Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.

Pathologic Disparities Between Peripheral Artery Disease and Coronary Artery Disease.

Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%-75%) and erosion (25%-35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery-like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.

Effect of vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease: Analysis from the TRA 2°P-TIMI 50 trial.

Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to vorapaxar or placebo. This analysis examined the effect of vorapaxar in a broad population of 6136 patients with PAD. Overall, vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.

Updates in Spontaneous Coronary Artery Dissection.

PURPOSE OF REVIEW: To review the epidemiology, pathogenesis, diagnosis using emerging imaging modalities, management strategy, and prevention of recurrent spontaneous coronary artery dissection (SCAD) and provide a more extensive review of the current data. RECENT FINDINGS: SCAD generally affects women without conventional cardiovascular risk factors. Diagnosis and management of SCAD are challenging due to heterogeneity, undefined mechanisms, differing phenotypes, and a lack of strong clinical evidence. After reviewing the current evidence to date, we recommend conservative management, including cardiac rehabilitation for SCAD with low-risk features, while coronary revascularization should be considered in SCAD with high-risk features. Non-invasive imaging (e.g., coronary computed tomography angiography, cardiac magnetic resonance, myocardial perfusion imaging) should be considered in diagnosing specific SCAD phenotypes. The standard guideline-based medical therapy for acute coronary syndrome, in the absence of contraindications, should be considered along with appropriate SCAD phenotypes. Discharge counseling and follow-up using emerging imaging modalities should be based on individuals' profiles and approached on a case by case basis.

First International Consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

Natural History of Cervical Artery Fibromuscular Dysplasia and Associated Neurovascular Events.

BACKGROUND AND PURPOSE: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy most often affecting the carotid and renal arteries. In the United States Registry for FMD, 41.7% of patients experienced an aneurysm and/or dissection by the time of entry into the Registry. We sought to determine the occurrence of neurovascular events after FMD diagnosis and any changes on cervical artery imaging that may be attributable to FMD. METHODS: Patients followed at the Mount Sinai Medical Center (US Registry for FMD enrollment center) with confirmed FMD and > 1 cervical artery imaging study (at least ± 6 months from the baseline carotid duplex ultrasound [CDU]) between the years 2003 and 2015 were included. Medical records and cervical artery imaging ([CDU], magnetic resonance angiogram [MRA], and computed tomography angiogram [CTA]) were reviewed. New arterial dissection, aneurysm, transient ischemic attack, stroke, or new FMD findings were recorded. RESULTS: Among 146 FMD patients with complete information, 52 (35.6%) had an aneurysm and 52 (35.6%) had a dissection. Mean clinical follow-up was 35.3 ± 25.3 months (range 5-153 months); patients underwent 4 ± 2.7 CDU (range 1-17); 86.3% had ≥1 neck MRA or CTA. After FMD diagnosis, 3 patients (2%) experienced a new carotid artery dissection; 1 patient experienced a stroke due to concomitant atherosclerosis. No new aneurysms occurred. In patients with cervical artery FMD, imaging findings remained stable throughout follow-up. No patient developed new cervical artery FMD findings on follow-up imaging. CONCLUSIONS: No new cervical artery FMD or aneurysm was observed on subsequent imaging. New carotid dissection was uncommon over a mean follow-up period of 35.3 ± 25.3 months and was the only non-atherosclerotic vascular event observed after FMD diagnosis.

The Society for Vascular Medicine: the first quarter century.

The Society for Vascular Medicine was founded in 1989. During the subsequent 25 years, the Society has grown to approximately 500 members and has achieved international recognition while making important contributions to vascular disease education, clinical vascular medicine and biology research, and patient care. In celebration of the Society's 25th anniversary, its past and current presidents reflect on the Society's history, challenges, and achievements, and emphasize the vital role of the SVM in the discipline of vascular medicine.

Anti-platelet and anti-hypertension medication use in patients with fibromuscular dysplasia: Results from the United States Registry for Fibromuscular Dysplasia.

Fibromuscular dysplasia (FMD), a non-inflammatory arterial disease, may lead to renovascular hypertension (HTN) and cerebrovascular disease. Little is known about medication use in FMD. Clinical features and medication use were reviewed in a national FMD registry (12 US sites). Medication usage was assessed in raw and adjusted analyses. Covariates included demographic characteristics, co-morbid conditions and vascular bed involvement. A total of 874 subjects (93.6% female) were included in the analysis. Mean age was 55.6±13.1 years, 74.5% had HTN, 25.4% had a history of transient ischemic attack or stroke, and 7.5% had a history of coronary artery disease (CAD). Renal and cerebrovascular arteries were affected in 70.4% and 74.7%, respectively. Anti-platelet agents were administered to 72.9% of patients. In multivariate analyses, factors associated with a greater likelihood of anti-platelet agent use were older age (OR=1.02 per year, p=0.005), CAD (OR=3.76, p=0.015), cerebrovascular artery FMD involvement in isolation (OR=2.31, p<0.0001) or a history of previous intervention for FMD (OR=1.52, p=0.036). A greater number of anti-HTN medications was evident in isolated renal versus isolated cerebrovascular FMD patients. Factors associated with a greater number of anti-HTN medications were older age (OR=1.03 per year, p<0.0001), history of HTN (OR=24.04, p<0.0001), history of CAD (OR=2.71, p=0.0008) and a history of a previous therapeutic procedure (OR=1.72, p=0.001). In conclusion, in FMD, medication use varies based on vascular bed involvement. Isolated renal FMD patients receive more anti-HTN agents and there is greater anti-platelet agent use among patients with cerebrovascular FMD. Further studies correlating medication use in FMD with clinically meaningful patient outcomes are necessary.

