Impaired renal vascular endothelial function in vitro in experimental hypercholesterolemia.

Hypercholesterolemia (HC) induces alterations in systemic vascular reactivity, which can manifest as an attenuated endothelium-dependent relaxation, partly consequent to an impairment in nitric oxide (NO) activity. To determine whether experimental HC has a similar effect on renal vascular function, renal artery segments obtained from pigs fed a HC (n=5) or normal (n=5) diet were studied in vitro. Endothelium-dependent relaxation was examined using increasing concentrations of acetylcholine (Ach), calcium ionophore A23187, and Ach following pre-incubation with N(G)-monomethyl-L-arginine or L-arginine (L-ARG). The NO-donor diethylamine (DEA) was used to examine smooth muscle relaxation response and cyclic GMP generation in endothelium-denuded vessels. The expression of endothelial NO synthase (eNOS) in the renal arteries was examined using Western blotting. Endothelium-dependent relaxation to Ach was significantly attenuated in the HC group compared to normal (53.3+/-9.1 vs. 98.8+/-3.7%, P<0.005), but normalized after pre-incubation with L-ARG (82.3+/-13.8%, P=0.21). Receptor-independent endothelium-dependent relaxation to A23187 was also significantly blunted in HC (75.2+/-10.5 vs. 115.5+/-4.2%, P<0. 017). Smooth muscle relaxation and cyclic GMP generation in response to DEA were greater in denuded HC vessels, while relaxation of intact vessels to nitroprusside was unaltered. In the HC vessels eNOS was almost undetectable. In conclusion, experimental HC attenuates in vitro endothelium-dependent relaxation of the porcine renal artery, possibly due to low bioavailability of NO. These vascular alterations in HC could play a role in the pathogenesis of renal disease or hypertension, supporting a role for HC as a risk factor for renovascular disease.

Transmyocardial and percutaneous myocardial revascularization: current and future role in the treatment of coronary artery disease.

Transmyocardial revascularization (TMR) is a new treatment modality under evaluation in patients with severely symptomatic, diffuse coronary artery disease, in whom the potential for medical or interventional management has been exhausted. Preliminary clinical trials show improved ischemic symptoms within the first 3 months in about 70% of TMR-treated patients. The original proposed mechanism of surgical or catheter-based TMR (percutaneous myocardial revascularization [PMR]) was that channels mediate direct blood flow between the left ventricular cavity and ischemic myocardium. However, several alternative explanations for the clinical success of TMR have recently been suggested, including improved perfusion by angiogenesis, an anesthetic effect by nerve destruction, and a potential placebo effect. This article reviews the clinical role of TMR/PMR, its possible pathophysiologic mechanisms, and its controversies. It provides an overview of the actual scientific and clinical status of TMR and details future directions.

Operation for anorexigen-associated valvular heart disease.

OBJECTIVES: Recently, valvular regurgitation has been observed in patients who have taken fenfluramine or dexfenfluramine with or without phentermine. This study describes the clinical, echocardiographic, and pathologic findings of anorexigen-associated valvular heart disease and the surgical interventions required to treat it. METHODS: We reviewed clinical information on 14 patients with severe anorexigen-associated valvular disease who underwent cardiac operations. RESULTS: Thirteen women (mean age 44.2 +/- 5.3 years) received fenfluramine, 58.5 +/- 22.3 mg/day, and phentermine, 32.1 +/- 11.4 mg/day, for an average of 12.1 +/- 7.3 months before presentation. One woman received dexfenfluramine, 30 mg/day for 13 months, and phentermine, 60 mg/day, concomitantly for 6 months. Presenting symptoms included dyspnea (12 cases), palpitations (3), and atypical chest pain (3). Six patients had heart failure, and 4 had a new murmur. Echocardiography demonstrated severe mitral valve regurgitation in all patients. Seven also had aortic regurgitation, and 4 had significant tricuspid regurgitation. Four patients had successful mitral valve repair, 1 with concomitant aortic valve repair. Ten additional patients eventually required mitral valve replacement, 5 with concomitant aortic valve replacement. Excised valves demonstrated a glistening white appearance with plaque-like encasement of leaflets and chordae. Focal surface proliferation and fibrosis with a "stuck-on" appearance was consistently found. CONCLUSIONS: Anorexigen use may lead to severe multivalvular regurgitation with characteristic echocardiographic and pathologic findings. Recognition of drug-induced valvulopathy is important because of widespread use of these medications and the uncertain natural history of the disease. Early surgical experience suggests that valve repair is possible in these young patients.

The current role of parathyroid cryopreservation and autotransplantation in parathyroid surgery: an institutional experience.

