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Biomedical subjects

George W Vetrovec

Publications and source records attributed to George W Vetrovec.

At least 19 recordsLinked to original sources
PubMed2006

Ischemia and apoptosis in an animal model of permanent infarct-related artery occlusion.

Apoptosis is a pathologic feature of cardiomyocytes in acute myocardial infarction (AMI) and heart failure. The temporal course of apoptosis in the peri-infarct area in the weeks following an AMI is still uncompletely defined. In order to study the time course of apoptosis after AMI, 16 rabbits underwent left coronary artery ligation and were sacrificed at 16, 26, 35, and 56 days after surgery. Increased apoptotic rate (AR) was observed at in the peri-infarct region than in remote myocardium (5.4% [2.5-9.6] vs 0.4% [0.1-0.9], respectively, P<0.001) and than in sham-operated cases (0.01% [0-0.02], P<0.001). A gradual decrease of AR in the peri-infarct region was observed over time with a 90% reduction at 8 weeks after coronary ligation.

Animals↗
PubMed2006

Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials.

More women than men with myocardial infarction have previous stable angina pectoris. Women also have an increased incidence of angina after percutaneous coronary intervention and coronary artery bypass grafting. Data from 1,737 patients with stable angina pectoris in 4 international trials (Monotherapy Assessment of Ranolazine In Stable Angina [MARISA], Combination Assessment of Ranolazine In Stable Angina [CARISA], Ranolazine Versus Atenolol Comparison in Chronic Angina [RAN080], and Efficacy of Ranolazine in Chronic Angina [ERICA]) were used to compare efficacy and safety of ranolazine therapy for angina in women and men. MARISA, CARISA, and RAN080 included exercise testing; CARISA, RAN080, and ERICA assessed angina frequency and nitroglycerin consumption; and ERICA included quality-of-life assessment using the Seattle Angina Questionnaire. MARISA, CARISA, and ERICA used the extended-release formulation of ranolazine; RAN080 used ranolazine immediate release. All 4 studies showed overall efficacy and safety of ranolazine. In subgroup analyses, women showed less improvement than men in exercise testing. However, similar improvements for women and men were noted in angina frequency and nitroglycerin consumption, and in ERICA, in the angina frequency dimension of the Seattle Angina Questionnaire. In conclusion, explanations for the gender treatment differences for exercise parameters but comparable effects on decrease in angina frequency and nitroglycerin use are uncertain, but may include differences in patient demographics, reasons for stopping exercise, and type of exercise protocol used.

Acetanilides↗
PubMed2006

Acute myocardial infarction and heart failure: role of apoptosis.

Apoptosis is a key pathologic feature in acute myocardial infarction and heart failure. Experimental animal studies have shown beneficial effects of inhibiting apoptosis. Understanding the mechanisms involved in the apoptotic cascade may be useful in better understanding of heart failure and its management. Not only in vivo detection of apoptosis may prove clinically useful in the diagnosis and risk stratification of patients with ischemic heart disease, but anti-apoptotic treatments (specific and non-specific) may be effective in the prevention and treatment of post-infarction remodelling and heart failure.

Animals↗
PubMed2006

Sirolimus PK trial: a pharmacokinetic study of the sirolimus-eluting Bx velocity stent in patients with de novo coronary lesions.

This study was conducted to assess the systemic drug release and distribution of sirolimus-eluting stents. Early results with sirolimus-eluting stents have demonstrated a favorable outcome for reducing restenosis post coronary intervention. However, the clinical systemic pharmacokinetics of sirolimus released from these stents has not been investigated. Sirolimus-eluting stents (150-178 mcg/18 mm stent) were implanted in 19 patients with coronary artery disease using standard techniques. Blood samples were obtained at multiple times to determine the kinetics of sirolimus release and elimination. Non-compartmental analysis showed that the maximum blood concentration of sirolimus occurred between 3 and 4 hr after implantation, with a peak concentration of 0.57 +/- 0.12 ng/mL (mean +/- SD) and 1.05 +/- 0.39 ng/mL in patients receiving one or two stents, respectively. Terminal-phase elimination half-life was independent of the number of stents and averaged at 213 hr, a value longer than that seen in patients following oral dosing. The apparent clearance was 1.46 +/- 0.45 L/hr with an apparent volume of distribution in the terminal phase of 407 +/- 111 L (data for both stent doses pooled). Minimal measurable blood levels were detectable at 7 days. Peak whole blood level following sirolimus stent implantation in humans is proportional to the number of stents implanted. The prolonged terminal half-life may reflect kinetics of blood clearance combined with continued drug elution and secondary local tissue release.

