Michael Mahmoudi

Atherogenesis: the role of inflammation and infection

Atherosclerosis is no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the ‘wound healing response’ of the vascular smooth muscle cells. Prospective epidemiological studies have unequivocally demonstrated increased vascular risk in individuals with elevated levels of (i) cytokines such as interleukin‐6 and tumour necrosis factor‐alpha, (ii) cell adhesion molecules such as intercellular adhesion molecule‐1 and P‐selectin, and (iii) acute‐phase proteins such as C‐reactive protein, fibrinogen and serum amyloid A. Furthermore, evidence from clinical trials have demonstrated that risk reduction achieved with anti‐inflammatory agents such as statins is significantly greater in patients with evidence of inflammation. A number of risk factors for atherogenesis, including infectious agents, have been shown to exert their influence via inflammatory mechanisms. However, despite compelling experimental evidence, clinical studies looking at the role of infection in atherogenesis have lacked consistency. The clinical product of this dynamic process is variable and unpredictable between individuals, even those with apparently similar risk profiles

Hypothermia Therapy: Neurological and Cardiac Benefits

Due to its protective effect on the brain and the myocardium, hypothermia therapy (HT) has been extensively studied in cardiac arrest patients with coma as well as in patients presenting with acute myocardial infarction (MI). In the setting of cardiac arrest, randomized studies have shown that HT decreases mortality and improves neurological outcomes. Subsequent guidelines have therefore recommended cooling (32°C to 34°C) for 12 to 24 h in unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest due to ventricular fibrillation. Observational studies have also confirmed the feasibility of this therapy in clinical practice and support its early application in patients with nonventricular fibrillation cardiac arrest and in post-resuscitation circulatory shock. In patients with acute MI, available clinical evidence does not yet support HT as the standard of care, because no study to date has shown a clear net benefit in such a cohort. After a brief review of the mechanisms of action for HT, we provide a review of the clinical evidence, cooling techniques, and potential adverse effects associated with HT in the setting of post-cardiac arrest patient and acute MI.

Patients With Severe Asymptomatic Carotid Artery Stenosis Do Not Have a Higher Risk of Stroke and Mortality After Coronary Artery Bypass Surgery

Background and Purpose— Stroke development is a major concern in patients undergoing coronary artery bypass grafting (CABG). Whether asymptomatic severe carotid artery stenosis (CAS) contributes to the development of stroke and mortality in such patients remains uncertain. Methods— A retrospective analysis of 878 consecutive patients with documented carotid duplex ultrasound who underwent isolated CABG in our institution from January 2003 to December 2009 was performed. Patients with severe CAS (n=117) were compared with those without severe CAS (n=761) to assess the rates of stroke and mortality during hospitalization for CABG. The 30-day mortality rate was also assessed. Results— Patients with severe CAS were older and had a higher prevalence of peripheral arterial disease and heart failure. Patients with severe CAS had similar rates of in-hospital stroke (3.4% versus 3.6%; P=1.0) and mortality (3.4% versus 4.2%; P=1.0) compared with patients without severe CAS. The 30-day rate of mortality was also similar between the 2 cohorts (3.4% versus 2.9%; P=0.51). Conclusions— Severe CAS alone is not a risk factor for stroke or mortality in patients undergoing CABG. The decision to perform carotid imaging and subsequent revascularization in association with CABG must be individualized and based on clinical judgment.

Effect of Insurance Type on Adverse Cardiac Events After Percutaneous Coronary Intervention

Previous studies have documented disparities in both access to invasive cardiovascular procedures and outcomes in patients with Medicaid, Medicare, or no insurance. Outcomes by insurance have yet not been examined in a percutaneous coronary intervention (PCI) population. Data from patients undergoing PCI from June 2000 to June 2009 were retrospectively analyzed. Insurance was categorized as private, Medicare, Medicaid, and uninsured, according to the primary insurance at discharge. The outcome variable of interest was major adverse cardiac events (a composite of death, Q-wave myocardial infarction, and target vessel revascularization) at 1 year. Multivariable Cox regression analysis was stratified according to age <65 and ≥65 years. Of the 13,573 patients who had undergone PCI, 6,653 (49.0%) had private insurance, 6,150 (45.3%) had Medicare, 486 (3.6%) had Medicaid, and 284 (2.1%) were uninsured. Of the patients <65 years old, Medicaid (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.04 to 2.43), Medicare (HR 2.18, 95% CI 1.58 to 2.99), and no insurance (HR 2.41, 95% CI 1.36 to 4.27) were associated with greater rates of adjusted major adverse cardiac events at 1 year compared with private insurance. Of the patients ≥65 years old, only Medicaid (HR 3.07, 95% CI 1.09 to 8.61) was associated with a greater rate of adjusted major adverse cardiac events at 1 year. In conclusion, patients with government-sponsored insurance and no insurance have worse cardiovascular outcomes than patients with private insurance after PCI at 1 year. This implies that the provision of health insurance alone might not have a dramatic effect on cardiovascular outcomes after PCI.