BACKGROUND: Hypoparathyroidism after cervical exploration is a rare but problematic complication. Cryopreservation and subsequent autotransplantation of parathyroid tissue are infrequently used to combat this problem; effective usage of this surgical adjunct remains variable. METHODS: From 1981 through 1995 we performed 3080 cervical explorations for hyperparathyroidism. Cryopreservation was performed in 112 (3.6%) patients. This review evaluates our indications and usage of cryopreservation and autotransplantation and the eventual outcome after autotransplantation. RESULTS: Of 81 women and 31 men, 106 (95%) had undergone previous exploration for hyperparathyroidism or thyroid disease. The primary indication for cryopreservation was uncertainty about the viability and number of remaining parathyroid glands. After operation 23 patients (20%) were permanently hypocalcemic and became autotransplantation candidates. Thirteen patients underwent a total of 15 autotransplantations (median postoperative interval, 7 months). Although 6 of 15 grafts (40%) were shown to secrete parathyroid hormone, only three patients (23%) were normocalcemic without supplemental therapy. CONCLUSIONS: Cryopreservation with autotransplantation is in theory a sound but difficult practice to correct postexploration hypocalcemia. The principal indication for cryopreservation is the uncertainty regarding the status of remaining normal parathyroid tissue. Because we cannot predict postexploration hypocalcemia, cryopreservation plays a small but sometimes integral role in parathyroid surgery. Indications for cryopreservation in our practice are rare, and the rate of cryopreservation tissue usage is low.

Endothelial regulation of vascular contraction in radial and internal mammary arteries.

BACKGROUND: The extent to which the endothelium regulates radial artery (RA) contractions is unknown. The goals of this study were to characterize endothelium-dependent relaxations in the RA, compare these responses with those in the internal mammary artery (IMA), and, subsequently, manipulate nitric oxide production in the RA with adenovirus-mediated gene transfer. METHODS: Segments of RA and IMA from 43 patients were studied initially in organ chambers. Endothelial function was evaluated and gene transfer, was examined. RESULTS: After precontraction to 80% maximum tension with prostaglandin F2alpha, acetylcholine produced lesser relaxations in the RA (21.5%+/-5.8%) than in the IMA (66.7%+/-10.6%); human thrombin and adenosine 5'-diphosphate yielded similar results. Reduced relaxations in the RA (16.8%+/-4.2%) compared with those in the IMA (71.6%+/-11.9%) were noted with calcium ionophore. Superfusion bioassay demonstrated a similar baseline release in both arteries but a reduced stimulated production of vasoactive substances in the RA, results confirmed by cyclic guanosine monophosphate level determination. The RA produced less 6-keto-prostaglandin F1alpha than the IMA. Light microscopy demonstrated an intact endothelium in both arteries. Adenovirus-mediated gene transfer of nitric oxide synthase augmented relaxations of the RA to acetylcholine. CONCLUSIONS: Reduced production of endothelium-derived relaxing factors suggests diminished endothelial regulation of vascular smooth muscle in the RA compared with the IMA. This finding may explain, in part, the predisposition to vasoconstriction in RA grafts.

Open-heart endocardial radiofrequency ablation: an alternative to incisions in Maze surgery.

BACKGROUND: Radiofrequency (RF) ablation produces transmural atrial lesions in vitro, and may provide advantages over incisions currently used in maze surgery. This study examines the feasibility, safety, and efficacy of open-heart endocardial RF ablation. METHODS: Eighteen sheep (42.8 +/- 4.4 kg, age < 2 years) underwent left thoracotomy with placement of pacing leads on a pulmonary vein and the left atrial dome. On cardiopulmonary bypass, lesions were made using incision and suture or a novel RF ablation device in three sites: PVC = circle excluding pulmonary veins, IAB = line across the interatrial bundle, SVC = line from the superior to the inferior vena cava. Pacing across the PVC lesion was attempted to assess the completeness of each lesion. Preselected animals (incision n = 4, RF n = 5) were recovered and pacing attempts were repeated at 1 month. After sacrifice, hearts were sectioned and measured for lesion size and completeness. RESULTS: RF ablation lesions took less time to create (total bypass time: RF 51.8 min vs incision 106 min, P < 0.001). No evidence of thromboembolism, atrial rupture, or coronary sinus thrombosis was seen. All PVC lesions were complete as demonstrated by the inability to pace across them. Stained sections demonstrated that acutely studied incision lesions were thinner than RF lesions; however, all lesions were transmural and similar in width at 1 month. CONCLUSIONS: RF ablation consistently created transmural lesions more quickly than the incision and suture method and without additional complications. Endocardial RF ablation appears to be a simple and effective alternative to surgical incisions during open-heart atrial Maze procedures.

