Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of IKr Inhibition on Ventricular Repolarization
- Particle Traps Prevent Adverse Vascular and Prothrombotic Effects of Diesel Engine Exhaust Inhalation in Men
- Use of Angiotensin Receptor Blockers and the Risk of Cancer
- Trends in Mortality From All Causes and Cardiovascular Disease Among Hypertensive and Nonhypertensive Adults in the United States
- Frequency and Predictors of Stent Thrombosis After Percutaneous Coronary Intervention in Acute Myocardial Infarction
- Wrist Circumference Is a Clinical Marker of Insulin Resistance in Overweight and Obese Children and Adolescents
- Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial
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Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of IKr Inhibition on Ventricular Repolarization
The reverse rate-dependent effect of drugs, especially those that inhibit IKr to prolong ventricular repolarization, has long been recognized as an important proarrhythmic risk factor. We hypothesize that inhibition of the small physiological late Na+ current (late INa) will reduce reverse rate dependence associated with IKr-blocking drugs. Late INa is greater, and reverse rate dependence of APD/QT interval is prominent in patients with structural heart diseases (heart failure, myocardial ischemia, etc), especially after treatment with an IKr-inhibiting drug. In this study, the amplitude of endogenous or physiological late INa in myocytes was increased as the frequency of stimulation slowed. Inhibition of late INa by tetrodotoxin or ranolazine diminished the reverse rate dependence of action potential duration prolongation and beat-to-beat variability of repolarization caused by IKr inhibitors in isolated hearts. Results of computer simulations of the effect of IKr block in the absence and presence of late INa block were consistent with the results of the experimental studies. The findings can explain, at least in part, why drugs that inhibit both IKr and late INa (ie, amiodarone and ranolazine) have no reverse rate-dependent effect and little or no proarrhythmic activity, whereas proarrhythmic activity associated with more selective IKr blockers is exacerbated when late INa is increased. This concept may be used to explain the occurrence of slow rate– or pause-triggered cardiac arrhythmias, and may be relevant in the choice of treatment drug(s) in patients with compromised repolarization reserve resulting from increased late INa or decreased IK, such as patients with heart failure. See p 1713.
Particle Traps Prevent Adverse Vascular and Prothrombotic Effects of Diesel Engine Exhaust Inhalation in Men
There is a robust and consistent association between air pollution and cardiovascular morbidity and mortality. These harmful effects are most strongly associated with exposure to traffic-derived fine particles that predominantly originate from diesel engine exhaust emissions. Using a purpose-built exposure chamber, we have demonstrated previously the adverse vascular and prothrombotic effects of exposure to diesel exhaust in healthy men. In the present study, using complementary and relevant measures of cardiovascular health, we have reconfirmed the adverse effects of exposure to diesel engine exhaust on endothelial function and ex vivo thrombosis. In addition, for the first time, we demonstrate that reducing the particulate component of diesel exhaust with a commercially available particle trap can prevent these detrimental cardiovascular effects. Our study provides support for the application of particle traps to diesel-powered vehicles to reduce urban particulate concentrations and limit a range of adverse cardiovascular effects related to exposure to traffic-derived air pollution. See p 1721.
Use of Angiotensin Receptor Blockers and the Risk of Cancer
A meta-analysis of randomized trials published in June 2010 suggested that use of angiotensin receptor blockers (ARBs) may be associated with an increased risk of cancer, lung cancer in particular. Because millions of patients use ARBs, monitoring their safety is of immediate clinical importance. Using individual-level data from registries in Denmark, including, for example, information on filled drug prescriptions and cancer diagnoses, we conducted a nationwide cohort study to compare the rates of incident cancer among users of ARBs and angiotensin-converting enzyme inhibitors. In an analysis including >100 000 users of ARBs and >200 000 users of angiotensin-converting enzyme inhibitors, we found no evidence of an increased risk of cancer overall associated with ARB use. Confidence intervals were narrow, allowing exclusion of a 4% increase in the risk of cancer. Results were similar when ARBs were compared with other antihypertensive drugs in a sensitivity analysis. In a subgroup analysis, there was no significant association between ARBs and lung cancer. Furthermore, although the angiotensin receptor system is involved in the process of carcinogenesis, experimental data point, if anything, toward beneficial effects of angiotensin signaling inhibition. Strengths of our study include the use of individual-level nationwide registry data and a comprehensive pharmacoepidemiological design. Clinicians can continue to prescribe ARBs without concern about an excess risk of cancer. See p 1729.
