Effects of Off-Pump Versus On-Pump Coronary Artery Bypass Grafting on Early and Late Right Ventricular Function
 

Off-pump CABG (OPCABG) results in better preservation of left ventricular function in the perioperative period than conventional on-pump CABG (ONCABG); however, evidence is conflicting as to the effect of OPCABG and ONCABG on right ventricular (RV) function, possibly because of the complexity involved in measuring this.
In a single-center randomized pilot study, 60 patients with normal left ventricular function undergoing CABG were randomly assigned to OPCABG or ONCABG. Patients underwent cardiac magnetic resonance imagine for assessment of RV function preoperatively, early postoperatively, and at 6 months after surgery. Fifty-one patients completed the first 2 scans, and 47 completed all 3 scans. Preoperative characteristics and RV function did not differ significantly between the 2 groups (mean ± SD): RV stroke volume index was 49±10 mL/m2 for OPCABG and 49 ± 16 mL/m2 for ONCABG. After surgery, RV stroke volume index fell to
36 ± 7 mL/m2 in the OPCABG group and 39 ± 11 mL/m2 in the ONCABG group, but this did not differ significantly between the 2 groups
(P = 0.41). All markers of RV function recovered to preoperative levels by 6 months, with no long-term difference between the surgical techniques.
RV function is impaired early after surgery but recovers by 6 months. The changes were similar in both the OPCABG and ONCABG groups.
Circulation. 2008;117:2202-2210

Stromal Cell-Derived Factor-1a 1s Cardioprotective After Myocardial Infarction

Heart disease is a leading cause of mortality throughout the world. Tissue damage from vascular occlusive events results in the replacement of contractile myocardium by nonfunctional scar tissue. The potential of new technologies to regenerate damaged myocardium is significant, although cell-based therapies must overcome several technical barriers. One possible cell-independent alternative is the direct administration of small proteins to damaged myocardium.
In this study, the authors show that the secreted signaling protein stromal cell-derived factor-1a (SDF-1a), which activates the cell-survival factor protein kinase B (PKB/Akt) via the G protein-coupled receptor CXCR4, protected tissue after an acute ischemic event in mice and activated Akt within endothelial cells and myocytes of the heart. Significantly better cardiac function than in control mice was evident as early as 24 hours after infarction as well as at 3, 14, and 28 days after infarction. Prolonged survival of hypoxic myocardium was followed by an increase in levels of vascular endothelial growth factor protein and neoangiogenesis. Consistent with improved cardiac function, mice exposed to SDF-1a demonstrated significantly decreased scar formation than control mice.
The authors conclude that these findings suggest that SDF-1a may serve a tissue-protective and regenerative role for solid organs suffering a hypoxic insult.
Circulation. 2008;117:2224-2231
 

Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics With a Prior Myocardial Infarction Carry the Same Cardiovascular Risk

A Population Study of 3.3 Million People
 

Previous studies reveal major differences in the estimated cardiovascular risk in diabetes mellitus, including uncertainty about the risk in young patients. Therefore, large studies of well-defined populations are needed.
All residents in Denmark 30 years of age were followed up for 5 years (1997 to 2002) by individual-level linkage of nationwide registers. Diabetes patients receiving glucose-lowering medications and nondiabetics with and without a prior myocardial infarction were compared. At baseline, 71 801 (2.2%) had diabetes mellitus and 79 575 (2.4%) had a prior myocardial infarction. Regardless of age, age-adjusted Cox proportional-hazard ratios for cardiovascular death were 2.42 (95% confidence interval [CI], 2.35 to 2.49) in men with diabetes mellitus without a prior myocardial infarction and 2.44 (95% CI, 2.39 to 2.49) in nondiabetic men with a prior myocardial infarction (P = 0.60), with nondiabetics without a prior myocardial infarction as the reference. Results for women were 2.45 (95% CI, 2.38 to 2.51) and 2.62 (95% CI, 2.55 to 2.69) (P = 0.001), respectively. For the composite of myocardial infarction, stroke, and cardiovascular death, the hazard ratios in men with diabetes only were 2.32 (95% CI, 2.27 to 2.38) and 2.48 (95% CI, 2.43 to 2.54) in those with a prior myocardial infarction only (P = 0.001). Results for women were 2.48 (95% CI, 2.43 to 2.54) and 2.71 (95% CI, 2.65 to 2.78) (P = 0.001), respectively. Risks were similar for both diabetes types. Analyses with adjustments for comorbidity, socioeconomic status, and prophylactic medical treatment showed similar results, and propensity score-based matched-pair analyses supported these findings.
Patients requiring glucose-lowering therapy who were 30 years of age exhibited a cardiovascular risk comparable to nondiabetics with a prior myocardial infarction, regardless of sex and diabetes type. Therefore, requirement for glucose-lowering therapy should prompt intensive prophylactic treatment for cardiovascular diseases.
Circulation. 2008;117:1945-1954.
 