New approaches to prevention and treatment of radial artery graft vasospasm.

BACKGROUND: There has been renewed interest in radial artery (RA) conduits for coronary artery bypass because of the relative resistance of arterial grafts to atherosclerosis compared with autogenous vein grafts. Although improved drug therapy for arterial spasm is now available, vasospasm still occurs in at least 5% to 10% of RA grafts. We systematically evaluated the effectiveness of calcium channel blockers and organic nitrates for inhibition or reversal of RA contraction in vitro. Additionally, we investigated the efficacy of novel gene therapy with endothelial nitric oxide synthase (eNOS) to inhibit RA contractions. METHODS AND RESULTS: Segments of RA from 28 patients undergoing coronary artery bypass grafting were mounted in organ chambers. In control experiments, KCl (5 to 50 mmol/L) produced dose-dependent increases in tension (maximum tension, 14.3 +/- 3.0 g, n = 7). Addition of diltiazem or verapamil had no significant effect on KCl contraction (128 +/- 36% and 88 +/- 24% control, respectively); however, nifedipine markedly inhibited KCl contraction (27 +/- 4% control, P = 0.005). Norepinephrine (NE, 10(-9) to 10(-4) M) produced dose-dependent increases in tension (maximum tension, 15.7 +/- 2.7 g in control rings, n = 8). Diltiazem and verapamil pretreatment had no significant effect on NE contraction (103 +/- 14% and 90 +/- 14% control, respectively); nifedipine significantly inhibited NE contraction (70 +/- 11% control, P = 0.02). Isosorbide dinitrate and nitroglycerin markedly inhibited KCl contractions (47 +/- 9% and 30 +/- 8% of controls, n = 6) and NE contractions (42 +/- 10% and 31 +/- 9% of controls, n = 6). Nifedipine, isosorbide, and nitroglycerin were further evaluated for the ability to reverse an established contraction (KCl 40 mmol/L); nitroglycerin was most effective in reversing RA contraction. In separate experiments, RA underwent adenoviral-mediated gene transfer with vehicle, Escherichia coli beta-galactosidase, or eNOS (eNOS, 10(10) PFU/mL x 1 hour). Transgene expression was confirmed by beta-galactosidase activity and eNOS immunohistochemistry after 40 hours of ex vivo incubation. Immunohistochemistry demonstrated recombinant NOS in adenovirus encoding bovine eNOS (Ad.CMVeNOS) RA only. Ad.CMVeNOS arteries contracted only 46.6 +/- 13.7% of controls to KCl (n = 5) and 48.2 +/- 11.4% of controls to prostaglandin F2 alpha a (10(-9) to 10(-6) M, n = 5). CONCLUSIONS: Diltiazem, which is used empirically to prevent RA vasospasm, had little effect on human RA contractions (receptor-independent and receptor-dependent). Organic nitrates inhibited and reversed RA contractions. Adenoviral transfer of NOS suggests that future clinical application of gene therapy may play an important role in prevention of RA vasospasm.

The role of gene therapy for intimal hyperplasia of bypass grafts.

BACKGROUND: Proliferation of the intima is an early lesion of saphenous vein graft disease. Early patency rates of radial artery grafts are acceptable, but little is known about their risk of intimal hyperplasia. METHODS AND RESULTS: To develop a model of intimal hyperplasia, we incubated human saphenous veins, internal mammary arteries, and radial arteries (n=6, 8, and 10, respectively) in an organ culture with Roswell Park Memorial Institute 1640 (30% serum) for 0, 4, 7, 10, and 14 days. Quantitative histological studies were performed, and the average intimal-to-medial (I/M) ratio was calculated for each incubation interval. After 10 and 14 days of culture, the I/M ratio increased in the saphenous veins (P=0. 03, P=0.04 versus 0 day, respectively). No significant increase occurred in the I/M ratio in either the internal mammary or radial arteries. Next, the ability of adenoviral gene transfers to inhibit intimal hyperplasia in the saphenous veins was evaluated. Adenoviral-mediated gene transfer of nitric oxide synthase significantly reduced the I/M ratio at 14 days compared with vehicle (P=0.001) and virus (P=0.004) controls. CONCLUSIONS: The human saphenous vein has a greater propensity for intimal hyperplasia than arterial grafts; the human radial artery behaves similarly to the internal mammary artery. In the future, gene therapy may augment nitric oxide synthase, limiting vein graft disease.