Vascular aging and cardiovascular disease: pathophysiology and measurement in the coronary arteries.

Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.

Is the number of ideal cardiovascular health metrics in midlife associated with lower risk of cancer? Evidence from 3 European prospective cohorts.

BACKGROUND: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. METHODS: In 3 European cohorts (NutriNet-Santé and GAZEL, France; Whitehall II, United Kingdom), the number of ideal cardiovascular health metrics was determined at baseline (range 0-7). Follow-up for cancer events was until October 2020 (NutriNet-Santé), March 2017 (Whitehall II) and December 2015 (GAZEL). Cox regression was conducted in each cohort, and results were thereafter pooled using a random-effects model. RESULTS: Data were available on 39 718 participants. A total of 16 237 were from NutriNet-Santé (mean age 51.3 yr; 28% men), 9418 were from Whitehall II (mean age 44.8 yr; 68% men) and 14 063 were from GAZEL (mean age 45.2 yr; 75% men). The median follow-up was 8.1 years in NutriNet-Santé, 29.6 years in Whitehall II and 24.8 years in GAZEL, and yielded a total of 4889 cancer events. A greater number of ideal cardiovascular health metrics was associated with a lower overall cancer risk in each cohort, with an aggregate hazard ratio (HR) per 1 increment in number of ideal metrics of 0.91 (95% confidence interval [CI] 0.88-0.93). This association remained after removal of the smoking metric (aggregate HR per unit increment in number of ideal metrics: 0.94, 95% CI 0.90-0.97), and site-specific analysis demonstrated a significant association with lung cancer. INTERPRETATION: A greater number of ideal cardiovascular health metrics in midlife was associated with lower cancer risk, notably lung cancer. Primordial prevention of cardiovascular risk factors in midlife may be a complementary strategy to prevent the onset of cancer.

Reimagining the Value of Brachial-Ankle Pulse Wave Velocity as a Biomarker of Cardiovascular Disease Risk-A Call to Action on Behalf of VascAgeNet.

This review critiques the literature supporting clinical assessment and management of cardiovascular disease and cardiovascular disease risk stratification with brachial-ankle pulse wave velocity (baPWV). First, we outline what baPWV actually measures-arterial stiffness of both large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb. Second, we argue that baPWV is not a surrogate for carotid-femoral pulse wave velocity. While both measures are dependent on the properties of the aorta, baPWV is also strongly dependent on the muscular arteries of the lower extremities. Increased lower-extremity arterial stiffness amplifies and hastens wave reflections at the level of the aorta, widens pulse pressure, increases afterload, and reduces coronary perfusion. Third, we used an established evaluation framework to identify the value of baPWV as an independent vascular biomarker. There is sufficient evidence to support (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. However, there is limited or no evidence to support (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values. Fourth, we address future research requirements. The majority of the evaluation criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets, whereas the (5) clinical outcomes and (6) cost-effectiveness criteria require prospective investigation. The (8) methodological consensus criteria will require an expert consensus statement. Finally, we finish this review by providing an example of a future clinical practice model.

Vascular Aging Is Accelerated in Hematological Cancer Survivors Who Undergo Allogeneic Stem Cell Transplant.

BACKGROUND: Survivors of allogeneic stem cell transplant (SCT) receive intensive cancer treatments that are associated with cardiovascular dysfunction. Markers of vascular age can indicate early signs of adverse (cardio)vascular changes; however, the impact of SCT on these makers is unknown. We aimed to determine the short (3 months) and longer-term (≥2 years) effect of SCT on markers of vascular age in hematologic cancer survivors compared with an age-matched noncancer control group. METHODS: The short-term effects of SCT, markers of vascular age (aortic compliance, arterial elastance, and ventricular-vascular coupling) were assessed via cardiac magnetic resonance imaging (cardiac and aortic volumes) before and ≈3 months post-SCT in 13 short-term survivors and compared with 11 controls. The longer-term impact was assessed by comparing 14 long-term survivors (6.5 [2-20] years post-SCT) to the short-term survivors (post-SCT) and controls (n=16). RESULTS: The groups were similar for age and body mass index. In the short-term survivors, no significant group-by-time interactions were observed for any markers of vascular aging from pretransplant to posttransplant (net difference for change in compliance between groups -0.07 [95% CI, -1.49 to 1.35]). For the time-course analysis, aortic compliance was significantly lower in both SCT groups (overall P=0.007) compared with controls, whereas ventricular-vascular coupling was higher in both survivor groups as was arterial elastance in long-term SCT survivors (ie, worse; P<0.01 for all). CONCLUSION: This study provides evidence of an accelerated vascular aging phenotype in allogeneic SCT survivors and provides insight into the increased burden of cardiovascular disease among hematologic cancer survivors.