Adult↗
PubMed2006

Effect of statins and white blood cell count on mortality in patients with ischemic left ventricular dysfunction undergoing percutaneous coronary intervention.

BACKGROUND: While morbidity and mortality were shown to be increased in the setting of an elevated white blood cell (WBC) count for patients with acute coronary syndrome, the impact of statin therapy on mortality for patients with an elevated WBC count is unknown in high-risk patients with coronary artery disease. HYPOTHESIS: The goal of this study was to determine whether statin therapy improved survival in patients with elevated WBC count undergoing percutaneous coronary intervention (PCI) with preexisting left ventricular (LV) dysfunction, a population at high risk for adverse outcomes. METHODS: We retrospectively evaluated consecutive patient procedures performed at our institution from 1996 through 1999. Patients had a technically adequate angiographic left ventriculogram with a calculated ejection fraction (EF) < or = 50%. Patients with prior coronary artery bypass graft were excluded. Mortality data were retrieved using the U.S. Social Security Death Index. Follow-up ranged from 3.5 to 6.5 years. Means are provided with +/- standard deviation, and p values < 0.05 were considered significant. RESULTS: Of the study population of 238 patients (average EF 39 +/- 9.8%, mean age 57.5 +/- 12 years, 68% men) 61% underwent PCI for a recent myocardial infarction, 68% received stents, and 65% were discharged on statins. Mean WBC count was 9,000 +/- 3,100 cells/mm3, with 28% of patients having a WBC > or = 10,000 cells/mm3. During follow-up, 27% of our population died. Patients with a WBC > or = 10,000 had worse survival than patients with WBC < 10,000 (1-year survival: 86 vs. 96%, p < 0.05; 3-year survival: 79 vs. 89%, p < 0.05). Survival was significantly improved in patients on statin therapy regardless of WBC count, but the greatest benefit tended to be in patients with WBC > or = 10,000 (WBC > or = 10,000; odds ratio [OR] 5.14, 95% confidence interval [CI] 1.44-19.0, WBC < 10,000; OR 2.79,95% CI 1.13-7.1). Proportional hazard regression analysis demonstrated that both statin therapy and WBC count predicted mortality. CONCLUSION: Patients undergoing PCI with LV dysfunction discharged on statins had improved survival regardless of WBC count, with a trend for greater improvement in patients with elevated WBC counts. In addition, WBC count predicts mortality in this high-risk population with LV dysfunction undergoing PCI.

Angioplasty, Balloon, Coronary↗
PubMed2006

Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes.

Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Recently, the antigrowth properties of rapamycin have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restenosis. We report here a novel role of this drug in protection against ischemia/reperfusion (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin). The hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. The blocker of mitochondrial KATP channel, 5-hydroxydecanoate (5-HD, 100 microM) was given 10 min before ischemia. Infarct size in the DMSO treated group was 28.2 +/- 1.3% and was reduced to 10.1 +/- 2.8% in the rapamycin-treated mice (64% decrease, P < 0.001). 5-HD blocked the protective effect (infarct area 32.2 +/- 1.8%, P < 0.001 vs. rapamycin). The infarct limiting effect of rapamycin was not associated with improved recovery of ventricular function. We further examined the effect of rapamycin in protection against necrosis and apoptosis in adult cardiomyocytes subjected to simulated ischemia and reoxygenation. Myocytes treated with rapamycin in doses from 25-100 nM demonstrated significantly lower trypan blue-positive necrotic cells and TUNEL-positive apoptotic nuclei, supporting the protective role of drug in the intact heart. These data suggest that rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial KATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart.

Animals↗
PubMed2006

Medical treatment of patients with heart failure or left ventricular dysfunction undergoing percutaneous coronary intervention.

