Rationale and design of the PACIFIC-PRESERVED (PhenomApping, ClassIFication and Innovation for Cardiac dysfunction in patients with heart failure and PRESERVED left ventricular ejection fraction) study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is poorly defined, reflecting an incomplete understanding of its pathophysiology. AIM: To redefine the phenotypic spectrum of HFpEF. METHODS: The PACIFIC-PRESERVED study is a prospective multicentre cohort study designed to perform multidimensional deep phenotyping of patients diagnosed with HFpEF (left ventricular ejection fraction≥50%), patients with heart failure with reduced ejection fraction (left ventricular ejection fraction≤40%) and subjects without overt heart failure (3:2:1 ratio). The study proposes prospective investigations in patients during a 1-day hospital stay: physical examination; electrocardiogram; performance-based tests; blood samples; cardiac magnetic resonance imaging; transthoracic echocardiography (rest and low-level exercise); myocardial shear wave elastography; chest computed tomography; and non-invasive measurement of arterial stiffness. Dyspnoea, depression, general health and quality of life will be assessed by dedicated questionnaires. A biobank will be established. After the hospital stay, patients are asked to wear a connected garment (with digital sensors) to collect electrocardiography, pulmonary and activity variables in real-life conditions (for up to 14 days). Data will be centralized for machine-learning-based analyses, with the aim of reclassifying HFpEF into more distinct subgroups, improving understanding of the disease mechanisms and identifying new biological pathways and molecular targets. The study will also serve as a platform to enable the development of innovative technologies and strategies for the diagnosis and stratification of patients with HFpEF. CONCLUSIONS: PACIFIC-PRESERVED is a prospective multicentre phenomapping study, using novel analytical techniques, which will provide a unique data resource to better define HFpEF and identify new clinically meaningful subgroups of patients.

Recalled body silhouette trajectories over the lifespan and oral conditions in adulthood: A cross-sectional analysis of the Paris Prospective Study 3.

OBJECTIVES: To examine the association between life-course body silhouette changes and oral conditions in adulthood. METHODS: At study recruitment (2008-2012), 5430 adults underwent a full-mouth clinical examination and recalled their body silhouettes at ages 8, 15, 25, 35 and 45. Life-course trajectories of body silhouettes were computed using group-based trajectory modelling. Gingival inflammation, dental plaque, masticatory units, numbers of healthy, missing, decayed and filled teeth at study recruitment were clustered. The associations between body silhouette trajectories and clusters of oral conditions were assessed by multinomial logistic regression. RESULTS: The final analysis included 4472 participants. Five body silhouette trajectories were established: lean-stable (30.0%), lean-increased (19.3%), moderate stable (18.1%), lean-marked increased (25.8%) and heavy stable (6.7%). Three clusters of oral conditions were identified: optimal oral health and preserved masticatory capacity (70.0%, cluster 1), moderate oral health and moderately impaired masticatory capacity (25.4%, cluster 2) and poor oral health and severely impaired masticatory capacity (4.7%, cluster 3). Participants with a lean-increased trajectory were 58% more likely than those with a lean-stable trajectory to be in cluster 3 (aOR 1.58 [95% CI 1.07; 2.35]) relative to cluster 1, independently of covariates measured at study recruitment and including age, sex, smoking, socioeconomic status, BMI, hypertension, type 2 diabetes, cholesterol and triglycerides. CONCLUSIONS: A life-course lean-increased body silhouette trajectory is associated with higher likelihood of poor oral health and severely impaired masticatory capacity in adulthood.

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices.

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension.

Enhancing Multichannel Laser-Doppler Vibrometry Signals with Application to (Carotid-Femoral) Pulse Transit Time Estimation.

