Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Impact of Cardiac Rehabilitation on Mortality and Cardiovascular Events After Percutaneous Coronary Intervention in the Community
- Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single Ventricle
- Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial
- Impact of Angiographic Complete Revascularization After Drug-Eluting Stent Implantation or Coronary Artery Bypass Graft Surgery for Multivessel Coronary Artery Disease
- Incidence, Risk Factors, and Clinical Sequelae of Angiographic Peri-Stent Contrast Staining After Sirolimus-Eluting Stent Implantation
- Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart
- Major Contribution of the P2Y1 Receptor in Purinergic Regulation of TNFα-Induced Vascular Inflammation
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Impact of Cardiac Rehabilitation on Mortality and Cardiovascular Events After Percutaneous Coronary Intervention in the Community
Although participation in cardiac rehabilitation has been associated with reduced mortality after myocardial infarction, less is known about its impact after percutaneous coronary intervention (PCI). We studied the association between cardiac rehabilitation participation and outcomes in 2395 consecutive patients who underwent PCI in Olmsted County, Minnesota, from 1994 to 2008. Overall participation in cardiac rehabilitation was 40% after PCI over the length of our study. Using 3 different analytical techniques aimed at reducing potential sources of bias, we found that cardiac rehabilitation participation was associated with a 45% to 47% reduction in 5-year all-cause mortality rate compared with nonparticipation. These findings provide support for national guidelines that recommend cardiac rehabilitation for patients after PCI, and for the decision in 2006 by the Centers for Medicare and Medicaid Services to include PCI as a covered indication for cardiac rehabilitation services. Cardiac rehabilitation participation should be encouraged as part of an evidence-based secondary prevention plan for patients who have undergone PCI. See p 2344.
Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single Ventricle
The Pediatric Heart Network conducted a pharmacogenetic study as part of a multicenter randomized, controlled trial of enalapril versus placebo in single-ventricle infants to assess if renin-angiotensin-aldosterone system (RAAS)–upregulation genotypes influence the response to enalapril. This represents the first pharmacogenetic study of enalapril in a congenital heart disease population. One-hundred fifty-four infants with single ventricle were genotyped and followed up until 14 months of age. Patients with RAAS-upregulation genotypes had persistent increase in ventricular mass and volume despite volume-unloading surgery (ie, superior cavopulmonary connection). Enalapril did not decrease ventricular mass or volume in either genotype group. Patients with high-risk genotypes had lower weight and height at enrollment, and the height impairment persisted in high-risk patients who were receiving enalapril whereas patients receiving placebo normalized their height by 14 months. The high-risk genotype group also showed mild but persistent renal dysfunction. In summary, patients with RAAS-upregulation genotypes failed to show reverse remodeling in response to volume-unloading surgery, had persistent growth abnormalities, especially with enalapril, and had persistent renal dysfunction. These patients may need earlier superior cavopulmonary connection to facilitate reversal of ventricular dilation and hypertrophy before the remodeling becomes irreversible. Because neither enalapril nor surgery showed significant benefit in high-risk genotype patients, there is a need to develop newer therapies in at-risk patients. See p 2353.
Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial
The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial in patients with atrial fibrillation and at least 1 additional risk factor for stroke demonstrated that dabigatran 110 mg twice a day compared with warfarin was associated with a similar risk of stroke or systemic embolism and a lower risk of major bleeding, and that dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of stroke or systemic embolism and a similar risk of major bleeding. The effects of dabigatran compared with warfarin on stroke or systemic embolism were consistent in all subgroups examined, but there was a significant treatment-by-age interaction for major bleeding such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years and a similar risk in those aged ≥75 years, whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years and a trend toward higher risk of major bleeding in those aged ≥75 years. The interaction between treatment and age was evident for extracranial bleeding but not for intracranial bleeding, which was consistently reduced with dabigatran compared with warfarin irrespective of age. These results suggest that in patients with atrial fibrillation and at least 1 additional risk factor for stroke who are aged <75 years, the higher dabigatran dose might be preferable, whereas in older patients, the lower dabigatran dose might be considered a means to reduce the risk of bleeding. See p 2363.
Impact of Angiographic Complete Revascularization After Drug-Eluting Stent Implantation or Coronary Artery Bypass Graft Surgery for Multivessel Coronary Artery Disease
Current guideline recommends complete revascularization with the use of percutaneous coronary intervention or coronary artery bypass grafting for stable patients with multivessel coronary disease because of its favorable long-term prognosis compared with the strategy of incomplete revascularization. However, in daily practice, complete revascularization is not always attempted because of hemodynamic instability, low ejection fraction, complex morphology, absence of objective ischemia, or preference for a minimally invasive procedure. In this regard, our study sought to investigate the benefit of complete revascularization with detailed angiographic analyses according to the Synergy Between PCI With Taxus and Cardiac Surgery classification for patients with multivessel disease undergoing percutaneous coronary intervention with drug-eluting stent or coronary artery bypass grafting. The major finding of our study was that complete revascularization, according to the varying definitions, did not improve clinical outcomes. Although the mechanism is not clear, the lack of association between complete revascularization and clinical prognosis may be closely related to the limitation of angiography to determine objective ischemia. In fact, recent clinical studies using fractional flow reserve, which is an invasive modality to determine objective ischemia in the tested epicardial coronary artery, demonstrated that the association between intermediate angiographic stenosis and functional ischemia is weak. Therefore, the strategy of angiographic complete revascularization might induce unnecessary procedures and subsequently fail to improve clinical outcome. Given this result and others with the use of invasive and noninvasive functional evaluation, an ischemia-guided procedure should be performed in treating patients with multivessel coronary disease. See p 2373.
