Numerical analysis of the radial force produced by the Medtronic-CoreValve and Edwards-SAPIEN after transcatheter aortic valve implantation (TAVI).

A better understanding of the mechanisms producing the radial force in transcatheter heart valves is essential in order to reduce the reported cases of migration and atrio-ventricular block and improve the effectiveness of the treatment. This paper presents a numerical study of the different mechanisms responsible for the radial force exerted on the aortic annulus by self-expanding and balloon-expandable prostheses. The behavior of the Medtronic CoreValve (self-expanding) and the Edwards SAPIEN (balloon-expandable) devices, both of size 26, has been simulated and compared. The results indicate that, for both prostheses, the radial force may vary considerably within the recommended functional range for the valve implantation and is substantially higher at the smallest annular sizes. In particular, in the case of the self-expanding valve the radial force is essentially dependent on the diameter of the left ventricular outflow tract, while for the balloon-expandable valve the radial force produced is influenced by both the geometry and stiffness of the host tissue. The outcomes of this study provide a better insight into the phenomenon and useful information that could support the development of improved solutions.

Left ventricular long axis dysfunction in adults with "corrected" aortic coarctation is related to an older age at intervention and increased aortic stiffness.

OBJECTIVES: This study examined the prevalence of left ventricular (LV) long axis dysfunction (LAD, septal annulus pulsed-wave (PW) tissue Doppler imaging (TDI) early diastolic velocity < or =8 cm/s) in patients with "corrected" aortic coarctation and its relationship to patient demographics and aortic elastic properties. METHODS: A retrospective study of 80 consecutive patients with "corrected" aortic coarctation (aged 27 (SD 6) years, seven postballoon aortoplasty, 41 poststenting and 32 postsurgical repair) was carried out. Patients' ages at intervention, comorbidities and medications were recorded. The LV long axis motions were recorded by M-mode and PW TDI. Aortic stiffness indices were calculated from the aortic diameters and pulse pressures. RESULTS: Forty-seven patients (59%) had LAD. They were older (28 (5) vs 9 (6) years) at treatment, had stiffer aorta (stiffness index 18.4 (6.0) vs 9.2 (2.3)), thicker LV walls (146.7 (59.7) vs 103.8 (44.9) g/m2), higher wall stress (80 (6) vs 70 (7) 10(3) dynes/cm2), larger left atria (31.7 (4.6) vs 24.5 (5.3) ml/m2) and higher LV filling pressures (p<0.01 for all) compared with those without LAD, despite a similar prevalence of antihypertensive use and bicuspid aortic valves. The age at intervention (OR 2.92, 95% CI 1.29 to 6.60, p<0.01) and aortic stiffness index (OR 1.98, 95% CI 1.41 to 2.79, p<0.001) were the two independent predictors for LAD in patients on multivariate analysis. A cut-off age of > or =25 year at intervention was 89% sensitive and 76% specific in predicting LAD (AUC = 0.90, p<0.001). CONCLUSIONS: LAD is common in adults with aortic coarctation despite apparently successful treatment. Its presence is related to older age at intervention and increased aortic stiffness.

Pulmonary homograft endocarditis 19 years after a Ross procedure.

We report the case of a patient with acute pulmonary homograft endocarditis secondary to Streptococcus agalactiae from a cat-bite. He had undergone a Ross procedure nineteen years earlier. In view of unremitting infection with large pulmonary trunk and right pulmonary artery vegetations, the patient underwent successful pulmonary vegetectomy and homograft replacement.

Candida endocarditis with mycotic pulmonary emboli following re-do Rastelli operation.

A case of a 19 year old patient with Candida endocarditis complicated by pulmonary infarction and pulmonary mycotic abscesses following replacement of a right ventricle to pulmonary artery homograft conduit is presented. Despite preceding hospital admissions with probable septic pulmonary emboli, diagnosis was made only after massive pulmonary haemorrhage that ultimately proved fatal. This case highlights that Candida endocarditis should be considered in patients with symptoms and signs compatible with bacterial endocarditis when blood cultures are negative, especially in the setting of congenital cardiac malformations, and illustrates the high mortality associated with delayed diagnosis.

Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function.