Trends in Mortality From All Causes and Cardiovascular Disease Among Hypertensive and Nonhypertensive Adults in the United States
In the period from 2007 to 2008, 29% of adults in the United States had hypertension, a major modifiable risk factor for cardiovascular disease. The control of hypertension is critical to reducing its excess morbidity and mortality. Although important advances in increasing awareness of hypertension and its treatment and control have been achieved, information about the direction of the mortality rate in hypertensive adults is scarce. The current study's results show that the age-adjusted mortality rate from all causes decreased by 4.6 per 1000 person-years in 2 national cohorts of hypertensive adults who were recruited from 1971 to 1975 and from 1988 to 1994. However, this decrease was comparable to the decrease of 4.2 per 1000 person-years among nonhypertensive adults. The reduction among hypertensive men (7.7 per 1000 person-years) significantly exceeded the reduction among hypertensive women (1.9 per 1000 person-years). The reduction among hypertensive blacks (5.4 per 1000 person-years) exceeded the reduction among hypertensive whites by a nonsignificant amount (4.4 per 1000 person-years). Besides having higher mean levels of systolic and diastolic blood pressure, hypertensive adults had a higher mean concentration of total cholesterol, mean body mass index, and prevalence of diabetes mellitus than nonhypertensive adults. Optimizing the control of hypertension and aggressively managing coexisting cardiovascular risk factors in adults with hypertension are key approaches to further reducing the mortality rate among hypertensive adults. Increased clinical and public health efforts are needed to lower the high mortality rate among blacks and to accelerate the tepid decline in the mortality rate among women. See p 1737.
Frequency and Predictors of Stent Thrombosis After Percutaneous Coronary Intervention in Acute Myocardial Infarction
The prospective, multicenter, randomized Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial included 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention who were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy. Stents were implanted in 3202 patients, including 2261 who received drug-eluting stents and 861 who received only bare metal stents. Definite or probable stent thrombosis within 2 years, occurred in 4.4% of patients, including 0.9% acute events, 1.6% subacute events, 1.0% late events, and 1.1% very late events. The 2-year cumulative rates of stent thrombosis were similar with both drug-eluting stents and bare metal stents, as well as in patients randomized to bivalirudin monotherapy versus heparin plus glycoprotein IIb/IIIa inhibitor. Acute stent thrombosis occurred more frequently in patients assigned to bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor, whereas stent thrombosis after 24 hours occurred less frequently in patients with bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor. Prerandomization heparin and a 600-mg clopidogrel loading dose were independent predictors of reduced acute and subacute stent thrombosis, respectively. Optimizing adjunct pharmacology, including early antithrombin therapy and preloading with a potent antiplatelet therapy, may further reduce stent thrombosis in ST-segment elevation myocardial infarction, thereby improving event-free survival in these high-risk patients. See p 1745.
Wrist Circumference Is a Clinical Marker of Insulin Resistance in Overweight and Obese Children and Adolescents
One of the major priorities of clinical practice is to identify young people at increased risk for obesity and insulin resistance, representing the metabolic basis for future cardiovascular disease. This study introduces a new clinical marker of insulin resistance in overweight/obese children and adolescents: the wrist circumference. This measurement has been historically included in the calculation of frame size, which is a parameter in evaluating the free fat mass to correct misclassification introduced by the use of body mass index. We produce the first evidence that wrist circumference is highly correlated with insulin resistance parameters (fasting insulin and homeostasis model assessment of insulin resistance index) in a population of overweight/obese children and adolescents. The association of wrist circumference with insulin resistance is explained only by the transversal wrist bone tissue–related areas and not by the wrist adipose tissue ones, reflecting the anabolic role of insulin on transversal bone growth. Wrist circumference is easily accessible and measurable by the doctor, minimizing the collaboration required of the patient, and its reproducibility is higher than that of waist circumference. Therefore, taking into account the high collinearity between the 2 parameters, wrist circumference could be considered in the classification of obesity for the prediction of insulin resistance and cardiovascular risk. The identification of youths with increased risk for insulin resistance–related complications could be achieved with minimal effort by measuring wrist circumference, thus avoiding testing the entire population of overweight/obese children for insulin resistance. Our findings open new perspectives in the prediction of cardiovascular risk. See p 1757.
Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial
Kidney transplant recipients experience an excess risk of cardiovascular disease and elevated total homocysteine concentrations. Although observational studies of patients with chronic kidney disease suggest that increased homocysteine is a risk factor for cardiovascular disease, the clinical benefit of lowering total homocysteine levels in kidney transplant recipients is unknown. We randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of arteriosclerotic cardiovascular disease outcomes. After a follow-up of 4.0 years, the high-dose multivitamin reduced homocysteine levels but not the rates of the pooled arteriosclerotic outcome (n=547 total events; hazards ratio [95% confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. We concluded that treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients does not reduce cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level. See p 1763.
- © 2011 American Heart Association, Inc.
- Use of Angiotensin Receptor Blockers and the Risk of Cancer
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