Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Ideal Cardiovascular Health in Childhood and Cardiometabolic Outcomes in Adulthood: The Cardiovascular Risk in Young Finns Study
- Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy: The Treating to New Targets (TNT) Study
- Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to β-Blocker Therapy in Type 1 Long-QT Syndrome
- A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)
- Application of Geographic Modeling Techniques to Quantify Spatial Access to Health Services Before and After an Acute Cardiac Event: The Cardiac Accessibility and Remoteness Index for Australia (ARIA) Project
- Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter Trial
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Ideal Cardiovascular Health in Childhood and Cardiometabolic Outcomes in Adulthood: The Cardiovascular Risk in Young Finns Study
The pediatric origin of atherosclerosis is now well accepted. Atherosclerosis is associated with early risk factor levels and is progressive. The clinical manifestations may occur even decades later. Recently, the American Heart Association (AHA) defined a new concept, cardiovascular health, and determined metrics needed to monitor it over time, as part of its 2020 Impact Goal definition. The report emphasized that monitoring of available data in children will be critical to increase the prevalence of ideal cardiovascular health and to maintain it through middle and older ages in the long term. In the present analysis, based on the Cardiovascular Risk in Young Finns Study cohort, we applied the construct of ideal cardiovascular health to a long-term prospective study of cardiovascular health in children and investigated its relationship with cardiometabolic outcomes in adulthood. The sample comprised 856 participants aged 12 to 18 years at baseline who were reexamined 21 years later. We observed that children who exhibited a high number of ideal cardiovascular health metrics were at lower risk to develop hypertension, metabolic syndrome, and dyslipidemia (high low-density lipoprotein cholesterol and high triglycerides) and had thinner carotid intima-media thickness in adulthood. Our findings suggest that pursuit of ideal cardiovascular health in childhood is important to prevent cardiometabolic outcomes in adulthood and provide support for intervention programs that target health factors and behaviors in childhood. See p 1971.
Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy: The Treating to New Targets (TNT) Study
Cardiovascular risk among statin-treated individuals remains high and has been called residual risk, but the mechanisms underlying this residual risk are uncertain. Hence, we aimed to identify determinants of this risk above and beyond lipid-related risk factors in a secondary prevention population that achieved low low-density lipoprotein cholesterol targets. The study population comprised 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study who had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age, increased body mass index, male sex, hypertension, diabetes mellitus, baseline apolipoprotein B and blood urea nitrogen, current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin, aspirin use, and baseline apolipoprotein A-I. These known baseline clinical and lipid-related variables performed moderately well in discriminating future cases from noncases. On-treatment 1-year levels of lipids and apolipoproteins were not selected into the multivariable model because they were not associated with risk after baseline apolipoproteins and clinical risk factors were taken into account. In sum, residual risk among statin-allocated coronary patients was related to baseline lipid-related and nonlipid risk factors. Thus, a multifaceted secondary prevention approach targeting modifiable risk factors should be underscored as the cornerstone of optimal residual risk assessment and prevention. See p 1979.
Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to β-Blocker Therapy in Type 1 Long-QT Syndrome
Long-QT syndrome type 1 (LQT1) arises from a decrease in repolarizing potassium current resulting from mutations in the KCNQ1 gene. The main trigger for cardiac arrhythmic events in patients with LQT1 is activation of β1-adrenergic receptors during exercise. Despite the observed reduction in the risk of cardiac events with β-blocker therapy among LQT1 patients, there is still a considerable cardiac residual event rate, suggesting that subgroups of LQT1 patients have differential response to β-blockers. The present study of 860 patients from the International LQTS Registry shows that the presence of missense mutations in distinct functional domains of the KCNQ1 protein, the S2-S3 and S4-S5 cytoplasmic loops (C loops), is associated with a significantly increased risk for life-threatening cardiac events compared with other mutations. Furthermore, patients with missense C-loop mutations gained greater benefit when treated with β-blockers compared with patients having other KCNQ1 mutations independently of clinical risk factors, demonstrating that LQT1 patients have differential response to β-blocker therapy depending on mutation location. Both a decrease in basal function and altered adrenergic regulation of the IKs channel underlie the increased cardiac risk and response to β-blockers in this subgroup of patients. Patients with missense C-loop mutations should be considered a high-risk group of patients but with a pronounced response to β-blockers. See p 1988.