An endothelial nitric oxide synthase (eNOS) gene polymorphism (Glu298Asp) has been associated with cardiovascular disease. We investigated whether carriage of the polymorphism was associated with functional changes in the endothelium, and how genotype altered the harmful and beneficial impact of environmental influences on the endothelium. Endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 248 subjects (131 female, 117 male, aged 20 to 28) genotyped for the Glu298Asp polymorphism. Vascular function was compared between genotype groups and interactions with the proatherogenic risk factor, smoking, and the antiatherogenic influence of n-3 fatty acids (n-3FA) were investigated. Vascular function was not related to genotype in the group as a whole or within sexes. However, among males, smoking was associated with lower FMD in Asp298 carriers (nonsmokers 0.125+/-0.085 mm versus smokers 0.070+/-0.060 mm, P=0.006) but not in Glu298 homozygotes (nonsmokers 0.103+/-0.090 mm versus smokers 0.124+/-0.106, P=0.5). In the whole group, n-3FA levels were positively related to FMD in Asp298 carriers (reg coeff=0.023 mm/%, P=0.04, r=0.20) but not in Glu298 homozygotes (reg coeff=-0.019 mm/%, P=0.1). These differences between genotype groups were significant in interaction models. The Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 FA in healthy young subjects. These findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease.

Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

The effect of amlodipine on endothelial function in young adults with a strong family history of premature coronary artery disease: a randomised double blind study.

Endothelial dysfunction, an early event in atherogenesis, has been demonstrated in young asymptomatic subjects with a strong family history of premature coronary artery disease (CAD). In these subjects, preventive measures involving risk factor modification are not appropriate, and strategies employing novel antiatherogenic agents, such as the dihydropyridine calcium channel blocker, amlodipine, may be useful. Ninety-one subjects (mean age, 28.6 years; range, 18-40) with a strong family history of premature CAD and no other identified vascular risk factors were randomised to either 5 mg amlodipine (49 subjects) or placebo (42 subjects). Brachial artery flow mediated dilatation (FMD) (endothelium-dependent response) and response to glyceryltrinitrate (GTN) (direct smooth muscle dilator) were assessed non-invasively at baseline, and after 12 and 24 weeks using high-resolution vascular ultrasound. In those treated with amlodipine, mean FMD increased from 2.32+/-2.23% at baseline to 3.52+/-3.1% at 24 weeks (P<0.005). However, FMD also increased in the placebo group from 1.64+/-2.12 to 3.37+/-2.68% (P<0.002), and the difference between the FMD response in the amlodipine and placebo groups was not significant. Dilatation to GTN did not change in either group. Therefore, impaired endothelial function improved in family history subjects taking both amlodipine and placebo, but there is no difference between the groups.

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.

Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study.

OBJECTIVES: We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM). BACKGROUND: Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown. METHODS: In a double-blind, 2x2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean+/-SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96+/-0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment. RESULTS: Atorvastatin resulted in a 48+/-10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247+/-141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention. CONCLUSIONS: In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.

Acute systemic inflammation impairs endothelium-dependent dilatation in humans.

BACKGROUND: We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. METHODS AND RESULTS: Salmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P:=0.0099) and ACh (P:=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. CONCLUSIONS: S typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Cholesterol and arterial distensibility in the first decade of life: a population-based study.

BACKGROUND: Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years. METHODS AND RESULTS: A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 microm. mmol(-1). L(-1), P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 microm. mmol(-1). L(-1), P=0. 005 and -36.9 microm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility. CONCLUSIONS: LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.

Determinants of the response of human blood vessels to nitric oxide donors in vivo.

