Citations

Background —The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. Methods and Results —Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components–based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I–converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme ( ACE ) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% ( P =0.04), and 16% ( P =0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [ P =0.005], and 32% [ P <0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [ P =0.03], 38% for DBP [ P =0.04], and 53% for MAP [ P <0.005]) but not in females. Conclusions —Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.

Background —The prognostic value of tomographic myocardial perfusion imaging with dipyridamole or adenosine in patients with left bundle-branch block has not been established. Methods and Results —The study group consisted of 245 patients with left bundle-branch block who underwent tomographic (single photon emission tomography) myocardial perfusion imaging with thallium-201 (n=173) or technetium-99m sestamibi (n=72) and either dipyridamole (n=153) or adenosine (n=92) stress. Patients were prospectively classified into two groups. Patients were classified as “high risk” if they had (1) a large severe fixed defect (n=28), (2) a large reversible defect (n=36), or (3) cardiac enlargement and either increased pulmonary uptake (thallium) or a decreased resting ejection fraction (sestamibi) (n=20). The remaining 161 patients (66% of the study group) were at “low risk.” Follow-up was 99% complete at 3±1.4 years. Three-year overall survival was 57% in the high-risk group compared with 87% in the low-risk group ( P <.0001). Survival free of cardiac death/nonfatal myocardial infarction/cardiac transplantation was 55% in the high-risk group and 93% in the low-risk group ( P <.0001). The presence of a high-risk scan had significant incremental prognostic value after adjustment for age, sex, diabetes, and previous myocardial infarction ( P <.0001). Patients with a low-risk scan had an overall survival that was not significantly different from that of a US age-matched population ( P =.86). Conclusions —Tomographic myocardial perfusion imaging with adenosine or dipyridamole stress provides important prognostic information in patients with left bundle-branch block, which is incremental to clinical assessment.

Background —Increasingly, dobutamine stress echocardiography has been used for detection of coronary artery disease. Less information exists regarding the incremental prognostic value of the test, including semiquantitative wall scoring, compared with clinical and rest echocardiographic variables. Methods and Results —Follow-up information was obtained from 860 patients who underwent dobutamine stress echocardiography over a 2-year period. To determine the value of dobutamine stress echocardiography in predicting cardiac events, including cardiac death and myocardial infarction, clinical and rest and stress echocardiographic data were considered in a stepwise Cox multivariate regression model. During follow-up of up to 52 months, 72 patients underwent coronary revascularization before any cardiac event and were censored. Eighty-six patients had cardiac events, including nonfatal myocardial infarction in 36 and cardiac death in 50. In a multivariate model, a history of congestive heart failure, the percentage of abnormal segments at peak stress, and an abnormal left ventricular end-systolic volume response to stress were independent predictors of cardiac events. The model that best predicted subsequent cardiac events included clinical and stress echocardiographic data. Conclusions —Dobutamine stress echocardiography with semiquantitative segmental wall scoring provides important incremental information in predicting subsequent cardiac events.

Background —Approximately 360 000 Americans experience sudden cardiac arrest each year; current treatments are expensive and not very effective. Public access defibrillation (PAD) is a novel treatment for out-of-hospital sudden cardiac arrest that refers to use of automated external defibrillators by the lay public or by nonmedical personnel such as police. A clinical trial has been proposed to evaluate the effectiveness of public access defibrillation, but it is unclear whether such early defibrillation will offer sufficient value for money. Our objective was to estimate the potential cost-effectiveness of public access defibrillation by use of decision analysis. Methods and Results —A decision model compared the potential cost-effectiveness of standard emergency medical services (EMS) systems with that of EMS supplemented by PAD. We considered defibrillation by lay responders or police, using an analysis with a US health-care perspective. Input data were derived from published data or fiscal databases. Future costs and effects were discounted at 3%. Monte Carlo simulation was performed to estimate the variability in the costs and effects of each program. Sensitivity analyses assessed the robustness of the results to changes in input data. A standard EMS system had a median cost of $5900 per cardiac arrest patient (interquartile range, IQR, $3200 to $10 900) and yielded a median of 0.25 quality-adjusted life years (IQR, 0.20 to 0.30). PAD by lay responders had a median incremental cost of $44 000 per additional quality-adjusted life year (IQR, $29 000 to $68 900). PAD by police had a median incremental cost of $27 200 per additional quality-adjusted life year (IQR, $15 700 to $47 800). The results were sensitive to changes in the cost and relative survival benefit of PAD. Conclusions —Although more expensive than standard EMS for sudden cardiac arrest, PAD may be economically attractive. The effectiveness and cost-effectiveness of PAD should be assessed in a randomized, controlled trial.

Background Transesophageal echocardiography (TEE) is the diagnostic modality of choice for visualizing the left atrial appendage (LAA). This study defined the morphology of the LAA in normal autopsy specimen hearts and considered the implications of these findings for TEE studies. Methods and Results Five hundred normal autopsy hearts were reviewed (25 male and 25 female subjects from each decade for 10 decades). LAA length, width, orifice size, and number of lobes were recorded. Number of lobes was compared between sexes with the rank sum test and regressed against age. Mean length, width, and orifice size increased with age, up to age 20 years, in both sexes. Rates were significantly different between sexes for LAA size ( P =.011) and width ( P =.006). After age 20, statistically significant but clinically insignificant age-related changes were observed. Fifty-four percent of LAAs had two lobes (range, 1 to 4), with no age or sex differences. Lobes exist in different planes of the heart. Most pectinate muscles were ≥1 mm in width. Pectinate muscles <1 mm (2.6% of cases) were seen in only the first and last decades. Conclusions Age- and sex-related differences in LAA dimensions exist. These differences and the existence of multilobed appendages are important in the accurate TEE evaluation of LAA. Because lobes exist in different planes, imaging must be done in multiple planes to visualize the entire LAA.