Pulse-wave velocity (PWV) can be used to quantify arterial stiffness, allowing for a diagnosis of this condition. Multi-beam laser-doppler vibrometry offers a cheap, non-invasive and user-friendly alternative to measuring PWV, and its feasibility has been previously demonstrated in the H2020 project CARDIS. The two handpieces of the prototype CARDIS device measure skin displacement above main arteries at two different sites, yielding an estimate of the pulse-transit time (PTT) and, consequently, PWV. The presence of multiple beams (channels) on each handpiece can be used to enhance the underlying signal, improving the quality of the signal for PTT estimation and further analysis. We propose two methods for multi-channel LDV data processing: beamforming and beamforming-driven ICA. Beamforming is done by an SNR-weighted linear combination of the time-aligned channels, where the SNR is blindly estimated from the signal statistics. ICA uses the beamformer to resolve its inherent permutation and scale ambiguities. Both methods yield a single enhanced signal at each handpiece, where spurious peaks in the individual channels as well as stochastic noise are well suppressed in the output. Using the enhanced signals yields individual PTT estimates with a low spread compared to the baseline approach. While the enhancement is introduced in the context of PTT estimation, the approaches can be used to enhance signals in other biomedical applications of multi-channel LDV as well.

Healthy sleep score changes and incident cardiovascular disease in European prospective community-based cohorts.

BACKGROUND AND AIMS: Evidence on the link between sleep patterns and cardiovascular diseases (CVDs) in the community essentially relies on studies that investigated one single sleep pattern at one point in time. This study examined the joint effect of five sleep patterns at two time points with incident CVD events. METHODS: By combining the data from two prospective studies, the Paris Prospective Study III (Paris, France) and the CoLaus|PsyCoLaus study (Lausanne, Switzerland), a healthy sleep score (HSS, range 0-5) combining five sleep patterns (early chronotype, sleep duration of 7-8 h/day, never/rarely insomnia, no sleep apnoea, and no excessive daytime sleepiness) was calculated at baseline and follow-up. RESULTS: The study sample included 11 347 CVD-free participants aged 53-64 years (44.6% women). During a median follow-up of 8.9 years [interquartile range (IQR): 8.0-10.0], 499 first CVD events occurred (339 coronary heart disease (CHD) and 175 stroke). In multivariate Cox analysis, the risk of CVD decreased by 18% [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.76-0.89] per one-point increment in the HSS. After a median follow-up of 6.0 years (IQR: 4.0-8.0) after the second follow-up, 262 first CVD events occurred including 194 CHD and 72 stroke. After adjusting for baseline HSS and covariates, the risk of CVD decreased by 16% (HR 0.84, 95% CI 0.73-0.97) per unit higher in the follow-up HSS over 2-5 years. CONCLUSIONS: Higher HSS and HSS improvement over time are associated with a lower risk of CHD and stroke in the community.

Long-term outcomes of CPAP-treated sleep apnea patients: Impact of blood-pressure responses after CPAP initiation and of treatment adherence.

BACKGROUND AND OBJECTIVE: In randomized controlled trials, continuous positive airway pressure (CPAP) is reported as lowering blood pressure (BP) with a mean systolic blood pressure effect size of 2.5 mmHg. These trials have a median follow-up of less than 6 months. Whether this initial BP response during the first months of CPAP treatment translates into a reduction in long-term cardiovascular events and mortality is unknown. METHODS: This observational study addressed long-term hard cardiovascular outcomes and all-cause mortality in a well-defined population of 241 patients previously included in the AgirSASadom parallel randomized controlled trial (assessing whether fixed-pressure CPAP was superior to auto-adjusted CPAP in reducing BP (baseline evaluations 2010-2012)). Long-term outcomes were analyzed using a Cox survival model, and a logistic regression analysis was performed for long-term CPAP adherence. RESULTS: Sixty-nine cardiovascular events occurred in 61 patients during a median follow-up of 113 months (interquartile range [102 ; 124]) giving an incidence of 26 for 1000 person-years. Twenty-one (8.7%) patients died. BP values at baseline (i.e., office and 24-h BP) was a strong predictor of incident cardiometabolic events and mortality (p < 0.01) whereas initial BP response after the first four months of CPAP was not related to outcomes. Long-term CPAP adherence above 4 h/night was associated with a reduction in all-cause mortality (Log-rank P = 0.02) but not in the occurrence of long-term cardiovascular events. CONCLUSION: Independently of initial blood pressure response, long-term CPAP adherence is one of the prerequisites for reducing mortality.

