOS and cNOS gene expression did not differ between the two groups. Transcardiac cytokine production was noted in 58.8% of patients for IL‐6 and in 53.3% for TNF‐α. Coronary sinus (CS) levels of TNF‐α, IL‐6 and nitrite were higher in group A. A significant increase in nitrite production was found only in patients with impaired endothelium dependent CFVR (aorta: 43.9 ± 3.7 vs CS: 52.8 ± 5.6, P = 0.05), suggesting transcardiac nitric oxide production. In addition, CS nitrite levels correlated with CS TNF‐a levels in patients with impaired CFVR (r = 0.44, P = 0.003). Microvascular endothelium dependent CFVR is impaired in 26% of patients early after HTx. Activation of cytokines and the NO pathway seem to be involved in this vasomotor dysfunction The association between cardiac nitric oxide production and TNF‐a in this group indicates a chronic high immunologic process, which may represent an early and important target for therapy and prevention of TxCAD.