Bogusław Kapelak

Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study

BACKGROUND Renal sympathetic hyperactivity is associated with hypertension and its progression, chronic kidney disease, and heart failure. We did a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (ie, systolic blood pressure >/=160 mm Hg on three or more antihypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness. METHODS We enrolled 50 patients at five Australian and European centres; 5 patients were excluded for anatomical reasons (mainly on the basis of dual renal artery systems). Patients received percutaneous radiofrequency catheter-based treatment between June, 2007, and November, 2008, with subsequent follow-up to 1 year. We assessed the effectiveness of renal sympathetic denervation with renal noradrenaline spillover in a subgroup of patients. Primary endpoints were office blood pressure and safety data before and at 1, 3, 6, 9, and 12 months after procedure. Renal angiography was done before, immediately after, and 14-30 days after procedure, and magnetic resonance angiogram 6 months after procedure. We assessed blood-pressure lowering effectiveness by repeated measures ANOVA. This study is registered in Australia and Europe with ClinicalTrials.gov, numbers NCT 00483808 and NCT 00664638. FINDINGS In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean 4.7 antihypertensive medications); estimated glomerular filtration rate was 81 mL/min/1.73m(2) (SD 23); and mean reduction in renal noradrenaline spillover was 47% (95% CI 28-65%). Office blood pressures after procedure were reduced by -14/-10, -21/-10, -22/-11, -24/-11, and -27/-17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five non-treated patients, mean rise in office blood pressure was +3/-2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae. There were no other renovascular complications. INTERPRETATION Catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension. Prospective randomised clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.

Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience.

OBJECTIVES The purpose of the study was to determine the efficacy and safety of left atrial appendage (LAA) closure via a percutaneous LAA ligation approach. BACKGROUND Embolic stroke is the most devastating consequence of atrial fibrillation. Exclusion of the LAA is believed to decrease the risk of embolic stroke. METHODS Eighty-nine patients with atrial fibrillation were enrolled to undergo percutaneous ligation of the LAA with the LARIAT device. The catheter-based LARIAT device consists of a snare with a pre-tied suture that is guided epicardially over the LAA. LAA closure was confirmed with transesophageal echocardiography (TEE) and contrast fluoroscopy immediately, then with TEE at 1 day, 30 days, 90 days, and 1 year post-LAA ligation. RESULTS Eighty-five (96%) of 89 patients underwent successful LAA ligation. Eighty-one of 85 patients had complete closure immediately. Three of 85 patients had a ≤ 2-mm residual LAA leak by TEE color Doppler evaluation. One of 85 patients had a ≤ 3-mm jet by TEE. There were no complications due to the device. There were 3 access-related complications (during pericardial access, n = 2; and transseptal catheterization, n = 1). Adverse events included severe pericarditis post-operatively (n = 2), late pericardial effusion (n = 1), unexplained sudden death (n = 2), and late strokes thought to be non-embolic (n = 2). At 1 month (81 of 85) and 3 months (77 of 81) post-ligation, 95% of the patients had complete LAA closure by TEE. Of the patients undergoing 1-year TEE (n = 65), there was 98% complete LAA closure, including the patients with previous leaks. CONCLUSIONS LAA closure with the LARIAT device can be performed effectively with acceptably low access complications and periprocedural adverse events in this observational study.

Coronary Artery Superoxide Production and Nox Isoform Expression in Human Coronary Artery Disease

