Aortic valve replacement in asymptomatic and symptomatic patients with preserved left ventricular ejection fraction.

BACKGROUND AND AIM OF THE STUDY: Patients with moderate-severe aortic stenosis (AS) who maintain that they have no symptoms pose a decision-making dilemma. In order to determine whether or not preoperative symptoms were related to outcomes in these patients, results were compared after aortic valve replacement (AVR) in asymptomatic and symptomatic AS patients with a preserved left ventricular ejection fraction (LVEF). METHODS: Twenty asymptomatic and 18 symptomatic AS patients were investigated retrospectively, with clinical and echocardiographic studies being performed before and at 610 +/- 409 days after AVR. The patients' cardiopulmonary function was monitored using spiroergometry. RESULTS: Symptomatic AS patients improved their exercise tolerance after surgery more than asymptomatic patients, although exercise tolerance and LVEF remained lower in symptomatic patients. On comparing all postoperative objective changes between the groups, a difference was observed only for aortic valve area index. Improvements in left ventricular structure, diastolic function, and filling pressures after AVR were similar in both groups. Systolic function, as assessed by tissue Doppler, was improved only in the symptomatic group. Regression analyses identified preoperative exercise tolerance as the strongest independent determinant of postoperative functional outcome. The postoperative LVEF was independently predicted by the preoperative LVEF and exercise tolerance. CONCLUSION: Asymptomatic patients with moderate-severe AS and preserved systolic function exhibited similar improvements in cardiac remodeling, diastolic function, and filling pressures following AVR, compared to symptomatic patients. Differences in exercise tolerance and systolic function observed preoperatively between these groups were decreased after AVR.

Pregnancy-associated plasma protein A values in patients with stable cardiovascular disease: use of a new monoclonal antibody-based assay.

BACKGROUND: PAPP-A is promising in improving risk stratification and invasive treatment decisions in stable cardiovascular patients. We evaluated the prognostic value of pregnancy-associated plasma protein A (PAPP-A) measured by a novel assay in stable cardiovascular patients. METHODS: We investigated 228 stable cardiovascular outpatients. Blood was drawn for PAPP-A measurement after echocardiography and ergometry prior to heart catheterization. Angiographically we determined severity as well as qualitative characteristics suspect for vulnerability of coronary lesions. After 1108±297 days, follow-up information was obtained by questionnaire mailings and interviews by phone. RESULTS: 104 patients had coronary stenosis≥70%, 75 had B-type lesions≥50%, 46 showed complex lesions, and 68 were suspected to have vulnerable lesions. Median PAPP-A was 1.76 (interquartile range 1.21, 2.63) µIU/ml in the entire cohort. PAPP-A concentrations did not differ in dependence on coronary artery findings. A cutpoint of 2.7 µIU/ml was derived from receiver-operator characteristics for outcome measures. For this cutoff, Cox proportional hazard models with 19 further clinical variables showed that PAPP-A was predictive for all-cause death (HR 4.73, 95% CI 1.46-15.31, p=0.01), all-cause death or nonfatal infarction (HR 4.01, 95% CI 1.58-10.13, p=0.003) and all-cause death, nonfatal myocardial infarction or hospitalization (HR 1.96, 95% CI 1.03-3.70, p=0.04). The predictive value of PAPP-A did not change substantially after correction for values of cardiac troponin, using a highly sensitive cardiac troponin I research assay. CONCLUSIONS: PAPP-A, measured by a new, monoclonal antibody-based assay is a promising prognostic marker in patients with stable cardiovascular disease and an indication for heart catheterization.

The CAIRP (CAndesartan for In-stent Restenosis Prevention) Trial--a multicenter study of AT1-receptor blocker therapy in coronary stenting.

Angiotensin II (Ang II) is implicated in the development of in-stent restenosis (ISR). Ang II- and AT1-receptor blockade could possibly reduce ISR. We enrolled 206 patients into a prospective double-blind, placebo-controlled, multicenter randomized trial of candesartan cilexitil 16 mg to test this notion. Mean lumen diameter (MLD) was the primary objective measured by quantitative coronary angiography and intravascular ultrasound. The Candesartan Group showed a trend towards a larger MLD at follow up without significant differences in the binary ISR rate. In vessels < 2.75 mm, we found a larger MLD in the treatment group after 6 months. This might indicate the potential benefit of AT1-receptor blocker therapy for certain subgroups when percutaneous coronary intervention is performed with bare-metal stent implantation.

