Citations

Background —After genome-wide linkage analyses of blood pressure levels, we resequenced 5 positional candidate genes in a linkage region on chromosome 5 and genotyped selected variants in several family samples from Rochester, Minn. Methods and Results —In a sample of 55 pedigrees containing ≥1 sibling-pair(s) discordant for systolic blood pressure, polymorphisms within the β 2 -adrenergic receptor gene (Arg16Gly, P =0.009) and the glutathione peroxidase 3 gene (−302G→A, P =0.037; −623A→C, P =0.013) were significantly related to blood pressure levels. In a second sample of 298 nuclear families (n=1283 individuals), the Arg16Gly polymorphism was significantly associated with diastolic blood pressure in family-based analyses ( P =0.016) and with both diastolic ( P =0.009) and mean arterial blood pressure ( P =0.038) in analyses of the parental generation only. Neither polymorphism in the glutathione peroxidase 3 gene was associated with blood pressure levels in this sample. An additional 291 families (n=1240 individuals) were added to the nuclear family sample, and the Gln27Glu polymorphism in the β 2 -adrenergic receptor gene was significantly associated with both systolic ( P =0.034) and mean arterial blood pressure ( P =0.035) in the parental generation of the combined 589 families. The frequencies of both the Gly16 and Glu27 alleles were higher in hypertensives than in normotensives (0.649 versus 0.604 and 0.490 versus 0.429, respectively), and the odds ratio for the occurrence of hypertension was 1.80 (95% confidence interval, 1.08 to 3.00; P =0.023) for the Glu27 allele. Conclusions —The results of this study provide support for further detailed investigations of the mechanistic pathways by which variations in the β 2 -adrenergic receptor gene may influence blood pressure levels.

Background —Monocytes are constitutively activated in unstable angina (UA), resulting in the production of IL-6 and the upregulation of acute phase proteins. Underlying mechanisms are not understood. To explore whether the production of the potent monocyte activator IFN-γ is altered in UA, we compared cytokine production by T lymphocytes in patients with UA (Braunwald’s class IIIB) and with stable angina (SA). Methods and Results —Peripheral blood lymphocytes were collected at the time of hospitalization and after 2 and 12 weeks. Cytokine-producing CD4 + and CD8 + T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA was associated with an increased number of CD4 + and CD8 + T cells producing IFN-γ, whereas patients with SA had higher frequencies of IL-2 + and IL-4 + CD4 + T cells. Expansion of the IFN-γ + T-cell population in UA persisted for at least 3 months. Increased production of IFN-γ in UA could be attributed to the expansion of an unusual subset of T cells, CD4 + CD28 null T cells. Conclusions —Patients with UA are characterized by a perturbation of the functional T-cell repertoire with a bias toward IFN-γ production, suggesting that monocyte activation and acute phase responses are consequences of T-cell activation. IFN-γ is produced by CD4 + CD28 null T cells, which are expanded in UA and distinctly low in SA and controls. The emergence of CD4 + CD28 null T cells may result from persistent antigenic stimulation.

Background —Time to treatment with thrombolytic therapy is a critical determinant of mortality in acute myocardial infarction. Little is known about the relationship between the time to treatment with direct coronary angioplasty and clinical outcome. The objectives of this study were to determine both the time required to perform direct coronary angioplasty in the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial and its relationship to clinical outcome. Methods and Results —Patients randomized to direct coronary angioplasty (n=565) were divided into groups based on the time between study enrollment and first balloon inflation. Patients randomized to angioplasty who did not undergo the procedure were also analyzed. The median time from study enrollment to first balloon inflation was 76 minutes; 19% of patients assigned to angioplasty did not undergo an angioplasty procedure. The 30-day mortality rate of patients who underwent balloon inflation ≤60 minutes after study enrollment was 1.0%; 61 to 75 minutes after enrollment, 3.7%; 76 to 90 minutes after enrollment, 4.0%; and ≥91 minutes after enrollment, 6.4%. The mortality rate of patients assigned to angioplasty who never underwent the procedure was 14.1% ( P =0.001). Logistic regression analysis revealed that the time from enrollment to first balloon inflation was a significant predictor of mortality within 30 days; after adjustment for differences in baseline characteristics, the odds of death increased 1.6 times ( P =0.008) for a movement from each time interval to the next. Conclusions —The time to treatment with direct PTCA, as with thrombolytic therapy, is a critical determinant of mortality.