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.

Vascular function in hypertension: does gender dimension matter?

Blood pressure and vascular ageing trajectories differ between men and women. These differences develop due to sex-related factors, attributable to sex chromosomes or sex hormones, and due to gender-related factors, mainly related to different sociocultural behaviors. The present review summarizes the relevant facts regarding gender-related differences in vascular function in hypertension. Among sex-related factors, endogenous 17ß-estradiol plays a key role in protecting pre-menopausal women from vascular ageing. However, as vascular ageing (preceding and inducing hypertension) has a steeper increase in women than in men starting already from the third decade, it is likely that gender-related factors play a prominent role, especially in the young. Among gender-related factors, psychological stress (including that one related to gender-based violence and discrimination), depression, some psychological traits, but also low socioeconomic status, are more common in women than men, and their impact on vascular ageing is likely to be greater in women. Men, on the contrary, are more exposed to the vascular adverse consequences of alcohol consumption, as well as of social deprivation, while "toxic masculinity" traits may result in lower adherence to lifestyle and preventive strategies. Unhealthy diet habits are more prevalent in men and smoking is equally prevalent in the two sexes, but have a disproportional negative effect on women's vascular health. In conclusion, given the major and complex role of gender-related factors in driving vascular alterations and blood pressure patterns, gender dimension should be systematically integrated into future research on vascular function and hypertension and to tailor cardiovascular prevention strategies.

The kidney, volume homeostasis and osmoregulation in space: current perspective and knowledge gaps.

Although we have sent humans into space for more than 50 years crucial questions regarding kidney physiology, volume regulation and osmoregulation remain unanswered. The complex interactions between the renin-angiotensin-aldosterone system, the sympathetic nervous system, osmoregulatory responses, glomerular function, tubular function, and environmental factors such as sodium and water intake, motion sickness and ambient temperature make it difficult to establish the exact effect of microgravity and the subsequent fluid shifts and muscle mass loss on these parameters. Unfortunately, not all responses to actual microgravity can be reproduced with head-down tilt bed rest studies, which complicates research on Earth. Better understanding of the effects of microgravity on kidney function, volume regulation and osmoregulation are needed with the advent of long-term deep space missions and planetary surface explorations during which orthostatic intolerance complaints or kidney stone formation can be life-threatening for astronauts. Galactic cosmic radiation may be a new threat to kidney function. In this review, we summarise and highlight the current understandings of the effects of microgravity on kidney function, volume regulation and osmoregulation and discuss knowledge gaps that future studies should address.

Dried Urine Spot Analysis for assessing cardiovascular drugs exposure applicable in spaceflight conditions.

Cardiovascular pharmacological countermeasures will be required as a preventive measure of cardiovascular deconditioning and early vascular ageing for long term space travelers. Physiological changes during spaceflight could have severe implications on drug pharmacokinetics and pharmacodynamics (PK/PD). However, limitations exist for the implementation of drug studies due to the requirements and constraints of this extreme environment. Therefore, we developed an easy sampling method on dried urine spot (DUS), for the simultaneous quantification of 5 antihypertensive drugs in human urine: irbesartan, valsartan, olmesartan, metoprolol and furosemide analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), considering spaceflight parameters. This assay was validated in terms of linearity, accuracy, and precision with satisfactory results. There were no relevant carry-over, matrix interferences. The targeted drugs were stable in urine collected by DUS until 6 months at +21 °C, +4°C, -20 °C (with or without desiccants) and at 30 °C during 48 h. Irbesartan, valsartan and olmesartan were not stable at 50 °C during 48 h. This method was found to be eligible for space pharmacology studies in terms of practicality, safety, robustness and energy costs. It has been successfully implemented in space tests programs led in 2022.

Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms.

Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain.

Ultrasensitive Troponin I and Incident Cardiovascular Disease.