Background This study was undertaken to test the hypothesis that β-adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing. Methods and Results To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V m ) ([K + ] o =5.4 μmol), 1 μmol flecainide decreased V̇ max from 698±55 to 610±72 V/s ( P =.003) and squared conduction velocity (θ 2 ) from 2.11±1.1 to 1.72±0.9 (m/s) 2 ( P =.001). With K + depolarization to V m =−70 mV, flecainide further reduced V̇ max from 306±101 to 245±65 V/s and θ 2 from 1.12±0.4 to 0.99±0.6 (m/s) 2 , producing a 2.0-mV hyperpolarizing shift of apparent Na + channel availability curves derived from θ 2 . The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V m increased θ 2 by 8% to 1.84±0.6 (m/s) 2 ( P <.01) without altering V̇ max . At −70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V̇ max an additional 24% to 185±52 V/s ( P <.01) and θ 2 by 17% to 0.82±0.5 (m/s) 2 ( P =.04), producing an additional 1.8-mV ( P =.002) and 1.9-mV ( P =.002) hyperpolarizing shift in the apparent Na + channel inactivation curves generated from V̇ max and θ 2 , respectively. At physiological V m , the action potential duration (APD 95 ) was reduced from 307±35 to 269±27 ms ( P <.001) by flecainide and subsequently to 217±4 ms ( P <.001) with isoproterenol addition. With 12 mmol/L K + , APD 95 decreased from 198±23 to 182±17 ms ( P =.005) with flecainide and to 164±10 ms ( P =.004) with isoproterenol. Conclusions At depolarized V m , isoproterenol amplified the flecainide-induced reduction of V̇ max and θ 2 , suggesting a further adrenergic-mediated reduction of Na + current. Consequently, the synergy between catecholamines and flecainide at depolarized V m and the shortened APD 95 could facilitate arrhythmogenesis in the presence of underlying ischemia.

Background Adventitial gene transfer may serve as a tool to study vascular biology and may have therapeutic potential. We investigated the hypothesis that adenovirus-mediated transfer of the gene for endothelial nitric oxide synthase (eNOS) to the adventitia would alter vascular reactivity. Methods and Results Rabbit carotid arteries were surgically isolated and adenoviral vectors encoding eNOS (AdeNOS) or β-galactosidase instilled into the periarterial sheath at a concentration of 1×10 10 pfu/mL. Arteries were harvested 4 days later for immunostaining, NOS enzymatic assay, measurement of cGMP, and vasomotor studies. Transgene expression in the adventitia was confirmed by histochemistry for β-galactosidase and immunostaining for eNOS with a monoclonal antibody. Calcium-dependent NOS enzymatic activity and cGMP levels were significantly greater in the AdeNOS-transduced arteries. Maximal contractions to phenylephrine (10 −5 mol/L) were diminished in the AdeNOS-transduced arteries (4.6±0.2 versus 5.6±0.2 g; P <.05), but in the presence of the eNOS inhibitor N G -monomethyl- l -arginine (3×10 −4 mol/L) there was no difference between the two groups (7.1±0.2 versus 7.5±0.3 g; P =NS). Relaxations to calcium ionophore obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (−log EC 50 , 7.77±0.08 versus 7.45±0.07; P <.02). Conclusions We conclude that eNOS gene transfer to the adventitia alters vascular reactivity, as demonstrated by diminished contractile responses to phenylephrine and enhanced relaxations to calcium ionophore. This may represent a therapeutic strategy for vascular diseases characterized by decreased bioavailability of NO.

Background Cardiac mortality and myocardial infarction (MI) rates are used to evaluate the efficacy of coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). We compared 5-year cardiac mortality and MI rates in 1829 patients with multivessel disease randomized to CABG or PTCA. Methods and Results The 5-year cardiac mortality rate was 8.0% in patients assigned to PTCA compared with 4.9% in those assigned to CABG (relative risk [RR] of 1.55 with a 95% confidence interval [CI] of 1.07 to 2.23; P =.022). In a subgroup of 1476 nondiabetic patients, there were no significant differences between treatment groups in cardiac mortality either overall (4.6% versus 4.2%; RR=1.04, 95% CI, 0.65 to 1.66; P =.908) or in subgroups based on symptoms, left ventricular function, number of diseased vessels, or stenotic proximal left anterior descending artery. The two treatment groups had similar event rates for the combined end point of cardiac death or MI. The RR for cardiac mortality in 264 patients who sustained an MI compared with those who did not was 5.9 ( P <.001). MIs were more common after CABG during index hospitalization ( P =.004), but in the PTCA group, they were more common after discharge ( P <.001). Conclusions The Bypass Angioplasty Revascularization Investigation (BARI) trial indicates 5-year cardiac mortality in patients with multivessel disease was significantly greater after initial treatment with PTCA than with CABG. The difference was manifest in diabetic patients on drug therapy. There were no significant differences overall for the composite end point of cardiac mortality or MI between treatment groups or for cardiac mortality in nondiabetic patients regardless of symptoms, left ventricular function, number of diseased vessels, or stenotic proximal left anterior descending artery.