Peter Skarsgard

Effect of Prosthesis-Patient Mismatch on Long-Term Survival With Aortic Valve Replacement: Assessment to 15 Years

BACKGROUND The effect of prosthesis-patient mismatch on long-term survival after aortic valve replacement has received considerable attention but there remains controversy. This study was performed to determine the predictors of mortality after aortic valve replacement and influence of prosthesis-patient mismatch on survival. METHODS Contemporary mechanical prostheses and bioprostheses were implanted in 3,343 patients with aortic valve replacement between 1982 and 2003. The mean age was 68.06 +/- 11.20 years (median 70.06; range, 19 to 94), and the mean follow-up was 6.18 +/- 4.96 years, for a total of 20,666 years of follow-up. Prosthesis-patient mismatch was classified by effective orifice area index categories: normal (> 0.85 cm(2)/m(2)), 1,547 (46.3%); mild-to-moderate (> 0.65 cm(2)/m(2) to < or = 0.85 cm(2)/m(2)), 1,584 (47.4%); and severe (< 0.65 cm(2)/m(2)), 212 (6.3%). RESULTS The predictors of overall mortality were age, age categorization, New York Heart Association functional class III/IV, concomitant coronary artery bypass graft surgery, prosthesis type, preoperative congestive heart failure, diabetes mellitus, renal failure, and chronic obstructive pulmonary disease. All categories of effective orifice area indexes were not predictive of overall mortality, late mortality, or early mortality. The 15-year overall survival was differentiated by effective orifice area index categories: 38.1% +/- 2.1%, 37.0% +/- 2.2%, and 22.1% +/- 6.5%, respectively, for the three categories. Survival adjusted for the covariates (effective orifice area index, age, basal mass index, and ejection fraction) determined no effect except severe effective orifice area index when adjusted for ejection fraction more than 50% (p = 0.049). CONCLUSIONS Prosthesis-patient mismatch is not a predictor of overall standard unadjusted mortality to 15 years after aortic valve replacement, regardless of the category of effective orifice area index.

Estrogen regulates myogenic tone in pressurized cerebral arteries by enhanced basal release of nitric oxide

Second-order middle cerebral arteries (135.0 +/- 4.6 microns ID) from male, female, ovariectomized female (no endogenous estrogen), and estrogen-treated ovariectomized female Sprague-Dawley rats were harvested and mounted in a pressure myograph. Myogenic response was recorded over a pressure range of 10-100 mmHg and was repeated in the presence of N omega-nitro-L-arginine methyl ester (L-NAME; 2 x 10(-4) M, an inhibitor of nitric oxide (NO) synthase, and after endothelium removal, to examine the contribution of NO to net myogenic tone. With intact endothelium, there were no differences in myogenic tone between the groups, but in the presence of L-NAME and after endothelium removal, estrogen-exposed vessels developed significantly greater tone at-high transmural pressure. There were no differences in sensitivity to sodium nitroprusside, an NO donor, or A-23187, a calcium ionophore. These results suggest an increase in basal release of NO in cerebral arteries exposed to estrogen, without change in NO sensitivity or maximally stimulated NO release.

Reactivity of mesenteric arteries from fructose hypertensive rats to endothelin-1.

