Assessment of atherosclerosis: the role of flow-mediated dilatation

Evidence suggests that endothelial dysfunction is on the causal pathway for both atherogenesis and destabilization of established plaques. In this review, the role of flow-mediated dilatation (FMD) as a non-invasive method to assess endothelial function is discussed. Technical modifications and development of analysis software have significantly improved the variability of the method. Following a strict standardized protocol enables reproducible measurements to be achieved and export of the technique from specialized laboratories to population studies and multicentre settings. Endothelial function assessed by FMD has been shown to be affected by cardiovascular risk factors, to be related to structural arterial disease and to cardiovascular outcome, validating its use for studying the pathophysiology of arterial disease. Numerous studies have also demonstrated that it is responsive to physiological and pharmacological interventions. Flow-mediated dilatation provides unique opportunities in drug development programmes to assess an early rapidly responsive signal of risk or benefit, complementing endpoints of structural arterial disease and cardiovascular outcomes that take much longer and are more expensiv

Cardiovascular computed tomography imaging for coronary artery disease risk: plaque, flow and fat

Cardiac imaging is central to the diagnosis and risk stratification of coronary artery disease, beyond symptoms and clinical risk factors, by providing objective evidence of myocardial ischaemia and characterisation of coronary artery plaque. CT coronary angiography can detect coronary plaque with high resolution, estimate the degree of functional stenosis and characterise plaque features. However, coronary artery disease risk is also driven by biological processes, such as inflammation, that are not fully reflected by severity of stenosis, myocardial ischaemia or by coronary plaque features. New cardiac CT techniques can assess coronary artery inflammation by imaging perivascular fat, and this may represent an important step forward in identifying the ‘residual risk’ that is not detected by plaque or ischaemia imaging. Coronary artery disease risk assessment that incorporates clinical factors, plaque characteristics and perivascular inflammation offers a more comprehensive individualised approach to quantify and stratify coronary artery disease risk, with potential healthcare benefits for prevention, diagnosis and treatment recommendations. Furthermore, identifying new biomarkers of cardiovascular risk has the potential to refine early-life prevention strategies, before atherosclerosis becomes established

Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences

Increased fibrinogen responses to psychophysiological stress predict future endothelial dysfunction implications for cardiovascular disease?

Stress influences the risk of cardiovascular disease. Acute mental stress can induce both low-grade inflammation and endothelial dysfunction. The relationship between inflammatory responses to stress and future endothelial function is unexplored. Knowledge on the impact of other cardiovascular risk factors, such as dyslipidaemia, on such relationships is also limited We investigated the relationship between inflammatory responses to an acute mental stress challenge and endothelial function plus the influence of dyslipidaemia on the associations. Interleukin-6 (IL-6), tumor necrosis factor α (TNFα) and fibrinogen were assessed at baseline, immediately following standardized behavioural tasks and 45 minutes post-task in 158 participants. Blood pressure and heart rate responses were measured. Flow-mediated dilatation (FMD) was measured 3 years later. Fibrinogen and IL-6 increased post-stress (p=<0.001 &0.003) but TNFα was unchanged (p=0.09). An independent negative association between FMD and change in fibrinogen at 45 minutes (β=-0.047 p=0.016) remained after multiple adjustment (baseline fibrinogen, baseline diameter, reactive hyperaemia, age, gender and other cardiovascular risk factors). There was no association between FMD and change in IL-6 or TNFα. There were no differences in the responses to stress between those with and without dyslipidaemia. However, there was an interaction between the presence of dyslipidaemia and immediate change in fibrinogen with stress which was associated with FMD. Those participants with dyslipidaemia who had a greater change in fibrinogen had lower FMD. We conclude that elevated fibrinogen responses to stress are associated with future endothelial dysfunction which may reflect increased cardiovascular risk

Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial

Aims The aim of this study was to assess the reproducibility of flow-mediated dilatation (FMD) in a multicentre setting. Methods and results This study was performed as part of the dal-VESSEL trial in which FMD was measured in 19 vascular imaging centres in six European countries. A subgroup of patients who were allocated in the placebo group and scanned twice at each trial time point (substudy) was analysed. Intra-sonographer variability was calculated from FMD measurements 48 h apart. Centre variability and short-, medium-, and long-term reproducibility of FMD were calculated at 48 h and at 3 and 9 months intervals, respectively. Intra- and inter-reader variability was assessed by re-analysing the FMD images by three certified readers at two time intervals, 7 days apart. Sixty-seven patients were included. Variability between centres was comparable at 48 h and 3 months interval but almost doubled at 9 months. The mean absolute difference in %FMD was 1.04, 0.99, and 1.45% at the three time intervals, respectively. Curves were generated to indicate the number of patients required for adequate power in crossover and parallel study designs. Conclusion This study demonstrates for the first time that in a multicentre setting reproducible FMD measurements can be achieved for short- and medium-term evaluation, which are comparable with those reported from specialized laboratories. These findings justify the use of FMD as an outcome measure for short- and medium-term assessment of pharmacological intervention

Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study

Objective Extended walking speed is a predictor of incident cardiovascular disease (CVD) in older individuals, but the ability of an objective short-distance walking speed test to stratify the severity of preclinical conditions remains unclear. This study examined whether performance in an 8-ft walking speed test is associated with metabolic risk factors and subclinical atherosclerosis.Design Cross-sectional.Setting Epidemiological cohort.Participants 530 adults (aged 63 +/- 6 years, 50.3% male) from the Whitehall II cohort study with no known history or objective signs of CVD.Main outcome Electron beam computed tomography and ultrasound was used to assess the presence and extent of coronary artery calcification (CAC) and carotid intima-media thickness (IMT), respectively.Results High levels of CAC (Agatston score > 100) were detected in 24% of the sample; the mean IMT was 0.75 mm (SD 0.15). Participants with no detectable CAC completed the walking course 0.16 s (95% CI 0.04 to 0.28) faster than those with CAC >= 400. Objectively assessed, but not self-reported, faster walking speed was associated with a lower risk of high CAC (odds ratio 0.62, 95% CI 0.40 to 0.96) and lower IMT (beta=-0.04, 95% CI -0.01 to -0.07 mm) in comparison with the slowest walkers ( bottom third), after adjusting for conventional risk factors. Faster walking speed was also associated with lower adiposity, C-reactive protein and low-density lipoprotein cholesterol.Conclusions Short-distance walking speed is associated with metabolic risk and subclinical atherosclerosis in older adults without overt CVD. These data suggest that a non-aerobically challenging walking test reflects the presence of underlying vascular disease

Detailed assessment of the hemodynamic response to psychosocial stress using real-time MRI

Purpose: To demonstrate that combining the Montreal Imaging Stress Task (MIST) with real-time cardiac magnetic resonance imaging (MRI) allows detailed assessment of the cardiovascular mental stress response.Materials and Methods: 22 healthy volunteers (1:1 M:F, 26-64 years) underwent MRI during rest and the MIST. Real-time spiral phase contrast MR, accelerated with sensitivity encoding (SENSE) was used to assess stroke volume (SV), and radial k-t SENSE was used to assess ventricular volumes. Simultaneous heart rate (HR) and blood pressure (BP) measures allowed calculation of cardiac output (CO), systemic vascular resistance (SVR), and arterial compliance (TAC). Endocrine responses were assessed using salivary cortisol.Results: In response to stress. BP increased due to increased CO and reduced TAC but not increased SVR, which fell. HR, not SV, determined CO increases. Greater BP responses occurred in men due to greater CO increases and relatively higher SVR. Older participants had greater BP responses due to greater falls in TAC. Greater cortisol response was correlated with greater falls In TAC but resting cortisol and TAC were not related.Conclusion: This new approach allows detailed, accurate assessment of stress physiology. Preliminary findings suggest stress exposes relationships, not seen at rest, of cardiovascular function with age, sex, and endocrine function

Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial

Aims High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538). Methods and results Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA2 mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo). Conclusion The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial functio

Outcome in neonates with Ebstein's anomaly

AbstractThe presentation and outcome of 50 patients with neonatal Ebstein's anomaly seen from 1961 to 1990 were reviewed. The majority (88%) presented in the 1st 3 days of life; cyanosis (80%) was the most common presenting feature. Associated defects, present in 27 infants (54%), included pulmonary stenosis in 11 and atresia in 7. Nine patients (18%) died in the neonatal period; there were 15 late deaths (due to hemodynamic deterioration in 9, sudden death in 5 and a noncardiac cause in 1) at a mean age of 4.5 years (range 4 months to 19 years). Actuarial survival at 10 years was 61%.A new echocardiographic grade (1 to 4 in order of increasing severity of the defect) was devised with use of the ratio of the area of the right atrium and atrialized right ventricle to the area of the functional right ventricle and left heart chambers. Cardiac death occured in 0 of 4 infants with grade 1, 1 (10%) of 16 with grade 2, 4 (44%) of 9 with grade 3 and 5 (100%) of 5 with grade 4. In a multivariate analysis of clinical and investigational features at presentation, echocardiographic grade of severity was the best independent predictor of death.Neonates with Ebstein's anomaly have a high early mortality rate and those surviving the 1st month of life remain at high risk of late hemodynamic deterioration or sudden death. Echocardiographic grading of severity of the defect permits prognostic stratification

Psychosocial Risk Factors for Health-Related Quality of Life in Adult Congenital Heart Disease

Background: There is variability in the impact of adult congenital heart disease (ACHD) on health-related quality of life (HRQoL). A greater insight into the impact of ACHD may be gained from investigating HRQoL in various diagnostic groups and considering the importance of psychosocial risk factors for poor HRQoL. / Objective: We compared the HRQoL of people with ACHD with normative data from the general population and among 4 diagnostic groups and identified risk factors for poor HRQoL in ACHD from a comprehensive set of sociodemographic, clinical, and psychosocial factors. / Methods: We conducted a cross-sectional study with 303 participants from 4 diagnostic groups Simple, Tetralogy of Fallot, Transposition of the Great Arteries, Single Ventricle who completed measures of illness perceptions, coping, social support, mood, and generic and disease-specific HRQoL. Data were analyzed using 1-sample t tests, analysis of variance, and hierarchical multiple regressions. / Results: There was diminished psychosocial HRQoL in the Simple group compared with the general population. Consistently significant risk factors for poor HRQoL included younger age, a perception of more severe symptoms due to ACHD, depression, and anxiety. Clinical factors were poor predictors of HRQoL. / Conclusions: The findings highlight the need to develop intervention studies aiming to improve HRQoL in people with ACHD and the routine assessment of illness perceptions and mood problems during key periods in people's lives. This will help address patient misconceptions that could be tackled by clinicians or specialist nurses during routine outpatient appointments and identify people in need of psychological support