The potency of the nitric oxide (NO) donors glyceryltrinitrate (GTN) and 3-morpholinosydnonimine was compared in human dorsal hand veins, the radial artery, and the forearm resistance vessels. NO donors were more potent in veins and the radial artery (vessels with minimal basal NO-mediated dilatation) than in the resistance vascular bed (where basal NO is a major determinant of vascular tone). In contrast, 8-bromoguanosine 3',5'-cyclic monophosphate (a cGMP mimetic) was approximately equipotent in resistance arteries and veins and was less potent in the radial artery. Inhibition of phosphodiesterase V with dipyridamole did not alter the arteriovenous profile of GTN. Increasing the local concentration of NO in veins (by infusing sodium nitroprusside) reduced their sensitivity to GTN but not to 8-bromoguanosine 3',5'-cyclic monophosphate. Conversely, reducing endogenous NO production in the resistance vasculature led to time-dependent increases in the response to GTN. These data suggest that soluble guanylate cyclase rather than cGMP-dependent protein kinase or phosphodiesterase V is the site in the second messenger pathway that determines the arteriovenous profile of NO donors. Moreover, the sensitivity of soluble guanylate cyclase to NO donors might be regulated by the ambient concentration of NO, with increased local NO down-regulating the dilator response to NO donors.

Exercise training enhances endothelial function in young men.

OBJECTIVES: The present study was designed to assess whether exercise training can enhance endothelium-dependent dilatation in healthy young men. BACKGROUND: Exercise has been shown to reduce cardiovascular morbidity and mortality, but the mechanisms for this benefit are unclear. Endothelial dysfunction is an early event in atherogenesis, and animal studies have shown that exercise training can enhance endothelial function. METHODS: We have examined the effect of a standardized, 10-week, aerobic and anaerobic exercise training program on arterial physiology in 25 healthy male military recruits, aged 17 to 24 (mean 20) years, of average fitness levels. Each subject was studied before starting, and after completing the exercise program. Baseline vascular reactivity was compared with that of 20 matched civilian controls. At each visit, the diameter of the right brachial artery was measured at rest, during reactive hyperemia (increased flow causing endothelium-dependent dilation) and after sublingual glyceryltrinitrate (GTN; an endothelium-independent dilator), using high-resolution external vascular ultrasound. RESULTS: At baseline, flow-mediated dilatation (FMD) and GTN-mediated dilatation were similar in the exercise and control groups (FMD 2.2+/-2.4% and 2.4+/-2.8%, respectively, p = 0.33; GTN 13.4+/-6.2 vs. 16.7+/-5.9, respectively, p = 0.53). In the military recruits, FMD improved from 2.2+/-2.4% to 3.9+/-2.5% (p = 0.01), with no change in the GTN-mediated dilation (13.4+/-6.2% vs. 13.9+/-5.8%, p = 0.31) following the exercise program. CONCLUSION: Exercise training enhances endothelium-dependent dilation in young men of average fitness. This may contribute to the benefit of regular exercise in preventing cardiovascular disease.

Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine.

OBJECTIVES: We sought to examine endothelial responses to L-arginine in three groups with isolated risk factors: hypercholesterolemia, smoking and insulin-dependent diabetes mellitus (IDDM). BACKGROUND: Endothelial dysfunction occurs early in atherosclerosis, predating clinical disease. We hypothesized that the nature of endothelial injury associated with individual cardiovascular risk factors might be different and that this might affect the response to L-arginine, the substrate for endothelial nitric oxide synthase. METHODS: We studied the effects of intravenous L-arginine on brachial artery flow-mediated dilation (FMD) and glyceryl trinitrate (GTN)-mediated dilation in 36 young subjects (18 to 40 years old) without clinical atherosclerosis: 9 each of normal control subjects, hypercholesterolemic subjects, cigarette smokers and subjects with IDDM. RESULTS: Baseline FMD was significantly impaired in hypercholesterolemic subjects (mean +/- SD 1.7 +/- 2.3%), smokers (1.6 +/- 1.8%) and diabetic subjects (1.8 +/- 1.5%) compared with that in control subjects (6.9 +/- 3.3%, p = 0.001). The response to GTN was not significantly different between the subjects with risk factors and control subjects, apart from those with IDDM, in whom it was significantly impaired (p = 0.026). After infusion of L-arginine, there was no change in FMD in control or diabetic subjects. In hypercholesterolemic subjects and smokers, FMD improved from 1.9 +/- 1.9% to 4.1 +/- 2.1% (p = 0.01) and from 2.0 +/- 1.71% to 3.1 +/- 2.5% (p = 0.02), respectively. CONCLUSIONS: FMD was impaired in all three risk factor groups; however, they responded differently to L-arginine, FMD being improved in hypercholesterolemic subjects and smokers but unchanged in diabetic subjects. These results indicate differing underlying pathophysiologies that may facilitate the design of treatment strategies for subjects with different risk factors.