The Ultrasound Window Into Vascular Ageing: A Technology Review by the VascAgeNet COST Action.

Non-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker.

Association of Midlife Cardiovascular Health and Subsequent Change in Cardiovascular Health With Incident Cancer.

Background: The commonality of risk factors between cancer and cardiovascular disease suggests that primordial prevention (preventing the onset of risk factors) is a relevant strategy for cancer prevention. Objectives: This study sought to examine the association between baseline and change in the cardiovascular health (CVH) score and incident cancer. Methods: Using serial examinations of the GAZEL (GAZ et ELECTRICITE de France) study in France, we examined the associations between the American Heart Association's Life's Simple 7 CVH score (range: 0-to 14 [poor, intermediate, and ideal level of smoking, physical activity, body mass index, diet, blood pressure, diabetes status, or lipids]) in 1989/1990, their change over 7 years, and incident cancer and cardiac events up to 2015. Results: The study population included 13,933 participants (mean age: 45.3 ± 3.4 years, 24% women). After a median follow-up of 24.8 years (Q1-Q3: 19.4-24.9 years), 2,010 participants had an incident cancer and 899 a cardiac event. The risk of cancer (any site) decreased by 9% (HR: 0.91; 95% CI: 0.88-0.93) per 1-point increase in the CVH score in 1989/1990 compared with a 20% (HR: 0.80; 95% CI: 0.77-0.83) risk reduction for cardiac events. The risk of cancer decreased by 5% (HR: 0.95; 95% CI: 0.92-0.99) per unit of change in the CVH score between 1989/1990 and 1996/1997 compared with a 7% risk reduction for cardiac events (HR: 0.93; 95% CI: 0.88-0.98). These associations remained after omitting the smoking metric from the CVH score. Conclusions: Primordial prevention is a relevant strategy for the prevention of cancer in the population.

Developing a Questionnaire on Knowledge, Perceptions and Application of Vascular-Aging Measurements.

BACKGROUND: Vascular age (VA) is independent and chronological age for assessing cardiovascular disease (CVD) risk. However, tools for the implementation of VA are currently lacking. We aimed to develop a questionnaire to assess the current knowledge gaps related to VA and barriers to its implementation in routine practice. METHODS: Using a stepwise mixed-method approach, a quantitative questionnaire was constructed in four phases: (1) basic item generation and the development of a semi-qualitative questionnaire (SQQ); (2) dissemination to the VascAgeNet extended network and an analysis of the semi-qualitative questionnaire responses; (3) the development of a quantitative questionnaire (QQ); and (4) an assessment of the content and face validity and internal reliability in an additional sample. RESULTS: Based on six main topics initially identified through an expert panel, a SQQ was developed and disseminated. Finally, a 22-item QQ was developed, with questions grouped around three main themes: knowledge of VA and its risk factors; perceptions and beliefs regarding the importance and contribution of VA to risk classification; and the application of VA measurements in clinical and research practice and its potential limitations (Cronbach's alpha between 0.920 and 0.982 for all three categories). CONCLUSION: We report the development of a QQ on VA addressed to both clinicians and non-clinicians aiming to assess their knowledge, perceptions and application of VA measurements.

Association of Cardiovascular Health With Risk of Clinically Relevant Depressive Symptoms.