BACKGROUND: To examine the association of ultrasensitive cTnI (cardiac troponin I) with incident cardiovascular disease events (CVDs) in the primary prevention setting. METHODS: cTnI was analyzed in the baseline plasma (2008-2012) of CVD-free volunteers from the Paris Prospective Study III using a novel ultrasensitive immunoassay (Simoa Troponin-I 2.0 Kit, Quanterix, Lexington) with a limit of detection of 0.013 pg/mL. Incident CVD hospitalizations (coronary heart disease, stroke, cardiac arrhythmias, deep venous thrombosis or pulmonary embolism, heart failure, or arterial aneurysm) were validated by critical review of the hospital records. Hazard ratios were estimated per log-transformed SD increase of cTnI in Cox models using age as the time scale. RESULTS: The study population includes 9503 participants (40% women) aged 59.6 (6.3) years. cTnI was detected in 99.6% of the participants (median value=0.63 pg/mL, interquartile range, 0.39-1.09). After a median follow-up of 8.34 years (interquartile range, 8.0-10.07), 516 participants suffered 612 events. In fully adjusted analysis, higher cTnI (per 1 SD increase of log cTnI) was significantly associated with CVD events combined (hazard ratio, 1.18 [1.08-1.30]). Among all single risk factors, cTnI had the highest discrimination capacity for incident CVD events (C index=0.6349). Adding log cTnI to the SCORE 2 (Systematic Coronary Risk Evaluation) risk improved moderately discriminatory capacity (C index 0.698 versus 0.685; bootstrapped C index difference: 0.0135 [95% CI, 0.0131-0.0138]), and reclassification of the participants (categorical net reclassification index, 0.0628 [95% CI, 0.023-0.102]). Findings were consistent using the US pooled cohort risk equation. CONCLUSIONS: Ultrasensitive cTnI is an independent marker of CVD events in the primary prevention setting.

Assessment of arterial damage in vascular Ehlers-Danlos syndrome: A retrospective multicentric cohort.

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to pathogenic variants in COL3A1 leading to medium-size-artery (MSA) dissection, aneurysm, rupture. Aortic lesions are rarer and less investigated. The objective was to describe the distribution of MSA and aortic lesions and the type of COL3A1 variants in a multicentric cohort of 330 adult vEDS patients. Methods: At the time of the study, 87% were alive, 60.3% were index cases, and 60.0% were women. COL3A1 variants were identified using NGS and/or Sanger sequencing and classified according to functional consequences: 80.6% leading to dominant-negative (DN) and 19.4% leading to haploinsufficiency (HI). Imaging was systematically performed during the initial workup. Carotid mechanics were assessed by echo tracking in a subgroup of patients. Results: Arterial lesions were reported in 82.4% of the patients (N = 272): 83.5% had MSA lesions alone, 3.3% had aortic lesions alone, and 13.2% both. DN variants were associated with a higher prevalence of arterial lesions (P < 0.044), especially in supra-aortic trunks and renal arteries. The prevalence of aortic lesions in HI patients with arterial lesions was higher than that in patients with DN (P 0.027), but not anymore when adjusted for age (P < 0.559). Carotid Young's modulus was lower in patients with DN, in association with the higher incidence of MSA lesions in this group. Conclusion: The prevalence of aortic lesions is not influenced by the COL3A1 genotype when adjusted for age. Patients with DN variant vEDS have a higher frequency of MSA lesions, especially in supra-aortic trunks associated with lower carotid stiffness. These results support optimized care and follow-up for these vulnerable patients.

Impact of 60 days of head-down bed rest on large arteries.

