Ultrastructural scoring of skin biopsies for diagnosis of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) results from a mutation in the gene encoding alpha-1, type III pro-collagen (COL3A1) and confers fragility to skin, ligament and vascular tissue. We tested the value of skin biopsy for diagnosis of vEDS through an ultrastructure scoring procedure. Study design was a multicentric, case-control, blinded trial consisting of two phases: phase 1 was to identify an ultra-structure score providing the best discriminative value for vEDS and phase 2 was to replicate this result in a different population. We enrolled 103 patients, 66 cases defined through the revised nosology for Ehlers-Danlos syndromes and 37 control subjects selected from patients referred for other pathologies. Ultrastructure of extracellular matrix was read by three to five experienced pathologists blinded for diagnosis. We used the receiver operating curves and logistic regression analysis for ranking ultrastructure scores. We created a detailed description of lesions observed in vEDS patients with 27 items (coded 0 or 1). In the phase 1 (17 cases and 20 controls), abnormal fibroblast shape, presence of lysosomes in the fibroblast and abnormal basal lamina were found to be independent discriminative items. Addition of these three items (defining an ultrastructure score) had the best diagnosis value (area under the curve (AUC) = 0.96). In the phase 2 (49 cases, 17 controls), ultrastructure score provided odds ratio of 9.76 (95 % CI 2.91-32.78), and AUC of 0.90. The ultrastructure score of skin biopsy has predictive value for the diagnosis of vEDS. Presence of two or more signs (either abnormal fibroblast, presence of lysosomes in the fibroblast or abnormal basal lamina) is very evocative of vEDS.

Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. METHODS AND RESULTS: We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. CONCLUSIONS: Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

Aortic stiffness is reduced beyond blood pressure lowering by short-term and long-term antihypertensive treatment: a meta-analysis of individual data in 294 patients.

BACKGROUND: Arterial stiffness is an independent predictor of cardiovascular events and mortality in hypertensive patients. The influence of different antihypertensive drug classes on improving arterial stiffness beyond blood pressure reduction is not widely available. We aimed to determine whether the artery stiffness can be improved because of antihypertensive treatments independently of blood pressure lowering. METHODS: We conducted a meta-analysis of individual data from 15 randomized, controlled, double-blind, parallel group trials performed in our laboratory between 1987 and 1994. The primary endpoint was the changes of carotid-femoral pulse wave velocity (PWV) after treatment in 294 patients with mild-to-moderate essential hypertension untreated. Treatments tested were placebo (n = 88), angiotensin-converting enzyme inhibitors (ACEIs) (n = 75), calcium antagonists (n = 75), beta-blocker (n = 30), and diuretic (n = 26). RESULTS: In the short-term and long-term trials, PWV decreased significantly by -0.75 and -1.3 m/s in the active treatment group compared with by +0.17 and -0.44 m/s in the placebo group, respectively. Active treatment was independently related to the changes in PWV and explained 5 and 4% of the variance in the short-term and long-term trials, respectively. In the short-term trials, ACEIs were more effective than calcium antagonists and placebo on improving arterial stiffness. In the long-term trials, ACEI, calcium antagonists, beta-blocker, and diuretic reduced significantly PWV compared to placebo. CONCLUSION: Our study shows that antihypertensive treatments improve the arterial stiffness beyond their effect on blood pressure.

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a ß(1)-adrenoceptor antagonist with a ß(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. METHODS: Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. FINDINGS: 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. INTERPRETATION: We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

Long-term reduction in aortic stiffness: a 5.3-year follow-up in routine clinical practice.

BACKGROUND: Whether a direct blood pressure-independent reduction in aortic stiffness can occur after several years of antihypertensive treatment has never been unequivocally demonstrated. METHOD: In this observational study, performed under conditions of routine clinical practice, we included 97 patients (age 63 ± 11 years) with treated essential hypertension who attended the outpatient hypertension clinic of a university hospital, had a significant blood pressure (BP) lowering under treatment before the first measurement of aortic stiffness, and had at least one additional measurement of aortic stiffness during follow-up. Aortic stiffness and carotid pulse pressure (PP) were determined through carotid-femoral pulse wave velocity (PWV) and applanation tonometry, respectively. RESULTS: A linear mixed model showed that the reduction in PWV (from 14.2 ± 4.2 to 11.0 ± 2.4 m/s; P < 0.0001) over a long follow-up (mean delay 5.3 ± 1.3 years) was associated with a significant reduction in central SBP (from 132 ± 22 to 122 ± 16 mmHg; P < 0.0001) and central PP (from 59 ± 22 to 54 ± 14; P < 0.001), contrasting with a smaller change in brachial SBP (from 132 ± 17 to 129 ± 16 mmHg; P < 0.02) and no change in brachial PP. In multivariate analysis, the decrease in PWV (-0.70 ± 0.07 m/s per year; P < 0.0001) was only slightly explained by the reduction in mean blood pressure. By contrast, the decrease in central PP (-0.83 ± 0.41 mmHg per year; P = 0.043) was largely explained by the reduction in PWV. CONCLUSION: These results indicate that a large and sustained decrease in aortic stiffness can be obtained in treated hypertensive patients under conditions of routine clinical practice. These changes likely represent a delayed response to the long-term normalization of BP and cardiovascular risk factors, through arterial remodeling.