A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)
Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Much of this variability is explained by common reduced-function variants in 2 genes, CYP2C9 and VKORC1. Pharmacogenetic (PG) guidance of warfarin initiation could improve dosing efficiency and safety, but evidence from clinical trials is still meager. To increase understanding of the potential role of PG guidance in warfarin dose initiation and to build on an earlier study (CoumaGen-I), we designed a second 3-month study (CoumaGen-II) with 2 parts: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step PG algorithm (PG-2) (N=504) and (2) a clinical effectiveness comparison of PG-guided with standard dosing in a parallel (nonrandomized) control group (N=1866) within the Intermountain Healthcare system. A rapid method provided same-day CYP2C9 and VKORC1 genotyping. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for the primary end point of percentage of out-of-range international normalized ratios at 1 month and at 3 months and for percentage of time in therapeutic range at 3 months, suggesting that the simpler 1-step PG algorithm may be preferable for clinical application. However, PG guidance (combined cohort) was substantially superior to standard dosing in the parallel control group for these end points (all P<0.001). PG guidance also reduced percentage of international normalized ratios ≥4 and ≤1.5 and serious adverse events. These clinical effectiveness findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-stage PG algorithm provided equivalent results and may be preferable for clinical application. See p 1997.
Application of Geographic Modeling Techniques to Quantify Spatial Access to Health Services Before and After an Acute Cardiac Event: The Cardiac Accessibility and Remoteness Index for Australia (ARIA) Project
In an acute cardiac event, access to timely and definitive care through specialist centers is critical to survival and to improving longer-term outcomes. Similarly, for survivors, ready access to more routine health care, including specialist management (through a cardiologist and cardiac rehabilitation program) and community-based primary care, is essential in preventing potentially fatal secondary events. Although evidence-based guidelines provide advice on managing a cardiac event in ideal circumstance, in reality, their implementation is often limited by the geographic location of the initial acute event and the location and level of facilities available to manage that event in a timely manner. For example, only an estimated 20% of emergency departments in the United States are located in hospitals with a cardiac catheterization laboratory. Still fewer have the capability to perform immediate revascularization. These data reinforce the importance of ready access to more portable and potentially life-saving therapies such as defibrillators and thrombolytic therapy, as well as efficient cardiac triage and transportation. The Cardiac Accessibility and Remoteness Index of Australia (Cardiac ARIA) measured access to cardiac care through a geographic lens via an objective, comparable measure of the time and distance from any population location to evidence-based cardiac care. An index of access to health services that was independent of professional, socioeconomic, or political influences was generated. It highlighted substantial inequities in access to cardiac services in Australia. Cardiac ARIA represents a powerful and adaptable tool to optimize outcomes by informing more equitable distribution of cost-effective, life-saving health care in any given geographic location. See p 2006.
Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter Trial
This study focusing on 2013 patients undergoing coronary stent implantation who received bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation and were subsequently allocated to up to 6 months versus 24 months of clopidogrel therapy in addition to aspirin failed to show the anticipated superiority of long-term duration of dual-antiplatelet therapy in terms of a lower composite ischemic end point of overall death, myocardial infarction, or cerebrovascular accidents. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Two Korean studies have also previously reported a lack of benefit of either 12 or 24 months of clopidogrel therapy over 6 or 12 months of therapy, respectively. Therefore, altogether, the available evidence does not support the concept that the longer the duration of clopidogrel therapy after drug-eluting stent implantation, the better the outcomes. On the contrary, this study identifies the potential for harm with respect to major bleeding associated with prolonged use of dual-antiplatelet therapy. See p 2015.
- © 2012 American Heart Association, Inc.
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