Blood pressure response to renal artery stenting in 901 patients from five prospective multicenter FDA-approved trials.

BACKGROUND: Renal artery stent revascularization is commonly used for renovascular hypertension. Clinical predictors associated with blood pressure (BP) improvement after renal artery stent revascularization are not well understood. METHODS: Patient-level data from 901 patients in five prospective multicenter Food and Drug Administration-approved investigational device exemption studies of renal artery stent revascularization was pooled. BP response was defined as reduction of systolic BP (SBP) by >10 mm Hg. Stent patency was defined within each study. Associations of BP reduction were determined by logistic regression. RESULTS: Of 901 patients, complete outcome information was available in 527. Of these, 212/527 (40%) were male, mean age was 63 ± 13 years, 196/544 (36%) were diabetic and 504/527 (96%) had a SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg at baseline. Compared to baseline, 9-month systolic (164 ± 21 mm Hg vs. 146 ± 22 mm Hg, P < 0.0001) and diastolic (79 ± 13 mm Hg vs. 76 ± 12 mm Hg, P < 0.0001) BP declined significantly. Nine-month stent patency was 90% (305/339). In a univariate analysis, baseline SBP >150 mm Hg (OR = 4.09, CI = 2.74-6.12, P < 0.0001) was positively associated with BP response following renal artery stent revascularization. In a multivariable analysis, baseline SBP remained associated with a positive BP response (OR = 1.76, CI = 1.53-2.03, P < 0.0001). CONCLUSIONS: In the largest pooled dataset of patients treated with renal artery stent revascularization, SBP and DBP were significantly lower at 9-months. Elevated baseline SBP (>150 mm Hg) was strongly associated with BP reduction after the procedure.

Renal artery duplex ultrasound criteria for the detection of significant in-stent restenosis.

OBJECTIVES: To define velocity criteria by ultrasonography for the detection of hemodynamically significant (>60%) renal artery in-stent restenosis (ISR). BACKGROUND: The restenosis rate after renal artery stenting ranges between 10% and 20%. While duplex ultrasound criteria have been validated for native renal artery stenosis, there are no uniformly accepted validated criteria for stented renal arteries. METHODS: Vascular laboratory databases from two academic medical centers were retrospectively reviewed for patients who underwent renal artery stenting followed by duplex ultrasound evaluation and angiography (CT angiography or catheter angiography) as the gold standard. RESULTS: A cohort of 132 stented renal arteries that had angiographic comparisons was analyzed. Eighty-eight renal arteries demonstrated 0-59% stenosis while 44 renal arteries revealed 60-99% stenosis by angiography. Both the mean peak systolic velocity (PSV) and the renal artery-to-aortic ratio (RAR) were significantly higher in renal arteries with 60-99% restenosis compared with those with 0-59% restenosis (PSV: 382 cm/sec ± 128 vs. 129 cm/sec ± 62, P<0.001; RAR: 5.3 ± 2.4 vs. 2.1 ± 1.0, P <0.001). The optimal PSV and RAR cutoffs for detecting 60-99% ISR were calculated by receiver operator characteristics curve analysis. The velocity criteria that are associated with these results will be discussed. CONCLUSION: Duplex ultrasonography is an accurate technique to identify significant restenosis in stented renal arteries. The PSV and RAR cutoffs for detecting renal artery ISR are higher than those in native, unstented renal arteries. A normal duplex ultrasound after renal artery stenting virtually excludes significant restenosis.

The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an 'S'-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92-72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16-5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.

Clinical and socioeconomic factors associated with unrecognized peripheral artery disease.

Peripheral artery disease (PAD) is a highly prevalent condition that frequently goes undetected and untreated. Socioeconomic factors associated with unrecognized PAD are not known. The ankle-brachial index (ABI) was calculated in 1656 study participants undergoing non-emergent coronary angiography with PAD defined as an ABI <0.9. Subjects were followed for mortality and cardiovascular outcomes. Compared to those without PAD, those with unrecognized PAD at enrollment were older, had higher rates of cardiovascular comorbidities, and had higher major adverse cardiovascular events (MACE) (p<0.03 for all). Among those enrolling without a reported history of PAD, there was a higher prevalence of PAD with decreasing income (p=0.004), education level (p<0.001), social isolation (p=0.027) and depression (p=0.034); 50% of these individuals reported symptoms suggestive of claudication. In conclusion, the prevalence of unrecognized PAD is high amongst a cohort of high-risk individuals referred for coronary angiography. A profile of lower socioeconomic status is associated with unrecognized PAD. These subjects will report symptoms suggestive of claudication and impaired walking ability when directly queried.