We previously demonstrated that mesenteric arteries from hyperinsulinemic, insulin resistant fructose hypertensive (FH) rats contain a higher absolute amount of ET-1 and exhibit defective endothelium-dependent vasodilation. Furthermore, chronic ET receptor blockade with bosentan completely prevented the rise in blood pressure in these rats. The present study was undertaken to examine 1) whether the reactivity of mesenteric arteries to ET-1 is altered in FH rats, and 2) whether chronic bosentan treatment has any effect on ET-1 responsiveness and endothelium-dependent vasodilation. Male Sprague Dawley rats were divided into four groups: control (C), control bosentan-treated (CB), fructose (F) and fructose bosentan-treated (FB). Chronic oral bosentan treatment (100 mg/kg/day) was initiated in the CB and FB groups 1 week prior to initiating the fructose diet. At week 16, the F group was hyperinsulinemic and hypertensive when compared to the C group (plasma insulin: 5.8 +/- 0.3 v C 3.2 +/- 0.5 ng/mL, P < .001; systolic BP: 157 +/- 5 v C 130 +/- 4 mm Hg, P < .001). Treatment of the F group with bosentan prevented the rise in BP (FB: 133 +/- 3 mm Hg; P < .001 v F). Analysis of the pressurized mesenteric resistance arterioles demonstrated that the wall thickness as expressed as percentage of internal diameter did not differ between arteries from C and F rats, when measured over a range of transmural pressures. Constrictor responses of resistance arterioles to NE were similar for C and F rats when studied at transmural pressures of either 120 mm Hg or 160 mm Hg, respectively. The maximum contractile response and the sensitivity of superior mesenteric arteries to NE did not differ between the groups, either with or without the endothelium. However, the maximum contractile response to ET-1 was depressed in the F group both with (+) and without (-) the endothelium [(+): 1.50 +/- 0.11 v C 1.88 +/- 0.1 g/mm3, P < .05, (-): 1.68 +/- 0.11 v C 2.05 +/- 0.1 g/mm3, P < .05.]. Furthermore, the endothelium intact F arteries exhibited a decreased sensitivity to ET-1 (pD2 values F 8.36 +/- 0.11 v C 8.83 +/- 0.07). Chronic bosentan treatment of the F group restored the maximum tension responses of arteries to ET-1 [(+) in the FB group: 1.88 +/- 0.12 g/mm3 v C, P > .05, (-): 1.95 +/- 0.05 g/mm3 v C, P > .05] but had no effect on the responses of the CB group. In arteries with intact endothelium, bosentan treatment restored the sensitivity of the F arteries to ET-1 (pD2 values FB 8.82 +/- 0.05 v C, P < .05). Endothelium-dependent relaxation responses were diminished in the F group, which were unaffected by bosentan treatment. These data suggest that mesenteric arteries from FH demonstrate a specific alteration towards the reactivity to ET-1, which is restored by long-term bosentan treatment.

ENDOTHELIUM-SMOOTH MUSCLE INTERACTIONS IN BLOOD VESSELS

1. Blood vessel tone is determined both by smooth muscle and endothelial functions. In coronary arteries taken from rat (Fisher‐Lewis) cardiac transplanted hearts, the inducible form of NOS (iNOS) in smooth muscle is more active, while acetylcholine‐induced nitric oxide production in the endothelium is greatly diminished. This causes a greatly reduced myogenic constriction, in pressurized septal arteries taken from immunologically challenged transplanted hearts.

Influence of patient gender on mortality after aortic valve replacement for aortic stenosis

OBJECTIVE To assess the influence of gender on mortality after aortic valve replacement for aortic stenosis. METHODS A retrospective analysis was performed on data prospectively collected from all patients undergoing aortic valve replacement for aortic stenosis. Multivariate regression analysis was performed to evaluate the effect of 22 preoperative and operative variables on early, late, and overall mortality. RESULTS Aortic valve replacement was performed in 3343 patients with aortic stenosis between 1982 and 2003. The female patients were older, with a smaller body mass index. The women were less likely to have diabetes, chronic obstructive pulmonary disease, previous myocardial infarction, or left ventricular ejection fraction <35% but were more likely to have hypertension or a New York Heart Association III-IV classification. The female patients received a smaller prosthetic valve, with a smaller effective orifice area index (EOAI). The mean follow-up period was 6.18 ± 4.96 years, with a total of 2066.142 years of follow-up. The independent predictors of early mortality for the male patients included age, concomitant surgical revascularization, congestive heart failure, and valve size of ≤21 mm. The independent predictors of late mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, chronic obstructive pulmonary disease, congestive heart failure, and a bioprosthetic valve. The independent predictors of overall mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, heart failure, and valve size of ≤21 mm. For the female patients, the risk factors for early mortality included body mass index <25 kg/m(2); for late mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and diabetes; and for overall mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and renal failure. Furthermore, male gender was an independent predictor of late (but not early or overall) mortality. CONCLUSIONS The independent predictors of mortality after aortic valve replacement for aortic stenosis differed between the male and female patients. Male gender increased the risk of late mortality, and a valve size of ≤21 mm increased the risk of early and overall mortality among the male patients only. These differences need to be taken into consideration preoperatively and require consideration during operative management.

