Mathew, Verghese

Background— High sensitivity C-reactive protein (hsCRP) has been identified as a predictor of adverse cardiovascular outcomes. Whether hsCRP is a useful biomarker for risk stratification in contemporary percutaneous coronary intervention remains unknown. Methods and Results— We conducted a prospective study among 513 patients undergoing non-emergency percutaneous coronary intervention and examined the relationship between pre- and postprocedural hsCRP levels and outcomes. The patients were divided according to the median preprocedural hsCRP level (0.3 mg/dL). Patients with high hsCRP had significantly more adverse clinical characteristics. Preprocedural hsCRP level was an independent predictor of periprocedural myocardial infarction (odds ratio per doubling of hsCRP 1.15 [95% confidence interval, 1.01–1.31]; P =0.038). Unadjusted mortality (29.7% versus 9.9%; P <0.001) and the combined end point of death or myocardial infarction (36.5% versus 16.0%, P <0.001) during a follow-up of 5 years were markedly greater in patients with high preprocedural hsCRP. Similar relationships existed for postprocedural hsCRP. However, after multivariable adjustment, neither preprocedural hsCRP levels (hazard ratio per doubling 0.96 [0.92, 1.00]; P =0.066) nor postprocedural hsCRP levels (hazard ratio 0.98 [0.94, 1.02]; P =0.27) were significantly associated with mortality. Conclusions— High hsCRP is associated with a greater independent risk of periprocedural myocardial infarction, as defined by the universal definition, but is not an independent determinant of mortality after percutaneous coronary intervention. Our findings suggest that routine measurement of hsCRP in patients undergoing percutaneous coronary intervention in contemporary practice is unlikely to be beneficial.

Background— Coronary stents, drug-eluting stents in particular, have been linked to coronary epicardial endothelial dysfunction after implantation. However, less is known about their impact on coronary microvascular function and their long-term effects on the vasculature. Methods and Results— We evaluated 71 patients (mean age, 53.0±10.1 years) with chest pain and angiographically nonsignificant coronary artery disease 17.1±17.1 months after left anterior descending coronary artery stenting. Seventy-one age- and sex-matched patients (mean age, 53.0±10.3 years) with chest pain but no prior coronary intervention served as controls. Coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine as well as the microvascular (endothelium-independent) coronary flow reserve in response to intracoronary adenosine were evaluated. Quantitative coronary angiography was used to study epicardial diameter changes to acetylcholine. Microcirculatory function was not significantly different between the stenting and control groups (median [interquartile range] coronary flow reserve, 2.9 [2.5–3.4] versus 3.0 [2.4–3.4] mL/min, P =0.24; change of coronary blood flow, 34.9% [−34.4% to 90.0%] versus 54.7% [−5.6% to 104.6%], P =0.18). Both groups exhibited epicardial endothelial dysfunction (−23.0% [−47.4% to −7.6%] versus −20.0% [−40.0% to 0.0%], P =0.4). Results did not differ between patients with drug-eluting stents (n=46) and patients with bare-metal stents (n=24). Conclusions— This study demonstrates that in patients with coronary arteries in which a stent has been placed, coronary microcirculatory and epicardial vascular function are not significantly different from that of an age- and sex-matched population with similar symptoms but nonsignificant coronary artery disease.

Background —This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain. Methods and Results —All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86; P <0.001). During a mean follow-up of 1.2±1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (χ 2 =16.64, P =0.0001). Conclusions —Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.

Background— Clinical outcomes after stent placement in patients with a history of metal allergy remain incompletely understood. We performed a single-center retrospective study to evaluate such outcomes. Methods and Results— Twenty-nine allergic patients who underwent coronary stent implantation were compared with a nonallergic group (n=250) matched for demographics and a propensity score for allergy to metal. Hypersensitivity to nickel was reported in 26 of 29 and chromium in 9 of 29. Patch testing performed in 11 of 29 patients was positive in all. Comparing allergy versus control subjects, there were no differences in number of segments treated (1.4±0.7 versus 1.5±0.7), stents placed (1.7±1.1 versus 1.6±0.9), and frequency of drug-eluting stent usage (52% versus 60%). In-hospital death (0% versus 0%), myocardial infarction (MI, 4% versus 3%, P =0.27), and 30-day death (3% versus 0%, P =0.53) and MI (3% versus 4%, P =0.71) were statistically similar. There were no differences in 4-year death (12% versus 13%), target lesion revascularization (TLR, 13 versus 17%, P =0.54), or death/MI/TLR (24% versus 34%, P =0.20). Clinically driven repeat angiography in 12 of 29 allergy patients revealed binary restenosis rates of 27% in bare metal stents and 0% in drug-eluting stents, with mean diameter in-stent restenosis of 36% and 8%, respectively. There was no change in circulating eosinophil and lymphocyte counts after stenting in the allergy group (0.19–0.20, P =0.67, and 1.90–1.79, P =0.59, respectively). Conclusions— A history of metal allergy was not associated with adverse early or late outcomes in this single-center study.

Abstract —Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia. We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, n=5; 5 ng · kg −1 · min −1 ) and acetylcholine (group III, n=7; 10 −6 to 10 −4 mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 μg · kg −1 · min −1 ; group II, n=6; group IV, n=6). Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg · kg −1 · h −1 , group V, n=5). The ETB-receptor agonist sarafotoxin 6c (5 ng · kg −1 · min −1 ; n=4) was also infused. The percentage change in coronary artery diameter (%ΔCAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %ΔCAD at baseline and 10 weeks (−10±2% and −12±3%, respectively). FR-139317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%ΔCAD −18±8% for group I versus −12±6% for group II; P =NS) but did at 10 weeks (%ΔCAD −77±14% for group I versus −14±6% for group II; P <.05). FR-139317 did not affect the response to acetylcholine at baseline (%ΔCAD 5±2% for group III versus 7±3% for group IV, P =NS) or at 10 weeks (%ΔCAD −23±12% for group III versus −19±7% for group IV; P =NS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. Short-term ET-receptor inhibition in experimental hypercholesterolemia attenuated the enhanced coronary epicardial vasoconstrictor effects of ET-1 but not acetylcholine-induced coronary epicardial vasoconstriction, suggesting that acetylcholine-induced coronary epicardial vasoconstriction may not be mediated by ET receptors.

Abstract The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (<481±25 μm in diameter) to cumulative concentrations (10 −10 to 10 −6 mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86±7% versus 47±7%, P =.001) and hypercholesterolemic (77±6% versus 37±7%, P <.001) pigs. At 10 −10 mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23±6% versus 8±3%, P =.02) and S6c (17±5% versus 4±2%, P =.02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR-139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10 −10 mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.

Background— Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET A ) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis. Methods and Results— Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET A receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10 −6 to 10 −4 mol/L) in the left anterior descending coronary artery. N G -monomethyl- l -arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus −2.22%, 95% confidence interval −27.37% to 15.28%; P <0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N G -monomethyl- l -arginine were similar between the groups at baseline and at 6 months. Conclusions— This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.