A novel, minimally invasive access technique versus standard 18‐gauge needle set for femoral access

Objective: To compare access site complications with the Micropuncture® 21 gauge (G) needle set to the standard 18G needle in patients undergoing percutaneous coronary intervention (PCI) using the femoral approach. Background: Vascular access site complications are the most common problems after PCI. The Micropuncture 21G needle set was recently introduced to minimize such complications. Methods: A cohort of 3,243 consecutive patients was studied. Patients receiving thrombolytics, IIb/IIIa antagonist, coumadin, or intra‐aortic balloon pump were excluded. Micropuncture access was used in 544 patients and standard 18G needle in 2,699. All access sites were managed with a vascular closure device. Primary endpoints included vascular perforation or limb ischemia requiring repair, retroperitoneal bleeding, pseudoaneurysm, arteriovenous fistula, and groin hematoma (>4 cm). Results: Patients undergoing PCI with Micropuncture were at higher risk: they were older (65.9 ± 9 vs. 64.7 ± 11.8, P = 0.03); had lower body surface area (1.9 ± 0.2 vs. 2.0 ± 0.3, P = 0.02); more prevalent peripheral vascular disease [119 (21.9%) vs. 380 (14.1%), P < 0.001] and renal failure [106 (19.6%) vs. 318 (11.8%), P < 0.001]. Overall, there was no significant difference in the access site complications rate using Micropuncture vs. standard needle, 7 (1.3%) vs. 27 (1.0%), respectively, P = 0.54. The Micropuncture group had significantly higher retroperitoneal bleeding, 0.7% vs. 0.18%, P = 0.04. After multivariable adjustment, only age remained significantly associated with vascular complications (OR 1.03, P = 0.04). Conclusions: Femoral access using the Micropuncture technique did not reduce the incidence of vascular complications and the marginally higher than expected retroperitoneal bleeding is based on very small numbers. The routine use of the Micropuncture set and its technique should be revisited.

Impact of smoking on acute phase outcomes of myocardial infarction

ObjectivesPrevious studies have found an apparent paradox in smokers: acute phase outcomes after an acute myocardial infarction are superior to those of nonsmokers. Furthermore, it is reported that smoking has an impact on the metabolism of clopidogrel. This study aimed to examine whether this paradoxical finding exists in patients who undergo drug-eluting stent implantation and are treated with clopidogrel. MethodsFrom April 2003 to June 2010, 1424 consecutive patients with acute myocardial infarction who underwent primary or rescue percutaneous coronary intervention with drug-eluting stent and clopidogrel were enrolled. They were divided into three groups: current smokers (n=486); previous smokers (n=349); and nonsmokers (n=589). The primary end point was a composite of 30-day, all-cause death, nonfatal myocardial infarction, or definite stent thrombosis. ResultsCompared with nonsmokers, current smokers were younger (P<0.001) and more often men (P<0.001). They had larger myocardial infarctions than did nonsmokers [maximum troponin I, 8.9 (2.4, 38.4) vs. 6.8 (1.4, 30.1) ng/ml, P=0.01]. Current smokers less frequently met the primary end point than did nonsmokers (2.9 vs. 6.1%, P=0.01). However, after adjustment for baseline and angiographic characteristics, the beneficial effect of smoking was no longer seen (odds ratio 1.35, confidence interval: 0.53–3.44, P=0.5). ConclusionA beneficial effect of smoking (‘smokers paradox’) in the unadjusted primary end point continues to be present; however, after adjustment for differences in baseline characteristics, no benefit was detectable.

Relation of Body Mass Index to On-Treatment (Clopidogrel + Aspirin) Platelet Reactivity

Previous research has suggested that obesity is associated with increased high on-treatment platelet reactivity. We therefore tested platelet reactivity in 251 patients with VerifyNow P2Y12, vasodilator-stimulated phosphoprotein phosphorylation, and light transmission aggregometry with adenosine diphosphate 5 and 20 μM 6 to 24 hours after percutaneous coronary intervention. High on-treatment platelet reactivity was defined as a maximum platelet aggregation ≥46% for light transmission aggregometry with adenosine diphosphate 5 μM or ≥60% for 20 μM, platelet reactivity index ≥50% for vasodilator-stimulated phosphoprotein phosphorylation, and P2Y12 reaction units ≥235 for VerifyNow. The relation between body mass index (BMI) and platelet reactivity values was examined with Spearman coefficients; BMI and high on-treatment platelet reactivity were assessed with Students t test. Multivariable logistic regression for high on-treatment platelet reactivity was also performed. Average BMI was 30.3 ± 5.9 kg/m² and 44% of patients had a BMI ≥30 kg/m². Overall there was very poor correlation between BMI and on-treatment platelet reactivity, with Spearman coefficients ranging from 0.08 to 0.10. BMI was also not associated with the various definitions of high on-treatment platelet reactivity. Multivariable logistic regressions showed no association between BMI and high on-treatment platelet reactivity. In conclusion, and contrary to previous reports, we found no association whatsoever between BMI and on-treatment platelet reactivity as quantified by a variety of platelet function tests.

