Functional outcomes after the Ross (pulmonary autograft) procedure assessed with magnetic resonance imaging and cardiopulmonary exercise testing.

OBJECTIVE: To assess autograft, homograft and ventricular function, as well as exercise capacity, in adult patients who have undergone the Ross procedure. SETTING: Single centre paediatric and adult congenital heart disease unit. Patients 45 subjects (24.6 years, range 16.9-52.2 years) who underwent the Ross procedure between 1994 and 2006 (8.1 years after the Ross operation, range 2.0-14.0 years). Interventions Cardiovascular magnetic resonance imaging, echocardiography and cardiopulmonary exercise testing. MAIN OUTCOME MEASURES: Autograft and homograft stenosis, and regurgitation. Autograft size. Biventricular function, scar volume and exercise capacity. RESULTS: Mean autograft regurgitation was 6.8%+/-8.3% (trivial regurgitation) and diameter was 40.0+/-7.0 mm. Mean homograft velocity was 2.4+/-0.6 m/s (mild-moderate stenosis) and regurgitation was 6.1%+/-8.3% (trivial regurgitation). Biventricular systolic function was normal (LV EF 63.1+/-6.4% and RV EF 60.1%+/-7.6%). In 38% of cases there was evidence of LV scar, mostly noted within the inter-ventricular septum. The mean exercise capacity achieved was 87%+/-22% of predicted. There was no correlation between exercise capacity and ventricular function or scar. CONCLUSION: This study demonstrates minor autograft and homograft dysfunction in the majority of patients after the Ross procedure, associated with good ventricular function and exercise capacity. In addition, minor scar was present in a third of patients with no functional consequences.

Metyrapone improves endothelial dysfunction in patients with treated depression.

OBJECTIVES: This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression. BACKGROUND: Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction, an atherogenic abnormality. This abnormality may be attributable to abnormal hypothalamic-pituitary-adrenal (HPA) axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects. METHODS: We measured endothelial function using flow-mediated dilation (FMD) of the brachial artery in 30 patients with depression and in 36 matched control subjects. Patients were randomized (double blind) to metyrapone (an inhibitor of cortisol synthesis) or placebo, and FMD was remeasured 6 h later. RESULTS: At baseline, FMD was impaired in patients versus control subjects (mean [standard error]), -1.27% [0.91%] vs. 4.37% [0.59%] (p < 0.001). The FMD was similar in the placebo and the metyrapone patient groups at baseline (0.17% [1.04%] vs. -2.72% [1.30%], p = 0.11). Metyrapone significantly reduced plasma cortisol levels. There was a significant improvement in FMD in the metyrapone group from -2.72% [1.30%] to 3.82% [0.99%] (p < 0.001), whereas the change in the placebo group, from 0.17% [1.04%] to 1.15% [1.14%], was not significant. Analysis of covariation showed that the effect of metyrapone was significant (p = 0.034). CONCLUSIONS: Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, suggesting that the mechanism of the endothelial dysfunction may involve cortisol.

Baroreflex sensitivity is reduced in depression.

OBJECTIVES: Depression is independently associated with increased cardiovascular morbidity and mortality, including sudden cardiac death, and this risk is observed even in patients who have been successfully treated for depression. Recent studies have emphasized the importance of impaired baroreceptor sensitivity (BRS) as a predisposing factor for sudden death in patients with manifest cardiac disease. Our objective was to test the hypothesis that BRS is impaired in subjects with depression in remission and with no other cardiac risk factors. METHODS: We measured BRS by the sequence method in 36 patients with treated recurrent depression, who were euthymic at the time of study and with no manifest cardiac disease or "conventional" cardiac risk factors, compared with 39 healthy controls. Exclusion criteria included manifest heart disease or any risk factor for IHD (smoking, hypertension, diabetes, hypercholesterolemia, or body mass index >30). Nine subjects were not on any medication, and 22 were taking antidepressants. None of the controls was taking any medication. RESULTS: BRS was significantly lower in patients than in controls (19.5 [1.78] versus 25.4 [1.69] ms/mm Hg, p = .017). Analysis of covariance, in which age, sex, cholesterol, and body mass index were included, also showed that depression was a significant (p = .027) predictor of BRS. There was no significant difference in BRS adjusted by age and sex between the subjects taking antidepressants compared with those on no medications (p = .40). CONCLUSIONS: These data indicate that BRS is impaired in otherwise healthy patients with depression and may contribute to their increased cardiac risk.

Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment.

OBJECTIVES: This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress. BACKGROUND: Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS. METHODS: We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS. RESULTS: Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mmHg to 16.3 (1.5) ms/mmHg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mmHg versus 24.9 (2.6) ms/mmHg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024). CONCLUSIONS: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Effects of exogenous and endogenous natriuretic peptides on forearm vascular function in chronic heart failure.

OBJECTIVE: Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects. METHODS AND RESULTS: Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%+/-1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001). CONCLUSIONS: In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Inhibition of platelet aggregation by nitric oxide donors improves with rest.

It has been suggested that the platelets of patients with acute coronary syndromes (ACS) exist in a more activated state than those of patients with stable coronary heart disease (CHD) or healthy individuals. "Platelet nitrate responsiveness" (PNR) has been suggested as a measure of platelet activation, and has been shown to be reduced in both ACS and stable CHD. We examined the effect of a short period of undisturbed supine rest, an intervention aimed at reducing levels of "stress", on PNR. In 8 healthy subjects we found that 45 minutes of rest led to a highly significant reduction in platelet aggregation and increase in PNR. Our finding supports the hypothesis that stress contributes to platelet activation as reflected in reduced PNR, which may contribute to the link between acute stress and cardiovascular events. It also emphasises that standardisation of sampling conditions in vitally important in studies utilizing PNR.

Atrial natriuretic peptide regulates regional vascular volume and venous tone in humans.

OBJECTIVE: To date, the contribution of basal atrial natriuretic peptide (ANP) levels to resting vascular function in humans is unknown. In the present study we sought to investigate the role of ANP in regulating regional vascular volume and venous tone in healthy subjects. METHODS AND RESULTS: We used radionuclide plethysmography to examine the effects of ANP and the ANP-receptor antagonist A71915 on forearm vascular volume. Creating pressure/volume relations, we determined changes in vascular volume, compliance, and tone. Performing dose-ranging studies, we additionally assessed the potency and specificity of A71915 in the forearm resistance vasculature. Equilibrium blood pool scintigraphy was then used to assess the effects of systemic administration of A71915 on regional intestinal vascular volume. Infusion of ANP increased forearm vascular volume in a dose-dependent manner (maximum 20%; P<0.001), exerting a maximum venodilating effect at plasma levels similar to that seen in heart failure. A71915 increased venous tone, thereby decreasing vascular volume by 9.6+/-1.1%, P<0.001 (forearm), and 2.6+/-0.5%, P=0.01 (intestinal beds). At an infusion ratio of 50:1, A71915 almost completely abolished the effects of ANP on forearm blood flow. CONCLUSIONS: ANP locally regulates regional vascular volume and tone without affecting compliance.

Supine rest reduces platelet activation and aggregation.

Platelet activation and aggregation are central processes in acute coronary syndromes and myocardial infarction, and are stimulated by physical and mental stress. However, it is not known if and to what extent the "ordinary" stress inherent in a person's daily routine contributes to platelet activation and aggregation. We measured platelet activation and aggregation in 12 healthy non-smokers, before and after 45 min supine rest in a calm environment. This simple manouver resulted in a highly significant fall in platelet aggregation (7.9-4.4 ohms, p<0.001) and in plasma epinephrine (35.6-22.5 ng/ml, p = 0.037), norepinephrine (392.8-202.7 ng/ml, p<0.001) and soluble P-selectin (51.9-44.7 ng/ml, p<0.001). Von Willebrand factor (86.2-80.9 IU/ml) and beta-thromboglobulin (279.1-262.4 IU/ml) did not change significantly. Our findings show that a person's ordinary daily routine contributes to platelet activation and aggregation, and that these can be reduced by supine rest. This has methodological implications for studies involving measures of platelet activation and aggregation, and also suggests a mechanism by which bed rest in a calm environment may contribute, however slightly, to the management of acute coronary syndromes.