Background—Oxidative stress plays important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). We aimed to determine the sources and selected molecular mechanisms of oxidative stress in CAD. Methods and Results—We examined basal and NAD(P)H oxidase-mediated superoxide (O2˙−) production using lucigenin chemiluminescence, ferricytochrome c and dihydroethidium fluorescence in human coronary arteries from 19 CAD and 17 non-CAD patients undergoing heart transplantation. NAD(P)H oxidase subunits and xanthine oxidase expression were measured. Superoxide production was greater in coronary arteries from patients with CAD, even in vessels without overt atherosclerotic plaques, and was doubled within branching points of coronary arteries. Studies using pharmacological inhibitors and specific substrates showed that NAD(P)H oxidases (60%) and xanthine oxidase (25%) are primary sources of O2˙− in CAD. Losartan significantly inhibited superoxide production in coronary arteries. NAD(P)H oxidase activity and protein levels of the NADPH oxidase subunits p22phox, p67phox, and p47phox were significantly increased in CAD, as were mRNA levels for p22phox and nox2, and no NAD(P)H oxidase subunit mRNA levels correlated with NAD(P)H oxidase activity in vessels from individual patients. Activity and protein expression of xanthine oxidase were increased in CAD, whereas xanthine dehydrogenase levels were not changed. Conclusions—Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease.

Calcium-Dependent NOX5 Nicotinamide Adenine Dinucleotide Phosphate Oxidase Contributes to Vascular Oxidative Stress in Human Coronary Artery Disease

OBJECTIVES This study sought to examine the expression and activity of the calcium-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in human atherosclerotic coronary arteries. BACKGROUND The NOX-based NADPH oxidases are major sources of reactive oxygen species (ROS) in human vessels. Several NOX homologues have been identified, but their relative contribution to vascular ROS production in coronary artery disease (CAD) is unclear; NOX5 is a unique homolog in that it is calcium dependent and thus could be activated by vasoconstrictor hormones. Its presence has not yet been studied in human vessels. METHODS Coronary arteries from patients undergoing cardiac transplantation with CAD or without CAD were studied; NOX5 was quantified and visualized using Western blotting, immunofluorescence, and quantitative real-time polymerase chain reaction. Calcium-dependent NADPH oxidase activity, corresponding greatly to NOX5 activity, was measured by electron paramagnetic resonance. RESULTS Both Western blotting and quantitative real-time polymerase chain reaction indicated a marked increase in NOX5 protein and messenger ribonucleic acid (mRNA) in CAD versus non-CAD vessels. Calcium-dependent NADPH-driven production of ROS in vascular membranes, reflecting NOX5 activity, was increased 7-fold in CAD and correlated significantly with NOX5 mRNA levels among subjects. Immunofluorescence showed that NOX5 was expressed in the endothelium in the early lesions and in vascular smooth muscle cells in the advanced coronary lesions. CONCLUSIONS These studies identify NOX5 as a novel, calcium-dependent source of ROS in atherosclerosis.

Systemic Regulation of Vascular NAD(P)H Oxidase Activity and Nox Isoform Expression in Human Arteries and Veins

Objective—Impaired endothelial function, characterized by nitric oxide scavenging by increased superoxide production, is a hallmark of vascular disease states. However, molecular mechanisms regulating superoxide production in human blood vessels remain poorly defined. Methods and Results—We compared endothelial function, vascular superoxide production, and the expression of NAD(P)H oxidase subunits in arteries and veins from patients undergoing coronary bypass surgery (n=86). Superoxide release was similar in arteries and veins. Inhibitor studies revealed that the NAD(P)H oxidase system was a quantitatively and proportionately greater source of superoxide in veins, whereas xanthine oxidase also contributed significantly to superoxide production in arteries. Moreover, NAD(P)H oxidase molecular composition differed in veins and arteries; veins expressed more nox2 and p22phox, whereas the relative expression of nox4 was greater in arteries. However, there were strong correlations between p22phox and nox4 expression and between superoxide production, NAD(P)H oxidase activity, and endothelial function in arteries and veins from the same patient. Conclusions—In individuals with coronary artery disease, changes in vascular superoxide production, endothelial function, and NAD(P)H oxidase activity and expression are related in veins and arteries. These findings highlight the importance of systemic effects on the molecular regulation of the NAD(P)H oxidases in human vascular disease.