Profound Inhibition of Myogenic Tone in Rat Cardiac Allografts Is Due to eNOS- and iNOS-Based Nitric Oxide and an Intrinsic Defect in Vascular Smooth Muscle Contraction

BACKGROUND The physiological consequences of inducible NO synthase (iNOS) expression were studied in allograft coronary arteries by pressure myography. METHODS AND RESULTS Septal coronary arteries (diameter, 200.6+/-3.3 microm) were harvested from allograft and isograft hearts, and their myogenic properties were measured before and after iNOS and nonselective NOS inhibition with aminoguanidine (AG, 100 micromol/L) and N(G)-nitro-L-arginine methyl ester (L-NAME) (200 micromol/L). Fura 2 fluorescence microscopy was used to measure [Ca(2+)](i) in isolated endothelial cells. Monoclonal anti-iNOS immunostains demonstrated iNOS protein in day 2, 7, 14, and 28 allograft vessels, but only in day 2 isograft vessels. Myogenic tone was profoundly inhibited in allograft vessels from day 4 onward. In day 4 allograft vessels, these differences were abolished by L-NAME but not AG, suggesting greater basal release of eNOS-based NO from allograft endothelium. Fluorescence measurements confirmed elevation of [Ca(2+)](i) in day 4 allograft endothelium, providing a mechanism for enhanced eNOS activity. For days 7 to 28, AG potentiated myogenic tone in allograft but not isograft vessels, indicating that vasoactive iNOS-based NO was present. In mature vessels, constriction via agonist- and depolarization-mediated mechanisms showed parallel inhibition, suggesting an intrinsic defect in vascular smooth muscle cell contraction. CONCLUSIONS Our data indicate that the profound inhibition of myogenic tone in allograft arteries involves direct vasodilation by eNOS- and iNOS-based NO, as well as an intrinsic defect in vascular smooth muscle contraction. The hemodynamic profile resulting from these changes in allograft resistance vessel function would favor movement of extracellular fluid from the intravascular space into the myocardial interstitium, resulting in edema, increased ventricular stiffness, and poor ventricular performance.

Ticagrelor and aspirin for the prevention of cardiovascular events after coronary artery bypass graft surgery

Background Ticagrelor was shown to reduce mortality in patients who underwent coronary artery bypass grafting (CABG), but its effect on graft patency is unknown. Methods We performed a prospective, randomised, double-blind, placebo-controlled trial, comparing ticagrelor 90 mg twice daily versus placebo for 3 months added to aspirin 81 mg/day, following isolated CABG. Aspirin was started within 12 h, and study medication within 72 h after CABG. Primary outcome was graft occlusion on CT angiography (CTA) performed 3 months post CABG. Patients were followed to 12 months for death, myocardial infarction, stroke, repeat revascularisation and bleeding. Results The study was terminated prematurely after randomising 70 patients between September 2011 and August 2014 because of slow recruitment. CTA was performed in 56 patients who completed >1 month of study drug. Graft occlusion occurred in 7/25 (28.0%) patients on ticagrelor and 17/31 (48.3%) on placebo, p=0.044. Of 207 analysable grafts, graft occlusion occurred in 9/87 (10.3%) with ticagrelor and 22/120 (18.3%) with placebo, p=0.112. Graft occlusion or stenosis ≥50% occurred in 10/87 (11.5%) ticagrelor vs 32/120 (26.7%) placebo, p=0.007. There was no major bleeding, but minor bleeding was higher with ticagrelor (31.4% vs 2.9%, p=0.003). In univariate analysis, ticagrelor use reduced graft occlusion (OR 0.32, 95% CI 0.10 to 0.97, p=0.047), which remained significant on multivariable analysis (OR 0.25, 95% CI 0.073 to 0.873, p=0.03). Conclusions Ticagrelor added to aspirin after CABG reduced the proportion of patients with graft occlusion, and was a significant univariate and multivariable predictor of graft occlusion. These results are hypothesis-generating and should be confirmed in larger studies. Trial registration number NCT01373411: Results.