BACKGROUND: The long-term cardiovascular consequences of microgravity on large arteries are a threat for long-term space missions. We hypothesized that changes in arterial properties differ according to the arterial territory (upper or lower body), and arterial structure (elastic vs. muscular arteries), in response to 60-day head-down bed rest (HDBR). METHOD: Twenty healthy male volunteers were included and received a daily multivitamin supplementation in a double-blind fashion. At baseline, 29 and 52 days during strict HDBR, then 12 and 30 days after HDBR, aortic stiffness was measured using carotid-to-femoral pulse wave velocity (cf-PWV) and aortic MRI. Carotid, femoral, brachial and popliteal arteries were studied by ultrasound echo tracking, central blood pressure (BP) by tonometry and endothelial function by flow-mediated dilatation. RESULTS: Cf-PWV increased during HDBR (+0.8 and +1.1m/s, at D29 and D52, respectively, P = 0.004), corresponding to an increase in vascular age up to +11 years (P = 0.003). Changes were similar to those observed on MRI (+0.8 m/s at D52, P < 0.01) and were independent of BP and heart rate changes. After HDBR, cf-PWV showed a substantial recovery at R12 but still remained higher than baseline at R30 (+0.8 m/s, P = 0.018), corresponding to +6.5 years of vascular aging (P = 0.018). Thoracic aorta diameter increased significantly (+6%, P = 0.0008). During HDBR, femoral and popliteal arteries showed dimensional changes, leading to femoral inward hypotrophic remodeling (femoral diameter: -12%, P < 0.05; wall cross-sectional area: -25%, P = 0.014) and popliteal inward eutrophic remodeling (popliteal diameter: -25%, P < 0.05; wall cross-sectional area: -3%, P = 0.51). After HDBR, both arterial territories of the leg recovered. We did not observe any significant changes for carotid arteries nor for endothelial function during and after HDBR. Multivitamin supplementation did not affect vascular changes. HDBR was associated with an important increase in aortic stiffness, which did not completely recover 1 month after the end of HDBR. The thoracic aorta and the lower body muscular arteries underwent significant changes in dimensions whereas the common carotid arteries were preserved. CONCLUSION: These results should raise caution for those exposed to microgravity, real or simulated.

International Guidelines for Hypertension: Resemblance, Divergence and Inconsistencies.

High blood pressure is the number one killer in the world. About 1.5 billion people suffered from hypertension in 2010, and these numbers are increasing year by year. The basics of the management of high blood pressure are described in the Canadian, American, International and European guidelines for hypertension. However, there are similarities and differences in the definition, measurement and management of blood pressure between these different guidelines. According to the Canadian guidelines, normal blood pressure is less than 140/90 mmHg (systolic blood pressure/diastolic blood pressure). The AHA and ESC estimate normal blood pressure to be less than 120/80 mmHg (systolic blood pressure/diastolic blood pressure). Regarding treatments, the AHA, ISH and ESC are also in agreement about dual therapy as the first-line therapy, while Canadian recommendations retain the idea of monotherapy as the initiation of treatment. When it comes to measuring blood pressure, the four entities agree on the stratification of intervention in absolute cardiovascular risk.

Validation and Feasibility of an Automated System for the Assessment of Vascular Structure and Mechanical Properties in the Digital Arteries: An Ultrahigh-Frequency Ultrasound Study.

Ultrahigh-frequency ultrasound (UHFUS) allows sharp visualization of human small muscular arteries. This may help in elucidating some aspects of the pathophysiology of arterial aging, such as the stiffness gradient between large and small conduit arteries and its consequences on the microcirculation, as well as vascular diseases affecting medium-sized arteries. However, UHFUS use is still limited, partly because of the lack of validated tools to quantify vascular structure and mechanical properties of small muscular arteries. In this validation study, scans of digital arteries were obtained with UHFUS (VevoMD, Visualsonics-Fujifilm, Toronto, ON, Canada), analyzed using Carotid Studio software (Quipu, Pisa, Italy) and compared with the manual measurement. Agreement between the two techniques on measures of diameter, distension and intima-media thickness (IMT) was evaluated using Bland-Altman analyses; inter- and intra-operator reproducibility was evaluated using coefficients of variation (CVs). Overall, no trend or significant bias was observed between Carotid Studio and manual analysis. All limits of agreement were acceptable. The intra-observer CV of diastolic diameter and IMT were 4.1% and 4.2%, respectively. The inter-observer CV for diastolic diameter and IMT were 7.3% and 5.4%, respectively. Intra- and inter-observer CVs for distension were higher (25.7% and 26.7%, respectively). These results suggest that the Carotid Studio software is a valid and reproducible tool to study UHFUS scans of digital arteries, with potential utility both in rare vascular diseases of medium-sized arteries and in the study of the pathophysiology of arterial aging in general.

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.