Feasibility of closed-chest ligation of the left atrial appendage in humans

BACKGROUND Atrial fibrillation is associated with an increased risk of embolic events. The left atrial appendage (LAA) is believed to be an incubator for thrombus formation. LAA exclusion has been advocated to potentially reduce embolic events arising from the LAA. OBJECTIVE The aim of the study was to determine the feasibility of a closed-chest surgical suture ligation of the LAA in man. METHODS Thirteen patients undergoing either mitral valve surgery (n = 2) or electrophysiological study and radiofrequency catheter ablation for atrial fibrillation (n = 11) underwent ligation of the LAA with the LARIAT snare device. In patients having an ablation procedure, pericardial access was obtained prior to the patients undergoing radiofrequency catheter ablation. After transseptal catheterization, endocardial and epicaridal magnet-tipped guide wires were positioned under fluoroscopic guidance to stabilize the LAA. Transesophageal echocardiography (TEE) was used as guidance for positioning a marker balloon at the ostium of the LAA. An over-the-wire approach was used to guide the LARIAT snare device over the LAA to allow closure and suture ligation of the LAA. TEE and contrast fluoroscopy were used to confirm acute closure of the LAA. RESULTS Both mitral valve replacement (MVR) patients had complete closure of the LAA determined by visual inspection. Ten of 11 patients having ablation underwent a successful closed-chest LAA ligation procedure with TEE and contrast fluoroscopy verification of closure of the LAA. Only one of 11 procedures was terminated owing to the lack of echocardiography guidance of the snare over the marker balloon. One patient with pectus excavatum did have ligation of his LAA; however, a thorascopic procedure was required to remove the snare from the LAA owing to compression of the LARIAT by the concave sternum. There were no other significant complications. CONCLUSIONS Catheter-based surgical suture ligation of the LAA is feasible in humans. This novel catheter approach may be appropriate for patients with atrial fibrillation who are ineligible for anticoagulation therapy. Further investigation is needed to demonstrate the long-term safety and efficacy of LAA closure.

The effects of LAA ligation on LAA electrical activity.

BACKGROUND The arrhythmic role of the left atrial appendage (LAA) has been implicated in the maintenance of persistent atrial fibrillation. LAA isolation with catheter ablation has been successful but is limited by the risk of tamponade and electromechanical dissociation with the potential for LAA thrombus formation. OBJECTIVE To assess whether LAA ligation results in LAA electrical isolation. METHODS A total of 68 patients with contraindication or intolerance to oral anticoagulation therapy underwent LAA ligation with the LARIAT suture delivery device. Patients had unipolar [n = 30(44%)] or bipolar [n = 38(56%)] voltage measurements pre- and post-LAA ligation. RESULTS All 68 patients underwent successful LAA ligation. There was a statistically significant reduction in the mean LAA voltage from pre-ligation (unipolar pre-ligation voltage 1.1 ± 0.53 mV; bipolar pre-ligation voltage 4.7 ± 2.83 mV) to post-ligation (unipolar post-ligation voltage 0.3 ± 0.38 mV; bipolar post-ligation voltage 0.6 ± 0.27 mV). Ninety-four percent of the patients had a reduction in the LAA voltage after the closure of the snare, with 10 of 30 (33%) of the patients having complete elimination of LAA voltage with the initial tightening of the suture. Pacing from the LAA after the closure of the snare resulted in lack of capture of the left atrium in 28 of 31 patients. CONCLUSIONS The snare closure of the LAA using the LARIAT device produces an acute reduction in the LAA voltage and inhibits the capture of the left atrium during LAA pacing. Future studies are needed to determine whether LAA ligation affects atrial fibrillation burden.

Mechanisms of oxidative stress in human aortic aneurysms — Association with clinical risk factors for atherosclerosis and disease severity

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2•−) production in human AAA. Methods and results AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2•− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size. Conclusions Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.