Asymptomatic Peripheral Arterial Disease is Associated with More Adverse Lower Extremity Characteristics than Intermittent Claudication
 

This study assessed functional performance, calf muscle characteristics, peripheral nerve function, and quality of life in asymptomatic persons with peripheral arterial disease (PAD).
PAD participants (n = 465) had an ankle brachial index < 0.90. Non-PAD participants
(n = 292) had an ankle brachial index of 0.90 to 1.30. PAD participants were categorized into leg symptom groups including intermittent claudication (n = 215) and always asymptomatic (participants who never experienced exertional leg pain, even during the 6-minute walk; n = 72). Calf muscle was measured with computed tomography. Analyses were adjusted for age, sex, race, ankle brachial index, comorbidities, and other confounders. Compared with participants with intermittent claudication, always asymptomatic PAD participants had smaller calf muscle area (4935 versus 5592 mm2; P < 0.001), higher calf muscle percent fat (16.10% versus 9.45%; P < 0.001), poorer 6-minute walk performance (966 versus 1129 ft; P = 0.0002), slower usual-paced walking speed (P = 0.0019), slower fast-paced walking speed (P < 0.001), and a poorer Short-Form 36 Physical Functioning score (P = 0.016). Compared with an age-matched, sedentary, non-PAD cohort, always asymptomatic PAD participants had smaller calf muscle area (5061 versus 5895 mm2; P=0.009), poorer 6-minute walk performance (1126 versus 1452 ft; P < 0.001), and poorer Walking Impairment Questionnaire speed scores (40.87 versus 57.78; P = 0.001).
Persons with PAD who never experience exertional leg symptoms have poorer functional performance, poorer quality of life, and more adverse calf muscle characteristics compared with persons with intermittent claudication and a sedentary, asymptomatic, age-matched group of non-PAD persons.
Circulation. 2008;117:2484-2491

 

Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction
 

Prior studies have demonstrated an inconsistent association between patients’ arrival time for acute myocardial infarction (AMI) and their subsequent medical care and outcomes.
Using a contemporary national clinical registry, investigators examined differences in medical care and in-hospital mortality among AMI patients admitted during regular hours (weekdays 7:00 am to 7:00 pm) versus off-hours (weekends, holidays, and 7:00 pm to 7:00 pm weeknights). The study cohort included 62,814 AMI patients from the Get With the Guidelines-Coronary Artery Disease database admitted to 379 hospitals throughout the United States from July 2000 through September 2005. Overall, 33,982 (54.1%) patients arrived during off-hours. Compared with those arriving during regular hours, eligible off-hour patients were slightly less likely to receive primary percutaneous coronary intervention (adjusted odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89 to 0.98), had longer door-to-balloon times (median, 110 versus 85 minutes; P < 0.0001), and were less likely to achieve door-to-balloon 90 minutes (adjusted OR, 0.34; 95% CI, 0.29 to 0.39).
Arrival during off-hours was associated with slightly lower overall revascularization rates (adjusted OR, 0.94; 95% CI, 0.90 to 0.97). No measurable differences, however, were found in in-hospital mortality between regular hours and off-hours in the overall AMI, ST-elevated MI, and non-ST-elevated MI cohorts (adjusted OR, 0.99; 95% CI, 0.93 to 1.06; adjusted OR, 1.05; 95% CI, 0.94 to 1.18; and adjusted OR, 0.97; 95% CI, 0.90 to 1.04, respectively). Similar observations were made across most age and sex subgroups and with an alternative definition for arrival time (weekends/holidays versus weekdays).
Despite slightly fewer primary percutaneous coronary interventions and overall revascularizations and significantly longer door-to-balloon times, patients presenting with AMI during off-hours had in-hospital mortality similar to those presenting during regular hours.
Circulation. 2008;117:2502-2509
N Engl J Med 3008;358:152 - 161

