C. Schulze

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.

Heart transplantation: an approach to treating primary cardiac sarcoma?

Treating rare, primary cardiac soft-tissue sarcomas (C-STS) with heart transplantation (HTx) is controversial. Conventional tumor resection only partially alleviates the disease, and patients die of local recurrence of the tumor or of distant metastases. Heart transplantation offers the opportunity to eradicate the primary malignancy completely. In our experience of 4 patients with C-STS indicates, HTx followed by post-operative chemotherapy does not affect the long-term outcome. However, pre-operative chemotherapy can regress tumors in chemosensitive C-STS and potentially eradicate early micrometastases. Consecutive HTx for responders may then offer a chance of long-term survival.

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.

Endothelin in coronary endothelial dysfunction early after human heart transplantation.

BACKGROUND Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy. METHODS We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin-mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5+/-3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. RESULTS The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. CONCLUSION Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.

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.

Coronary flow reserve and nitric oxide synthases after cardiac transplantation in humans

OBJECTIVE Coronary endothelial dysfunction may precede morphological changes in both the epicardial conduit and microvascular resistance vessels in heart transplant recipients. Since the development of transplant atherosclerosis is the major limiting factor for long-term survival, the identification of early mediators of vasomotor dysfunction may be of therapeutic interest. We therefore investigated the potential relationship between the expression of nitric oxide synthases (NOS) and coronary endothelial function in human cardiac transplant recipients over time. METHODS Forty-two human cardiac transplant recipients were studied at 1 and 12 months after heart transplantation (HTx). The microvascular coronary flow velocity reserve (CFVR) was tested for endothelium-dependent (acetylcholine) and -independent (adenosine) stimuli by intravascular Doppler flow-wire. Epicardial diameter changes were evaluated by quantitative coronary angiography. Endomyocardial inducible (iNOS) and endothelial constitutive nitric oxide synthase were determined by RT-PCR. Nitric oxide production (nitrite and nitrate (NOx)) and TNF-alpha were measured in plasma samples from the aorta and coronary sinus. RESULTS CFVR was impaired in 26.1% (n=11) of patients at 1 month and in 31% (n=13) 12 months after HTx. iNOS-mRNA levels were significantly higher in patients with impaired endothelium-dependent CFVR. In addition, only in these patients were TNF-alpha levels higher and these correlated with plasma NOx levels at 1 and 12 months post-HTx (1 month: r=0.81, P=0.001; 12 months: r=0.62, P=0.04). CONCLUSIONS Coronary microcirculatory dysfunction in response to acetylcholine is present in nearly 30% of patients during the first year following transplantation. These patients present with higher iNOS-mRNA expression and TNF-alpha plasma levels. Selective modulation of the TNF-alpha/iNOS-pathway may be of therapeutic value to improve coronary endothelial dysfunction in cardiac transplant recipients.