Progression of coronary artery disease during long-term follow-up of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II)

Background: This study evaluates cardiovascular risk factors associated with progression of coronary artery disease (CAD) in patientswith silent ischemia followingmyocardial infarction. Hypothesis: Coronary artery disease only progresses slowly with comprehensive risk factor intervention. Methods: A total of 104 of 201 patients (51.7%) of the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) with baseline and follow-up coronary angiography were included. All patients received comprehensive cardiovascular risk factor intervention according to study protocol. Logistic regression was used to evaluate associationsbetween baseline cardiovascular risk factors and CAD progression. Results: The mean duration of follow-upwas 10.3 ± 2.4 years. At baseline, 77.9% of patients were smokers, 45.2% had hypertension, 73.1% had dyslipidemia, 7.7% had diabetes, and 48.1% had a family history of CAD. At last follow-up, only 27 patients of the initial 81 smokers still smoked, only 2.1% of the patients had uncontrolled hypertension, 10.6%of the patientshad uncontrolled dyslipidemia, and 2.1%of the patientshad uncontrolled diabetes. Coronary artery disease progression was found in up to 81 (77.9%) patients. Baseline diabetes and younger age were associatedwith increased odds of CAD progression.The time intervalbetween baseline and follow-up angiography was also associatedwith CAD progression. Conclusion: Coronary artery disease progressionwas highly prevalent in these patients despite comprehensive risk factor intervention. Further research is needed to optimize treatment of known risk factors and to identify other unknown and potentiallymodifiable risk factors.

Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial

CONTEXT: The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. OBJECTIVE: To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. DESIGN, SETTING, AND PARTICIPANTS: Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. INTERVENTIONS: Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. MAIN OUTCOME MEASURES: Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. RESULTS: During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). CONCLUSION: Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00387231.

Sudden cardiac death in patients with silent myocardial ischemia after myocardial infarction (from the Swiss Interventional Study on Silent Ischemia Type II [SWISSI II])

The occurrence of sudden cardiac death (SCD) in patients with silent ischemia after myocardial infarction (MI) and the factors facilitating SCD are unknown. This study aimed to determine the factors facilitating SCD in patients with silent ischemia after MI. In the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II), 201 patients with silent ischemia after MI were randomized to percutaneous coronary intervention (PCI) or medical management. The main end point of the present analysis was SCD. Multivariable regression models were used to detect potential associations between baseline or follow-up variables and SCD. During a mean follow-up of 10.3 +/- 2.6 years, 12 SCDs occurred, corresponding to an average annual event rate of 0.6%. On multivariate regression analysis, the decline in the left ventricular ejection fraction (LVEF) during follow-up was the only independent predictor of SCD (p = 0.011), other than age; however, the baseline LVEF was not. The decline in LVEF was greater in patients receiving medical management than in those who had received PCI (p <0.001), as well as in patients with residual myocardial ischemia or recurrent MI compared with patients without these findings (p = 0.038 and p <0.001, respectively). Compared with medical management, PCI reduced the rate of residual myocardial ischemia (p <0.001) and recurrent MI (p = 0.001) during follow-up. In conclusion, patients with silent ischemia after MI are at a substantial risk of SCD. The prevention of residual myocardial ischemia and recurrent MI using PCI resulted in better long-term LVEF and a reduced SCD incidence.

Coronary artery disease is common in asymptomatic patients with signs of myocardial ischemia

BACKGROUND: The incidence of coronary artery disease (CAD) in totally asymptomatic patients with myocardial ischemia during stress testing is unknown. METHODS: 54 patients with asymptomatic myocardial ischemia participated in the Swiss Interventional Study on Silent Ischemia type I (SWISSI I). Asymptomatic myocardial ischemia was verified by bicycle ergometry and stress imaging (echocardiography or scintigraphy). Findings from coronary angiographies in the course of the study constituted the main outcome. RESULTS: Of the 54 study participants, 29 patients (53.7%) underwent coronary angiography. CAD was found in 27 of 29 patients (93.1%). In those 27 patients with CAD, 9 patients (33.3%) suffered from single vessel disease, 9 patients (33.3%) from two vessel disease, and 9 patients (33.3%) from triple vessel disease. Two patients showed left main coronary artery stenosis. CONCLUSION: This study shows a high incidence of relevant CAD among totally asymptomatic patients with myocardial ischemia during stress testing. Previously healthy subjects with exercise-induced ST-segment depression at check-up examinations, even if asymptomatic, should have further diagnostic evaluation.

Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice

Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. CONCLUSION: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.

Role of complement and perspectives for intervention in ischemia-reperfusion damage

Reperfusion of an organ following prolonged ischemia instigates the pro-inflammatory and pro-coagulant response of ischemia / reperfusion (IR) injury. IR injury is a wide-spread pathology, observed in many clinically relevant situations, including myocardial infarction, stroke, organ transplantation, sepsis and shock, and cardiovascular surgery on cardiopulmonary bypass. Activation of the classical, alternative, and lectin complement pathways and the generation of the anaphylatoxins C3a and C5a lead to recruitment of polymorphonuclear leukocytes, generation of radical oxygen species, up-regulation of adhesion molecules on the endothelium and platelets, and induction of cytokine release. Generalized or pathway-specific complement inhibition using protein-based drugs or low-molecular-weight inhibitors has been shown to significantly reduce tissue injury and improve outcome in numerous in-vitro, ex-vivo, and in-vivo models. Despite the obvious benefits in experimental research, only few complement inhibitors, including C1-esterase inhibitor, anti-C5 antibody, and soluble complement receptor 1, have made it into clinical trials of IR injury. The results are mixed, and the next objectives should be to combine knowledge and experience obtained in the past from animal models and channel future work to translate this into clinical trials in surgical and interventional reperfusion therapy as well as organ transplantation.

Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation

Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew F344) and syngeneic (Lew Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction.

Impact of renal insufficiency on clinical outcomes in patients with critical limb ischemia undergoing endovascular revascularization

Patients with renal insufficiency (RI) are frequently excluded from trials assessing various endovascular revascularization concepts in critical limb ischemia (CLI) although information on clinical outcomes is scarce.

Long-term clinical outcomes in patients diagnosed with severe digital ischemia

To investigate the aetiology and long-term clinical outcomes of patients diagnosed with digital ischemia.

Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA)

Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking.

Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia

Intravascular transplantation of neural stem cells represents a minimally invasive therapeutic approach for the treatment of central nervous system diseases. The cellular biodistribution after intravascular injection needs to be analyzed to determine the ideal delivery modality. We studied the biodistribution and efficiency of targeted central nervous system delivery comparing intravenous and intra-arterial (IA) administration of neural stem cells after brain ischemia.

Is the surgical repair of unruptured atherosclerotic aneurysms at a higher risk of intraoperative ischemia?

The incidence of ischemia might be increased in the surgical repair of atherosclerotic unruptured aneurysms compared to non-atherosclerotic aneurysms. The atherosclerotic wall might increase the occurrence of thrombembolic events or its rigidity might endanger the occlusion of perforators within the aneurysm vicinity.