Importance: Cardiovascular health may be used for prevention of depressive symptoms. However, data on the association of cardiovascular health across midlife with depressive symptoms are lacking. Objective: To evaluate whether better baseline cardiovascular health and improvement of cardiovascular health over time are associated with a lower risk of both incident depressive symptoms and unfavorable trajectories of depressive symptoms. Design, Setting, and Participants: Participants without depressive symptoms were included from a prospective community-based cohort in France (GAZEL cohort). Cardiovascular health examinations occurred in 1990 and 1997 and assessment of depressive symptoms in 1997 and every 3 years thereafter until 2015. Data were analyzed from January to October 2022. Exposures: Number of cardiovascular health metrics (smoking, body mass index, physical activity, diet, blood pressure, glucose, and cholesterol) at an intermediate or ideal level in 1997 (range, 0-7) and 7-year change in cardiovascular health between 1990 and 1997. Main Outcomes and Measures: Primary outcome was incident depressive symptoms (20-item Center for Epidemiologic Studies-Depression Scale [CES-D] score of 17 or greater in men or 23 or greater in women); secondary outcome was trajectories of depressive symptoms scores. Trajectories included consistently low scores, moderately elevated scores, low starting then increasing scores, moderately high starting, increasing, then remitting scores, and moderately high starting then increasing scores. Results: Of 6980 included patients, 1671 (23.9%) were women, and the mean (SD) age was 53.3 (3.5) years. During a follow-up spanning 19 years after 1997, 1858 individuals (26.5%) had incident depressive symptoms. Higher baseline cardiovascular health in 1997 and improvement in cardiovascular health over 7 years were each associated with lower risk of depressive symptoms (odds ratio [OR] per additional metric at intermediate or ideal level at baseline, 0.87; 95% CI, 0.84-0.91; OR per 1 higher metric at intermediate or ideal level over 7 years, 0.91; 95% CI, 0.86-0.96). Also, better cardiovascular health was associated with lower risk of unfavorable depressive symptoms trajectories. Compared with the consistently low score trajectory, the lowest risks were observed for the low starting then increasing score trajectory (OR per additional metric at intermediate or ideal level at baseline, 0.70; 95% CI, 0.64-0.76; OR per 1 higher metric at intermediate or ideal level over 7 years, 0.73; 95% CI, 0.68-0.79) and the moderately high starting then increasing score trajectory (OR per additional metric at intermediate or ideal level at baseline, 0.71; 95% CI, 0.64-0.79; OR per 1 higher metric at intermediate or ideal level over 7 years, 0.71; 95% CI, 0.64-0.77). Conclusions and Relevance: In this prospective community-based cohort study of adults, higher cardiovascular health was associated with a lower risk of depressive symptoms over time. Elucidating which set of cardiovascular factors may affect depression risk could be important for prevention.

Vascular ageing: moving from bench towards bedside.

Prevention of cardiovascular disease (CVD) remains one of the largest public health challenges of our time. Identifying individuals at increased cardiovascular risk at an asymptomatic, sub-clinical stage is of paramount importance for minimizing disease progression as well as the substantial health and economic burden associated with overt CVD. Vascular ageing (VA) involves the deterioration in vascular structure and function over time and ultimately leads to damage in the heart, brain, kidney, and other organs. Vascular ageing encompasses the cumulative effect of all cardiovascular risk factors on the arterial wall over the life course and thus may help identify those at elevated cardiovascular risk, early in disease development. Although the concept of VA is gaining interest clinically, it is seldom measured in routine clinical practice due to lack of consensus on how to characterize VA as physiological vs. pathological and various practical issues. In this state-of-the-art review and as a network of scientists, clinicians, engineers, and industry partners with expertise in VA, we address six questions related to VA in an attempt to increase knowledge among the broader medical community and move the routine measurement of VA a little closer from bench towards bedside.

Sex differences in pressure and flow waveform physiology across the life course.

Cardiovascular disease (CVD) has long been deemed a disease of old men. However, in 2019 CVD accounted for 35% of all deaths in women and, therefore, remains the leading cause of death in both men and women. There is increasing evidence to show that risk factors, pathophysiology and health outcomes related to CVD differ in women compared with men, yet CVD in women remains understudied, underdiagnosed and undertreated. Differences exist between the sexes in relation to the structure of the heart and vasculature, which translate into differences in blood pressure and flow waveform physiology. These physiological differences between women and men may represent an important explanatory factor contributing to the sex disparity in CVD presentation and outcomes but remain understudied. In this review we aim to describe sex differences in arterial pressure and flow waveform physiology and explore how they may contribute to differences in CVD in women compared to men. Given that unfavourable alterations in the cardiovascular structure and function can start as early as in utero, we report sex differences in waveform physiology across the entire life course.

Separate and Joint Associations of Cardiorespiratory Fitness and Healthy Vascular Aging With Subclinical Atherosclerosis in Men.

BACKGROUND: Achieving healthy vascular aging (HVA) is important for decelerating age-related cardiovascular disease risk. We evaluated the interplay between HVA, cardiorespiratory fitness (CRF), and subclinical atherosclerosis. METHODS: We analyzed data on 3722 men who underwent cardiopulmonary exercise testing in a health examination program. HVA was defined as blood pressure <140/90 mm Hg without hypertension and brachial-ankle pulse wave velocity <1266 cm/s. CRF was directly measured by peak oxygen uptake. Subclinical atherosclerosis was defined as coronary artery calcification scores of >0 and ≥100 and a mean carotid artery intima-media thickness (CIMT) >75th percentile for each age group as well as >0.8 mm of CIMT. Separate and joint associations of HVA and CRF with subclinical atherosclerosis were evaluated. RESULTS: Each 1 metabolic equivalent increment in CRF was associated with 23% higher odds for having HVA. HVA was associated with lower odds of coronary artery calcification but not CIMT. CRF modified the association between HVA and CIMT>0.8 mm (interaction: P=0.01); HVA was associated with lower odds of CIMT>0.8 mm in fit men with no significant association between HVA and CIMT>0.8 mm in unfit men. Compared with no HVA and being unfit, HVA and being fit was associated with lower odds of subclinical atherosclerosis, but there was no significant association between HVA and being unfit with subclinical atherosclerosis. CONCLUSIONS: HVA and higher CRF are each associated with a lower risk of subclinical atherosclerosis in men. Higher CRF is associated with a higher prevalence of HVA and may modify the association between HVA and subclinical atherosclerosis.