Inhibition of myogenic tone by mibefradil in rat cerebral arteries

The inhibitory effects of mibefradil (1.0 nM-1.0 microM), a putative selective inhibitor of T-type Ca2+ channels that has peripheral and coronary vasodilating properties with few negative inotropic effects, on pressure-induced vasoconstrictions were compared to depolarization- and [Arg8] vasopressin-induced tone in isolated middle cerebral arteries of the rat. The concentration-response relationships (IC50) for myogenic tone (70 +/- 20 nM), depolarization- (53 +/- 9 nM) and vasopressin-induced tone (70 +/- 10 nM) were equally inhibited by mibefradil. Pressure-induced responses were consistently inhibited by mibefradil throughout the myogenically active pressure range (20-100 mmHg). These results demonstrate that mibefradil is nonselective in inhibiting Ca2+ dependent cerebral artery tone due to myogenic activation, depolarization or receptor activation.

Cardiac computed tomography facilitates operative planning in patients with mitral calcification.

Extensive mitral annular calcification (MAC) can represent a significant surgical challenge. We use three illustrative examples to describe our early experience with electrocardiogram-gated cardiac computed tomography (CT) as a preoperative tool to localize MAC and to predict requisite surgical techniques. In all three cases, cardiac CT accurately delineated the location and extent of calcification compared with intraoperative findings, and in each case, it assisted in predicting the required operation (avoidance vs resection of calcification; need for annular reconstruction). All 3 patients experienced an uneventful postoperative course with no evidence of paravalvular leak on follow-up echocardiography.

Long-term Outcomes of Multiple Arterial Coronary Artery Bypass Grafting: A Population-Based Study of Patients in British Columbia, Canada

Importance Although the long-term survival advantage of multiple arterial grafting (MAG) vs the standard use of left internal thoracic artery (LITA) supplemented by saphenous vein grafts (LITA+SVG) has been demonstrated in several observational studies, to our knowledge its safety and other long-term clinical benefits in a large, population-based cohort are unknown. Objective To compare the safety and long-term outcomes of MAG vs LITA+SVG among overall and selected subgroups of patients. Design, Setting, and Participants In this population-based observational study, we included 20 076 adult patients with triple-vessel or left-main disease who underwent primary isolated coronary artery bypass grafting (MAG, n = 5580; LITA+SVG, n = 14 496) in the province of British Columbia, Canada, from January 2000 to December 2014, with follow-up to December 2015. We performed propensity-score analyses by weighting and matching and multivariable Cox regression to minimize treatment selection bias. Exposures Multiple arterial grafting or LITA+SVG. Main Outcomes and Measures Mortality, repeated revascularization, myocardial infarction, heart failure, and stroke. Results Of 5580 participants who underwent MAG, 586 (11%) were women and the mean (SD) age was 60 (8.7) years. Of 14 496 participants who underwent LITA+SVG, 2803 (19%) were women and the mean (SD) age was 68 (8.9) years. The median (interquartile range) follow-up time was 9.1 (5.1-12.6) years and 8.1 (4.5-11.7) years for the groups receiving MAG and LITA+SVG, respectively. Compared with LITA+SVG, MAG was associated with reduced mortality rates (hazard ratio [HR], 0.79; 95% CI, 0.72-0.87) and repeated revascularization rates (HR, 0.74; 95% CI, 0.66-0.84) in 15-year follow-up and reduced incidences of myocardial infarction (HR, 0.63; 95% CI, 0.47-0.85) and heart failure (HR, 0.79; 95% CI, 0.64-0.98) in 7-year follow-up. The long-term benefits were coherent by all 3 statistical methods and persisted among patient subgroups with diabetes, obesity, moderately impaired ejection fraction, chronic obstructive pulmonary disease, peripheral vascular disease, or renal disease. Multiple arterial grafting was not associated with increased morbidity or mortality rates at 30 days overall or within patient subgroups. Conclusions and Relevance Compared with LITA+SVG, MAG is associated with reduced mortality, repeated revascularization, myocardial infarction, and heart failure among patients with multivessel disease who are undergoing coronary artery bypass grafting without increased mortality or other adverse events at 30 days. The long-term benefits consistently observed across multiple outcomes and subgroups support the consideration of MAG for a broader spectrum of patients who are undergoing coronary artery bypass grafting in routine practice.