The role of DNA damage and repair in atherosclerosis: A review ☆ ☆☆ ★

The global burden of cardiovascular disease is increasing despite therapeutic advances in medication and interventional technologies. Accumulated deoxyribonucleic acid (DNA) damage and subsequent repair pathways are now increasingly recognised as a causal factor in the initiation and progression of atherosclerosis. These molecular alterations have been shown to occur within affected vasculature, plaque microenvironment as well as in circulating cells. The DNA damage response (DDR) pathway is reliant on post-translational modification of sensing proteins which activate a signalling cascade to repair, if possible, DNA damaged sites in response to various environmental and physiological insults. This review summarises the current evidence for DNA damage in atherosclerosis, the key steps involved in the DDR pathway, DNA repair and their subsequent effects on atherosclerotic plaques, as well as the therapeutic options in managing DNA damage-induced atherosclerosis.

Correlates and consequences of gastrointestinal bleeding complicating percutaneous coronary intervention.

Gastrointestinal bleeding (GIB) complicating percutaneous coronary intervention (PCI) results in high mortality, but clinical factors associated with and long-term outcomes of GIB are poorly understood. We sought to examine clinical and procedural factors associated with GIB complicating PCI. We also examined the impact of GIB on 30-day mortality and 1-year major adverse cardiac events (MACEs). Patients undergoing PCI from January 2000 to January 2010 were retrospectively analyzed for the occurrence of in-hospital GIB. Multivariable logistic regression and Cox proportional hazards regression were used to identify predictors of in-hospital GIB and 30-day mortality. Landmark analysis of patients surviving to hospital discharge was performed to assess the impact of GIB on 1-year MACEs. Of 20,621 patients who underwent PCI, 147 (0.72%) who developed in-hospital GIB were identified. Variables associated with increased risk of GIB included older age, shock, acute myocardial infarction, chronic renal insufficiency, lower baseline hematocrit, and glycoprotein IIb/IIIa inhibitors; bivalirudin decreased the risk. Unadjusted 30-day mortality rate of patients with GIB was 20.5% compared to 2.4% of patients without GIB. After multivariable adjustment, GIB and shock (and an interaction between the 2) were the most important correlates of 30-day mortality. In the population surviving to discharge, however, GIB was not associated with adjusted mortality or MACEs. In conclusion, GIB complicating PCI has a dramatic impact on 30-day mortality, and bivalirudin was associated with lower rates of GIB.

Clinical Outcomes and Treatment After Drug-Eluting Stent Failure The Absence of Traditional Risk Factors for In-Stent Restenosis

Background— The optimal percutaneous treatment of drug-eluting stent (DES) in-stent restenosis (ISR) and the correlates for recurrent DES ISR remain unclear. Methods and Results— From 2003 to 2008, 563 patients presenting with recurrent symptoms of ischemia and angiographic ISR after DES implantation were included. Of these, 327 were treated with re-DES (58.1%), 132 underwent vascular brachytherapy (23.4%), and 104 were treated with conventional balloon angioplasty (18.5%). Variables associated with target lesion revascularization at 1 year were explored by individual proportional hazard models. This population presents a high prevalence of comorbidities, including diabetes (43.7%), previous myocardial infarction (MI) (45.8%), coronary bypass graft surgery (39.2%), chronic renal failure (18.8%), and heart failure (17.3%). Baseline clinical characteristics were balanced among the 3 groups; however, patients undergoing vascular brachytherapy presented with more complex lesions and a higher prevalence of prior stent/vascular brachytherapy failure than did the rest of the population. The overall incidence of recurrent DES failure at 1-year follow-up was 12.2%, which was similar among the 3 groups (P=0.41). The rate of the composite end point (death, Q-wave-MI and target lesion revascularization) at 1-year follow-up was 14.1% for re-DES, 17.5% for vascular brachytherapy, and 18.0% for conventional balloon angioplasty (P=0.57). After univariable analysis tested the traditional known covariates related to ISR, none of them were associated with repeat target lesion revascularization. Conclusions— Recurrence of ISR after DES treatment failure is neither infrequent nor benign, and optimal therapy remains unclear and challenging. Given the absence of traditional risk factors for ISR in this population, further research is required to elucidate both the correlates involved in DES ISR and the optimal treatment for this condition.