Management of ischemic patients with pre-existing or new-onset left ventricular (LV) dysfunction poses a special challenge in terms of the timing of percutaneous coronary intervention (PCI) and appropriate adjunctive medications to optimize outcome while minimizing risk. In a systematic fashion, this review attempts to provide a management scheme for patients with heart failure or LV dysfunction that present with stable angina, ST-segment elevation myocardial infarction, or unstable angina/non-ST-segment elevation myocardial infarction. By addressing therapeutic approaches to acute or decompensated heart failure and timing of coronary angiography based on severity of ischemia, we provide evidence-based recommendations for medications to initiate before, during, and following PCI.

Angina Pectoris↗
PubMed2005

Myocardial expression of survivin, an apoptosis inhibitor, in aging and heart failure. An experimental study in the spontaneously hypertensive rat.

BACKGROUND: Apoptosis plays a major role in the transition to heart failure (HF) in systemic hypertension although the underlying mechanisms are still unclear. The aim of this study was to determine the relationship between apoptosis, left ventricular remodeling, heart failure and the myocyte expression of survivin, an inhibitor of apoptosis. METHODS: Spontaneously hypertensive rats (SHR) were used as a model of hypertensive cardiopathy, and Wistar Kyoto Stars rats (WKY) were used as controls. Animals were allowed to survive up to 18 months of age. The animals underwent echocardiography (EDD, ESD and FS were measured). The median section of the heart was processed for in situ end-labeling of DNA fragmentation (TUNEL) and for survivin expression by immunohistochemistry. RESULTS: All SHR presented features of adverse cardiac remodeling. Apoptotic cells were increased in SHR compared with WKY, measured as apoptotic cells per high power field (1.08+/-0.43 vs. 0.27+/-0.15, P<0.001), and as apoptotic rate (0.16+/-0.06% vs. 0.04+/-0.02%, P<0.001). The incidence of apoptosis showed a positive correlation with unfavorable ventricular remodeling, assessed by echocardiogram. Survivin expression was found in all cases, but the survivin expression index was significantly lower in SHR vs. WKY (43+/-40% vs. 86+/-18%, respectively, P=0.014). Moreover the survivin expression index was inversely correlated with features of adverse remodeling (i.e., Heart Weight, R=-0.79, P<0.001) and with apoptosis (i.e., apoptotic rate, R=-0.52, P=0.050). CONCLUSION: Survivin myocardial expression in aging SHR is associated with reduced apoptosis and more favorable cardiac remodeling. Modulation of this pathway may prove beneficial in preventing pressure overload cardiac remodeling and heart failure.

Animals↗
PubMed2005

Infarct-related artery occlusion, tissue markers of ischaemia, and increased apoptosis in the peri-infarct viable myocardium.

AIMS: Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. METHODS AND RESULTS: In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P=0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P<0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P=0.42] CONCLUSION: Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences.

Actins↗
PubMed2005

Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare-metal-stent-controlled trials.

AIMS: Drug-eluting stents (DES) have been recently investigated, with favorable data for many devices, but comparative data are lacking. We thus performed an adjusted indirect comparison metaanalysis of DES. METHODS: Randomized trials comparing DES vs. bare-metal stents (BMS) were systematically searched, and random effect odds ratios (OR) were computed for target lesion revascularization (TLR) and binary in-stent restenosis rate (BRR) at 6-12 months. We then generated interaction OR for the comparison of different DES. RESULTS: We pooled data from 17 studies (allocating 3048 patients to BMS and 3392 to nine different DES). Indirect head-to-head comparison of sirolimus-eluting Cypher (N=1007) vs. polymeric paclitaxel-eluting Taxus (N=959) showed nonsignificant differences in TLR [OR=0.8 (0.5-1.4), p=0.45] but significant reductions in BRR favoring Cypher [OR=0.3 (0.1-0.6), p<0.001]. Everolimus-eluting stents appeared noninferior to Cypher or Taxus (p>0.50 for both TLR and BRR). Actinomycin-, mycophenolate-, and apolymeric paclitaxel-eluting stents (PES) all proved significantly worse than Cypher or Taxus for TLR or BRR. CONCLUSION: Notwithstanding its inherent limitations, the present metaanalysis confirms the effectiveness of both Cypher and Taxus, supports the promising role of everolimus-eluting stents, and suggests the significant inferiority of most other devices. These post hoc findings, albeit intriguing, await prospective confirmation.