Incidence, Risk Factors, and Clinical Sequelae of Angiographic Peri-Stent Contrast Staining After Sirolimus-Eluting Stent Implantation
We have noted abnormal angiographic findings at the site of drug-eluting stent implantation, suggesting contrast staining outside the stent struts that do not fulfill the classic definition of coronary aneurysm. We propose a new term, peri-stent contrast staining (PSS), for these abnormal angiographic findings and assess their incidence, risk factors, and clinical sequelae. Peri-stent contrast staining was defined as contrast staining outside the stent contour, extending to ≥20% of the stent diameter. The study population consisted of 3081 lesions (1998 patients) that were treated exclusively with sirolimus-eluting stents and were evaluated by follow-up angiography within 12 months after sirolimus-eluting stent implantation. Late acquired PSS was observed in 58 lesions (1.9%) in 49 patients (2.5). The independent risk factor of PSS was chronic total occlusion, whereas negative risk factors for PSS were left circumflex coronary artery lesion and in-stent restenosis lesion. Stent fracture was more frequently observed in lesions with PSS than in lesions without PSS (43.1% versus 5.4%, P<0.0001). Cumulative incidence of target-lesion revascularization and definite very late stent thrombosis at 3 years after the index follow-up angiography in the PSS group was higher than that in the non-PSS group (15.0% versus 6.5%, and 8.2% versus 0.2%, respectively). Peri-stent contrast staining found within 12 months after sirolimus-eluting stent implantation appeared to be associated with subsequent target-lesion revascularization and very late stent thrombosis. Although the real incidences and risk factors of very late stent thrombosis and target-lesion revascularization after PSS diagnosis should be evaluated in a larger number of patients with longer follow-up duration, patients with PSS should be followed up very carefully. See p 2382.
Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart
Cardiac hypertrophy is a response to diverse forms of heart disease, including myocardial infarction, hypertension, and valvular dysfunctions. Although the initial hypertrophic responses are an adaptation to those stimuli, the sustained stress may lead to cardiomyopathy and heart failure, a major cause of human morbidity and mortality. Few interventions have proven effective in blocking hypertrophy or in preventing the transition to heart failure. Recently, transcriptional reprogramming of fetal gene expression by histone deacetylases (HDACs) was shown to be tightly linked to cardiac hypertrophy. We showed previously that inhibition of class I HDACs prevents cardiac hypertrophy, and that activation of HDAC2, 1 of the class I HDACs, in association with heat shock protein 70, is essential for hypertrophy. In addition, we have reported that Krüppel-like factor 4, a novel antihypertrophic mediator, relays the HDAC2 effects. Here, we show that casein kinase-2α1 (CK2α1)–dependent phosphorylation of HDAC2 S394 induces enzymatic activation of HDAC2 and thereby mediates hypertrophy. Interestingly, the phosphorylation of HDAC2 S394 was dramatically increased in hearts from hypertrophic cardiomyopathy patients. Hypertrophic stimuli led CK2α1 to be activated, and overexpression of CK2α1 caused cardiac hypertrophy both in vivo and in vitro, whereas chemical inhibitors of CK2α1 blunted this response. Modulators of the activity of both CK2 and HDAC are under extensive investigation for widespread clinical use for noncardiac diseases, including neoplasia. Our work implicates CK2α1/HDAC2 signal cascades as novel therapeutic targets for the treatment or prevention of cardiac hypertrophy and heart failure worthy of further validation and investigation. See p 2392.
Major Contribution of the P2Y1 Receptor in Purinergic Regulation of TNFα-Induced Vascular Inflammation
The P2Y1 receptor plays a key role in platelet activation and arterial thrombosis, as has been shown in P2Y1-deficient mice and through the use of selective P2Y1 antagonists in vitro in platelet function studies and in vivo in animal models of thrombosis. It is thus a potentially promising target for new antiplatelet drugs. In addition, the P2Y1 receptor is involved in atherosclerosis, and the present study demonstrates the role of the endothelial receptor in inflammatory events in arteries. Altogether, these findings add to interest in simultaneously targeting separate aspects of atherothrombosis (ie, platelet activation, vascular inflammation, and development of atherosclerosis). Moreover, because the P2Y1 receptor plays a minor role in normal hemostasis when compared with the P2Y12 receptor, one can expect a smaller risk of bleeding with P2Y1-targeting drugs, bleeding being the major limitation of aggressive antiplatelet therapy, especially when targeting the P2Y12 receptor. The pharmacological inhibition of the leukocyte recruitment in vivo using the selective antagonist MRS2500 is very promising. P2Y1-targeting drugs might therefore be efficient in patients requiring long-term treatment. See p 2404.
- © 2011 American Heart Association, Inc.
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