Depressive Symptoms and the Risk of Atherosclerotic Progression among Patients with Coronary Artery Bypass Grafts
 

Depressive symptoms have been associated with increased risk of coronary artery disease and poor prognosis among patients with existing coronary artery disease, but whether depressive symptoms specifically influence atherosclerotic progression among such patients is uncertain.
The Post-CABG Trial randomized patients with a history of coronary bypass graft surgery to either an aggressive or a moderate lipid-lowering strategy and to either warfarin or placebo. Coronary angiography was conducted at enrollment and after a median follow-up of 4.2 years. Depressive symptoms were assessed at enrollment with the Centers for Epidemiologic Studies Depression scale (CES-D) in 1319 patients with 2496 grafts. In models that adjusted for age, gender, race, treatment assignment, and years since coronary bypass graft surgery, a CES-D score 16 was positively associated with risk of substantial graft disease progression (OR 1.50, 95% CI 1.08 to 2.10,
P = 0.02) and marginally associated with a 0.11-mm (95% CI -0.22 to 0.01 mm, P = 0.07) decrease in minimum lumen diameter, but not with risk of graft occlusion (P = 0.30). Additional adjustment for past medical history, blood pressure, and renal function did not materially alter these results. This association was virtually absent among participants randomly assigned to aggressive lipid-lowering therapy.
These findings suggest that depressive symptoms are associated with a higher risk of atherosclerotic progression among patients with saphenous vein grafts and that aggressive lipid lowering can minimize this increased risk. Whether depressive symptoms increase progression in other types of coronary atherosclerosis and whether aggressive lipid lowering attenuates such progression will require additional study.
Circulation. 2008;117:2313-2319.

 

Independent Prognostic Importance of a Restrictive Left Ventricular Filling Pattern After Myocardial Infarction

Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved.
Investigators undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI.
Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20; P < 0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF.
The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (< 39%) and lowest (9%) in patients with the highest LVEF (> 53%; P < 0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (P = 0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome.
Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.
Circulation. 2008;117:2591-2598

High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury
 

The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Investigators tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury.
Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n = 131; subgroups used for various analyses). FA (4.5x10-6 mol/L IC) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n = 28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (dP/dtmax, -878 ± 586 versus -1956±351 mm Hg/s placebo; P = 0.03), and regional thickening was better preserved (37.3 ± 5.3% versus 5.1 ± 0.6% placebo; P = 0.004). Anterior wall perfusion fell similarly (-78.4 ± 9.3% versus -71.2 ± 13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740 ± 58 nmol/g; ischemia, 947 ± 55 nmol/g; ischemia plus FA, 1332 ± 101 nmol/g; P = 0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124 ± 280 cpm/mg FA versus 5898 ± 474 cpm/mg placebo; P = 0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8 ± 1.2% versus 60.3 ± 4.1% placebo area at risk; P < 0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA.
FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.
Circulation. 2008;117:1810-1819.

Results of the Predictors of Response to CRT (PROSPECT) Trial
 

Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response.
Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction 35%, QRS 130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler-based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and 15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased 15% in 56% of 286 patients with paired data.
The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was 0.62. There was large variability in the analysis of the dyssynchrony parameters.
Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting.
Circulation. 2008;117:2608-2616.
The study concluded that markedly abnormal ECGs in young and apparently healthy athletes may represent the initial expression of underlying cardiomyopathies that may not be evident until many years later and that may ultimately be associated with adverse outcomes. Athletes with such ECG patterns merit continued clinical surveillance.
N Engl J Med 3008;358:152 - 161