Coronary Disease↗
PubMed2005

Improved survival for stenting vs. balloon angioplasty for the treatment of coronary artery disease in patients with ischemic left ventricular dysfunction.

While earlier studies of balloon angioplasty (BA) in patients with left ventricular (LV) dysfunction suggested high late mortality, a study directly comparing coronary stenting and BA has not been performed. Since stenting provides a more durable revascularization, we sought to compare long-term survival in patients undergoing stenting vs BA in patients with decreased left ventricular ejection fractions (LVEF). We evaluated consecutive patient procedures performed in our institution from 1996 through 1999. Patients were considered part of the stent group if they received at least one stent. To be included, patients had to have a technically adequate angiographic LV gram with a calculated LVEF<or=50%. Patients with prior CABG were excluded. Mortality data was retrieved using the United States Social Security Death Index. Follow-up ranged from 3.5 to 6.5 years. Statistical analysis was performed and tests were significant with a P-value<0.05. A total of 238 patients fulfilled our criteria. Mean age was 57.5+/-12 years, mean LVEF was 39+/-10%, 67% were males, 71.5% received stents, 62% had a recent MI, and 19% died during follow-up. Overall 5-year survival was 84% for stenting and 77% for BA (P=NS). Patients with an LVEF<or=40% (n=110) had better survival at 5 years if they received a stent compared with BA alone (76% for stents vs. 53% for BA; P<0.05). Stenting was found to be significant predictor of late survival on Cox Hazard Regression analysis in patients with an LVEF<or=50% and LVEF<or=40%. This study demonstrates improved 5-year survival for patients undergoing stenting compared with balloon angioplasty in patients with LVEF<or=40%.

Angioplasty, Balloon, Coronary↗
PubMed2005

The importance of heart rate recovery in patients with heart failure or left ventricular systolic dysfunction.

BACKGROUND: The ability to better predict outcome with exercise testing in patients with heart failure (HF) and left ventricular systolic dysfunction (LVSD) may prove extremely valuable in determining which patients are at increased risk. This study evaluated the ability of heart rate recovery (HRR) to predict outcome in patients with HF and validate previous findings in LVSD. METHODS AND RESULTS: HRR was measured at 1-, 2-, 3-, and 5-minute time points after treadmill testing in 2,193 males being evaluated for chest pain at the Palo Alto and Long Beach VA Hospitals. Left ventricular ejection fraction (LVEF) was calculated using biplane ventriculography and patients were considered to have LVSD if they had an LVEF <50%. Angiographic and clinical data was available for all patients. Of the 2,193 patients, 314 patients had LVSD and 109 had a history of HF. Both HF patients and patients with LVSD with a normal HRR at 2 minutes had improved survival compared with patients that had an abnormal HRR at 2 minutes when adjusted for age and beta-blocker use (HF adjusted odds ratio 0.25, 95% CI 0.10-0.66, P < .006; LVSD alone adjusted odds ratio 0.25, 95% CI 0.13-0.47, P < .0001). Stepwise proportional hazard regression analysis revealed that only 2-minute HRR, age, LVEF, and chronic obstructive pulmonary disorder were significant predictors of mortality in patients with LVSD and only HRR at 2 minutes and LV hypertrophy were significant predictors of mortality in patients with HF. CONCLUSION: HRR is a significant predictor of mortality in patients with HF and patients with LVSD and may be useful in better determining prognosis.

Adrenergic beta-Antagonists↗
PubMed2004

Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study).

In a nonrandomized feasibility study of therapeutic hypothermia in acute myocardial infarction, 18 patients were treated with endovascular cooling (Alsius, Irvine, California) as adjunctive therapy to primary percutaneous coronary intervention to assess measures of infarct size (area under the curve creatinine kinase-MB and technetium-99m single-photon emission computed tomography sestamibi) and the quality of myocardial perfusion (continuous ST-segment monitoring). Periprocedural endovascular cooling successfully decreased core body temperature (median 33.5 degrees C) and was well tolerated, which supports the evaluation of adjunctive hypothermia in pivotal trials to limit infarct size and decrease reperfusion injury.

Angioplasty, Balloon, Coronary↗