Effect of enalapril on endothelial function in young insulin-dependent diabetic patients: a randomized, double-blind study.

OBJECTIVES: We sought to determine whether 6 months of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can improve conduit artery endothelial function in young subjects with insulin-dependent diabetes mellitus (IDDM). BACKGROUND: Endothelial dysfunction is an early event in atherogenesis and has been demonstrated in young subjects with IDDM. ACE inhibitors have been shown to enhance conduit artery endothelial function in animal experiments and in patients with established coronary atherosclerosis, although their effect in IDDM is not known. METHODS: Ninety-one subjects (mean age 30.9 years, range 18 to 44) with stable IDDM but no clinical evidence of vascular disease were randomized to receive enalapril (20 mg once daily) (46 subjects) or placebo (45 subjects) in a randomized, double-blind, parallel-group study. Brachial artery flow-mediated dilation (FMD), an endothelium-dependent stimulus, and response to glyceryl trinitrate (GTN), which acts directly on vascular smooth muscle, were assessed noninvasively by means of high resolution external vascular ultrasound at baseline and after 12 and 24 weeks of treatment. RESULTS: FMD was inversely correlated with total cholesterol (r=0.22, p=0.041) but not with any diabetic variables. Treatment with enalapril had no significant effect on FMD (p=0.67) or response to the endothelial-independent dilator GTN (p=0.45). CONCLUSIONS: These data suggest that impairment of endothelial-dependent dilation in young subjects with IDDM is not improved by treatment with the ACE inhibitor enalapril. This lack of improvement may reflect the complex nature of vascular disease in IDDM, which can affect both endothelial and smooth muscle function.

Preparation of PCR products for DNA sequencing.

We demonstrate that routine PCR product analytical agarose gels can also serve as preparative gels for quick DNA template purification before sequencing. The band of interest is excised, placed into a Gel Nebulizer inside a Micropure separator and rapidly purified in a single centrifugation step. Gel-purified PCR product, suitable for manual and automated sequencing, is delivered within 10 min.

Physiology and biochemistry of endothelial function in children with chronic renal failure.

Premature atherosclerosis is a major cause of morbidity and mortality in chronic renal failure (CRF). Endothelial dysfunction is a key early event in atherogenesis. The aim of this study was to assess the effect of CRF on endothelial function using physiological and biochemical measures. To focus on the effect of CRF itself, 23 children (matched with 23 controls for age and vessel diameter) were selected because they were normotensive, had normal total cholesterol (TC) levels, and were not on vasoactive drugs. Their mean (range) age was 12.0 (7.8 to 17.0) years; GFR 17.5 (8.8 to 34.5) ml/min/1.73 m2. The physiology of endothelial function in the brachial artery was assessed using high resolution ultrasound by measuring its diameter at rest, during reactive hyperemia (endothelium dependent dilation) and after sublingual glyceryl trinitrate (GTN; endothelium independent dilation). Nitric oxide (NO) metabolites and endogenous NO synthetase (eNOS) inhibitors were measured as an assessment of endothelial metabolism. Brachial artery dilation to flow [FMD, mean (SEM)%] was reduced in CRF to 4.9 (0.6) and controls 8.6 (0.6), P < 0.0001. In contrast, the response to GTN was similar in both groups: CRF 25.1 (1.6), controls 23.3 (1.2), P = 0.31. There was no difference in TC, low density lipoprotein (LDL) or high density lipoprotein (HDL) between the patients and the controls. Triglycerides (TG) were higher in the patients but within the normal range. Antibodies against oxidized LDL (ox-LDL) were high in CRF. Endogenous NOS inhibitors were high in CRF, and intermediate NO metabolites were low. There was no correlation between FMD of the brachial artery and lipid subfractions, or with NO metabolites or eNOS inhibitors. Endothelium dependent dilation of the brachial artery is impaired in children with CRF who do not have co-existing risk factors for atherosclerosis. This may represent early evidence of atherogenic vascular disease.