Reoperation after fresh homograft replacement: 23 years’ experience with 655 patients

OBJECTIVE Through a retrospective study on the use of fresh homografts in 655 aortic valve replacement patients over a period of 23 years, we aimed to assess the reasons for eventual reoperation and causes of valve dysfunction. METHODS Between January 1980 and December 2002, 655 patients received fresh homografts. All homografts were antibiotic sterilized and stored at 4 degrees C. During this time, 139 patients (116 male and 23 female) with a mean age of 46.7 years (range 18-72) required reoperation. RESULTS The 30-day hospital overall mortality was 2.87%. The mean durability for all homografts was 12.4+/-4.54 years (1 month to 23 years). The cumulative rates for freedom from reoperation for any cause were 94.09+/-2% at 5 years and 87.9%+/-4% at 10 years, 76.6 at 15 years, 49.55 at 20 years. The major cause of valve dysfunction and indication for reoperation was degeneration in 111 patients (79.8%). Predominant aortic valve insufficiency in 87 patients (62.5%) and predominant stenosis in 24 patients (17.26%). Endocarditis occurred in 21 patients (15.1%). Early endocarditis was diagnosed in five patients (3.59%), late endocarditis in 16 patients (11.5%). Additional causes for reoperation included ascending aortic aneurysm, mitral valve insufficiency and congestive cardiomyopathy. Seventeen patients (12.2%) required concomitant procedures. Coronary artery bypass grafting was performed in six cases (4.3%), mitral valve replacement in five cases (3.59%), mitral valve annuloplasty in six (4.3%). The primary reoperative procedure was artificial/mechanical aortic valve implantation. In five cases, St. Jude Medical conduit grafts were implanted due to ascending aortic aneurysms. Homograft reimplantation was performed in four cases. One patient underwent mitral valve replacement and one patient received a heart transplant. CONCLUSION The results of the study suggest that reoperation in patients with aortic homografts is a low-risk procedure as compared to alternative therapies. Primary allograft aortic valve replacement can give acceptable results for up to 23 years. The major cause of valve dysfunction and indication for reoperation was degeneration. Cumulative rates for freedom from reoperation for any cause in age groups suggest careful selection and indications in homograft implantation in the younger patients. Young age is a risk factor for an early homograft structural deterioration (degeneration).

Anatomic Analysis of the Left Atrial Appendage After Closure With the LARIAT Device

The pathophysiologic role of the left atrial appendage (LAA) in thromboembolic disease and as the primary source for cardioembolic events in patients with atrial fibrillation (AF) has been recognized since the 1950s.1 This has led to the development of percutaneous approaches to exclude LAA, including LAA ligation with the LARIAT suture delivery device (SentreHEART, Inc, Redwood City, CA).2 However, the anatomic consequences of percutaneous LAA ligation are unknown. This report describes LAA gross anatomy and histological consequences of LAA ligation from 2 patients. A 63-year-old man with a history of persistent AF on chronic warfarin oral anticoagulation was referred for LAA exclusion after severe gastrointestinal bleeding and history of falling resulting in a hip fracture. His past medical history included hypertension, diabetes mellitus, previous myocardial infarctions, congestive heart failure, end-stage renal disease on hemodialysis, peripheral vascular disease, status post–femoral popliteal bypass surgery, and hip fracture. The patient had a CHADS2 score of 3, CHADS-Vasc score of 4, and a HAS-Bleed score of 4. The patient underwent an uncomplicated closed-chested LAA ligation with the LARIAT suture delivery device.2 LAA closure was confirmed with transesophageal echocardiography (TEE) and contrast fluoroscopy acutely (Figure 1). The patient did well post-LAA closure and was on no antiplatelet or antithrombin medications. A follow-up TEE performed at 8 months revealed a closed LAA with no leaks. Eleven months after his LAA ligation, the patient was admitted to the hospital with pneumonia and volume-overloaded congestive heart failure. During dialysis, the patient had a ventricular fibrillation arrest. Cardiac resuscitation was initiated but was unsuccessful and the patient …