Recurrent in-stent restenosis is not associated with the angiotensin-converting enzyme D/I, angiotensinogen Thr174Met and Met235Thr, and the angiotensin-II receptor 1 A1166C polymorphism.

Although great progress has been made in reducing renarrowing of the lumen after stenting of coronary arteries, a considerable number of patients develop recurrent in-stent stenosis. Several studies suggest that neointimal proliferation is the crucial pathophysiological process underlying restenosis after stenting. The renin-angiotensin-aldosterone system (RAS) has been implicated in the development of neointimal hyperplasia. We tested the hypothesis that polymorphisms of the RAS genes are associated with recurrent in-stent restenosis (ISR). Coronary stent implantation was performed in 272 patients with clinical symptoms or objective signs of ischemia. At follow-up angiography 6 months after stenting, 81 patients (29.8%) revealed in-stent restenosis. These patients underwent balloon angioplasty and were scheduled for a further 6 months of follow up. One year after initial stenting of the coronary artery, 39 patients displayed no significant angiographic ISR, whereas 42 patients developed recurrent in-stent restenosis (RISR). The survey of specific functional polymorphisms of the RAS, namely the angiotensin-I converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence RISR in the high-risk cohort was not associated with any of the polymorphisms examined in this study.

Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor.

The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.

Blood pressure-independent ETA and AT1 receptor blocker effects on the coronaries of rats harboring human renin and angiotensinogen genes.

BACKGROUND: Blood pressure-independent (BP) effects of angiotensin (Ang) II and endothelin (ET) on coronaries (remodeling) in high renin hypertension are incompletely understood. METHODS: We studied the effects of subdepressor doses of Ang II receptor (AT1) blockade with losartan (10 mg/kg/day gavage) and endothelin A receptor (ETA) blockade with LU135252 (30 mg/kg/day) on the coronaries of rats harboring human renin and angiotensinogen genes (dTGR). Nontransgenic Sprague-Dawley rats were controls. The rats were treated between the ages of 6 and 10 weeks. Coronary cross-sectional area [CSA; 0.79 x (external diameter2 - internal diameter2)], cell proliferation, and infiltration of monocytes/macrophages were determined. RESULTS: Monotherapy did not lower BP while combination treatment did (p < 0.05). All treatments reduced mortality (p < 0.01). CSA was decreased by all treatments compared to vehicle, independent of blood pressure (p < 0.05). Extensive proliferation by PCNA staining and infiltration of ED-1-positive cells was diminished by both treatment and the combination. CONCLUSIONS: The data show that Ang II promotes coronary inflammation and remodeling, in part independent of blood pressure but dependent upon ET signaling. Combination treatment directed at both pathways may improve outcome, independent of blood pressure reduction.

Percutaneous transluminal septal artery ablation using polyvinyl alcohol foam particles for septal hypertrophy in patients with hypertrophic obstructive cardiomyopathy: acute and 3-year outcomes.

PURPOSE: To investigate the effect of septal artery occlusion with transluminally delivered polyvinyl alcohol (PVA) foam particles for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). METHODS: Percutaneous septal artery ablation was performed in 18 symptomatic patients (13 men; mean age 60+/-17 years, range 28-89) with drug-resistant HOCM. PVA foam particles were mixed with contrast medium and injected through an angiographic catheter under fluoroscopic control until complete stasis in the septal branch was achieved. Patients were monitored with echocardiography and cardiovascular magnetic resonance imaging. RESULTS: The septal artery was successfully occluded in all patients; no embolization of other coronary branches occurred after infusion of 3 to 8 mL (5.2+/-0.8) of PVA foam particles. The resting pressure gradient was diminished from 83+/-32 to 31+/-35 mmHg (p<0.05). Over a mean follow-up of 44+/-4 months, all patients had symptomatic improvement of their dyspnea and workload without the need for intensified drug therapy. The average NYHA functional class decreased from 3.3+/-0.5 to 1.3+/-0.7 (p<0.0001), with a significant increase in the area of the left ventricular outflow tract (1.3+/-0.2 to 2.6+/-0.2 cm2, p<0.0001). Three instances of transient atrioventricular block occurred, but no complete heart block was produced by the embolization procedure. CONCLUSIONS: Embolization of the septal artery with PVA foam particles appears effective and safe in this series of patients with hypertrophic obstructive cardiomyopathy. The pure ischemic infarction produced by PVA ablation might be the responsible for the lack of complete heart block and the need for permanent pacing.