A roadmap of strategies to support cardiovascular researchers: from policy to practice.

Cardiovascular disease remains the leading cause of death worldwide. Cardiovascular research has therefore never been more crucial. Cardiovascular researchers must be provided with a research environment that enables them to perform at their highest level, maximizing their opportunities to work effectively with key stakeholders to address this global issue. At present, cardiovascular researchers face a range of challenges and barriers, including a decline in funding, job insecurity and a lack of diversity at senior leadership levels. Indeed, many cardiovascular researchers, particularly women, have considered leaving the sector, highlighting a crucial need to develop strategies to support and retain researchers working in the cardiovascular field. In this Roadmap article, we present solutions to problems relevant to cardiovascular researchers worldwide that are broadly classified across three key areas: capacity building, research funding and fostering diversity and equity. This Roadmap provides opportunities for research institutions, as well as governments and funding bodies, to implement changes from policy to practice, to address the most important factors restricting the career progression of cardiovascular researchers.

Cardiovascular Health at Age 5 Years: Distribution, Determinants, and Association With Neurodevelopment.

Background: Early childhood may represent an opportune time to commence primordial prevention of cardiovascular disease (CVD, i.e., prevention of risk factors onset), but epidemiological evidence is scarce. We aimed to examine the distribution and parental and early life determinants of ideal cardiovascular health (CVH) in children up to 5 years and to compare the level of cognitive development between children with and without ideal CVH at age 5 years. Methods: Using data from the Etude sur les déterminants pré et post natals précoces du Développement psychomoteur et de la santé de l'Enfant (EDEN) study, a French population-based mother-child cohort study, CVH was examined in children at 5 years of age based on the American Heart Association CVH metrics (ideal body mass index, physical activity, diet, blood pressure, cholesterol and glucose levels, and passive smoking, considered in sensitivity analysis only). Children were categorized as having ideal (five to six ideal metrics) or non-ideal CVH (<5 ideal metrics). Intelligence quotient (IQ) at age 5 years was assessed using the French version of the Wechsler Preschool and Primary Scale of Intelligence. Results: Among the 566 children (55% boys), only 34% had ideal CVH. In fully adjusted logistic regression, boys compared to girls (OR = 1.77, 95% CI 1.13-2.78), children with intermediate (1.77, 1.05-2.98) or ideal (2.58, 1.38-4.82) behavioral CVH at age 3 years and children who spent < 30 min/day watching television (1.91, 1.09-3.34) at age 3 years were more likely to have ideal CVH at age 5 years. At age 5 years, there was a significant 2.98-point difference (95% CI 0.64-5.32) in IQ between children with and without ideal biological CVH after adjusting for confounders. Conclusion: This study highlights that only a third of children aged 5 years had ideal CVH and identified modifiable determinants of ideal CVH and is suggestive of an association between CVH and neurodevelopment at a young age.

The Identification and Management of High Blood Pressure Using Exercise Blood Pressure: Current Evidence and Practical Guidance.

High blood pressure (BP) is a leading risk factor for cardiovascular disease (CVD). The identification of high BP is conventionally based on in-clinic (resting) BP measures, performed within primary health care settings. However, many cases of high BP go unrecognised or remain inadequately controlled. Thus, there is a need for complementary settings and methods for BP assessment to identify and control high BP more effectively. Exaggerated exercise BP is associated with increased CVD risk and may be a medium to improve identification and control of high BP because it is suggestive of high BP gone undetected on the basis of standard in-clinic BP measures at rest. This paper provides the evidence to support a pathway to aid identification and control of high BP in clinical exercise settings via the measurement of exercise BP. It is recommended that exercise professionals conducting exercise testing should measure BP at a fixed submaximal exercise workload at moderate intensity (e.g., ~70% age-predicted heart rate maximum, stage 1-2 of a standard Bruce treadmill protocol). If exercise systolic BP is raised (≥170 mmHg), uncontrolled high BP should be assumed and should trigger correspondence with a primary care physician to encourage follow-up care to ascertain true BP control (i.e., home, or ambulatory BP) alongside a hypertension-guided exercise and lifestyle intervention to lower CVD risk related to high BP.