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 Although an inverse relation between physician caseload and complications has been conclusively demonstrated for several surgical procedures, such data are lacking for percutaneous coronary intervention, and the ACC/AHA guidelines requiring ≥75 cases per year for operator “competency” are considered by some physicians to be arbitrary. Methods and Results From quality-controlled databases at five high-volume centers, models predictive of death and the composite outcome of death, Q-wave infarction, or emergency bypass surgery were developed from 12 985 consecutively treated patients during 1993 through 1994. Models had moderate to high discriminative capacity (area under ROC curves, 0.65 to 0.85), were well calibrated, and were not overfitted by standard tests. These models were used for risk adjustment, and the relations between both yearly caseload and years of interventional experience and the two adverse outcome measures were explored for all 38 physicians with ≥30 cases per year. The average physician performed a mean±SD of 163±24 cases per year and had been practicing angioplasty for 8±5 years. Risk-adjusted measures of both death and the composite adverse outcome were inversely related to the number of cases each operator performed annually but bore no relation to total years of experience. Both adverse outcomes were more closely related to the logarithm of caseload (for death, r =.37, P =.01; for death, Q-wave infarction, or bypass surgery, r =.58, P <.001) than to linear caseload. Conclusions In this analysis, high-volume operators had a lower incidence of major complications than did lower-volume operators, but the difference was not consistent for all operators. If these data are validated, their implications for hospital, physician, and payer policy will require exploration.

Background With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery. Methods and Results Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90° of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79±0.22, 1.12±0.01, 2.36±0.60, 1.24±0.36, and 1.43±0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46±0.18 and 0.61±0.23 mm, respectively) and for the nonbiodegradable PETP (0.46±0.11 mm). Conclusions An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

The objective of this study was to evaluate whether renal excretion of sodium is impaired and whether tubular reabsorption of sodium is increased in normotensive white men with a familial predisposition to develop essential hypertension. We compared 11 normotensive sons of two hypertensive parents (SOHT) with 11 normotensive sons of two normotensive parents (SONT); renal sodium handling was assessed after 1 week of low-sodium diet (10 mmol/d) and after 1 week of high-sodium diet (200 mmol/d). The SOHT were on average 5.5 years older than the SONT (46.9 +/- 5.2 [SD] vs 41.4 +/- 4.1, P = .012). On the sixth day of each diet, mean urinary sodium excretion did not differ between the two groups (12.9 +/- 6.3 vs 12.7 +/- 6.7 mmol/d on low-sodium diet, P = .930; 197 +/- 25 vs 200 +/- 27 mmol/d on high-sodium diet, P = .817). On the seventh day of each diet, baseline means for filtered load of sodium, absolute excretion of sodium, fractional excretion of sodium (an index of total tubular sodium reabsorption), and fractional excretion of lithium (an inverse index of proximal tubular sodium reabsorption) also did not differ between the groups. To assess renal sodium handling under non-steady-state conditions, we infused 2 L normal saline intravenously over a 2-hour period. The means for absolute excretion of sodium, fractional excretion of sodium, and fractional excretion of lithium increased from baseline, but the increases did not differ in magnitude between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension develops in most patients after transplantation when immunosuppression is based on cyclosporine and prednisone. The pathogenesis appears to be multifactorial but involves rapidly rising vasoconstrictor tone in renal and systemic vascular beds. Much of this tone reflects abnormal vascular function, characterized by impaired prostacyclin and EDRF effects, in conjunction with increased vasoconstriction due to endothelin and possibly other factors. Effective management of the transplant recipient depends on preventing excessive vasoconstriction, usually with calcium channel blocking agents.

The objectives of the present study were to determine whether sodium-lithium countertransport contributes to predicting the probability of having hypertension and to determine whether it does so after other predictor traits have been considered. We used logistic regression to model the relation between sodium-lithium countertransport and the probability of having hypertension, estimated by the prevalence of hypertension among 172 men and 252 women, aged 47-89 years, from the Caucasian population of Rochester, Minn. When sodium-lithium countertransport was the only predictor trait considered, it made a statistically significant contribution to prediction both in men (model chi(2)1df = 20.50, p < 0.001) and in women (model chi(2)1df = 16.69, p < 0.001). For each standard deviation increase in sodium-lithium counter-transport, the expected odds of having hypertension increased 2.25 times in men (95% confidence interval [CI], 1.44-3.51) and 1.77 times in women (95% CI, 1.32-2.37). When sodium-lithium countertransport was not considered, the other traits identified as predictors were age, body mass index, and plasma apolipoprotein CII and CII squared; plasma apolipoprotein AI was an additional predictor in women but not in men. When sodium-lithium countertransport was added to models that included the other predictors, it improved prediction both in men (increase in model chi(2)1df = 12.29, p < 0.001) and in women (increase in model chi(2)1df = 4.86, p < 0.027). Based on these complete models, when the other predictors remained at their mean values, each standard deviation increase in sodium-lithium countertransport increased the expected odds of having hypertension 2.06 times in men (95% CI, 1.31-3.22) and 1.48 times in women (95% CI, 1.04-2.21). These results establish that sodium-lithium countertransport provides information that is helpful in predicting the probability of having hypertension and is not reflected in other identified predictor traits.