The intron 6 G/T polymorphism of c-myb oncogene and the risk for coronary in-stent restenosis.

BACKGROUND: The principle mechanisms leading to the development of atherosclerosis are long-term accumulation of lipids and cell proliferation. We have recently shown that a single nucleotide polymorphism in the c-myb gene is associated with the development of coronary artery disease in humans and intracellular lipid accumulation. C-myb expression has been further shown to be up-regulated during cell proliferation. The development of in-stent restenosis is predominantly driven by smooth muscle cell proliferation. METHODS: To study a possible association of c-myb with neointima formation in humans we genotyped 485 consecutive patients undergoing coronary stenting for a G/T-single nucleotide polymorphism in intron 6 of the cmyb gene. Restenosis was assessed by quantitative coronary angiography and angiographic follow-up after 6 months. To study the effect of c-myb on smooth muscle cell proliferation primary human smooth muscle cells were infected with recombinant adenovirus expressing c-myb, a dominant negative myb-engrailed fusion protein or control virus. RESULTS AND CONCLUSION: Restenosis > 50% occurred in 27.6% of patients with at least one G-allele and in 20.8% of those without (p = 0.10). Even after adjustment for the independent risk factors diabetes mellitus, reference lumen diameter, smoking, dyslipidemia and number of diseased vessels, the observed difference in the distribution of the c-myb alleles did not reach statistical significance (p = 0.08). Adenoviral gene transfer of c-myb did not increase proliferation of cultured smooth muscle compared to control virus or untransfected cells, while the expression of the dominant negative mutant reduced proliferation of VSMC as previously shown. Our results indicate that expression of c-myb, while being important for cell cycle is not sufficient to induce smooth muscle cell proliferation. The G/T-nucleotide transversion polymorphism in intron 6 of the c-myb oncogene that has been associated with atherosclerosis and lipid accumulation is not a risk factor for human in-stent restenosis.

Angiotensin II type 1 receptor expression in human coronary arteries with variable degrees of atherosclerosis.

Autopsy specimens of human coronary arteries were collected from 65 men and women ranging in age from 40-76 years of age. We made 209 coronary artery sections, which were graded in terms of severity of atherosclerosis by means of the Stary classification. Sections were stained using an antibody directed against the angiotensin II type 1 (AT1) receptor. We found that in non-atherosclerotic sections, staining was confined to vascular smooth muscle cells in the media. However, with the advent of atherosclerosis, AT1 receptor expression was also present in atherosclerotic plaque and involved other cell types including inflammatory cells and myofibroblasts. We identified a remarkable correlation between AT1 receptor staining and the severity of coronary atherosclerosis as well as intima-media thickness. These human data correspond well to animal models of atherosclerosis indicating an upregulation of AT1 receptor expression in atherosclerotic tissue.

Smoothelin contains a novel actin cytoskeleton localization sequence with similarity to troponin T.

Smoothelin, a cytoskeletal protein, exists in a large isoform specifically expressed in vascular smooth muscle cells, and a small visceral isoform generated by a downstream transcriptional start site. Using fusions to the green fluorescent protein, we could show that both smoothelin isoforms are localized at actin containing filaments and mapped two domains that are each sufficient for localization at the actin cytoskeleton. The first domain is located in the vascular-specific, N-terminal half of smoothelin and the second in the common, C-terminal half. The second domain shares clear sequence similarity with a domain of troponin T involved in actin filament association. These results suggest that the tissue-specific expression of smoothelin isoforms might contribute to the different contractile properties of smooth muscle cells.