Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. METHODS: Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events. RESULTS: Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011-2019. The median follow up was 22 months (range 1-98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n = 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. CONCLUSION: Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS.

Results of renal artery revascularization in the post-ASTRAL era with 4 years mean follow-up.

Purpose: To investigate contemporary results of percutaneous transluminal renal angioplasty (PTRA).Materials and Methods: A multicentre retrospective study analysing all patients treated with PTRA for primary symptomatic renal artery stenosis (RAS) between 2010 and 2013 at four tertiary centres. Procedures during the preceding four years were counted to evaluate for change in PTRA frequency.Results: The number of PTRA procedures decreased by approximately 50% from 2006 to 2013. Patients treated in the post-ASTRAL period (n = 224) had a significant reduction in mean systolic pressure (168 to 146 mmHg, p < 0.01), diastolic pressure (84 to 76 mmHg, p < 0.01), number of anti-hypertensive drugs (3.54 to 3.05, p < 0.01), and anti-hypertensive treatment index (21.75 to 16.92, p < 0.01) compared to before PTRA. These improvements were maintained at one year and at the last clinical evaluation after a mean follow-up of 4.31 years. Renal function increased transiently without sustained improvement, or deterioration, during later follow-up. Thirteen patients (5.8%) eventually required dialysis, nine of these had eGFR <20 ml/min/1.73 m2 before PTRA. There was no difference in outcomes between subgroups differentiated by different indications for PTRA.Conclusion: The frequency of PTRA has decreased, indicating a higher threshold for invasive treatment of RAS in recent years. The reduction in blood pressures, the reduced need for anti-hypertensive medication, and stabilization of renal function over time suggest a clinical benefit for most patients who are now being treated with PTRA.

Renal sympathetic denervation in Sweden: a report from the Swedish registry for renal denervation.

BACKGROUND: Renal denervation (RDN) is a catheter-based intervention to treat patients with resistant hypertension. The biological effects of RDN are not fully understood, and randomized controlled trials have generated conflicting evidence. This report presents data from the Swedish Registry for Renal Denervation, an investigator-driven nationwide registry. PURPOSE: To assess the safety and efficacy of RDN on patients with resistant hypertension in a real-world clinical setting. METHODS: This nationwide database contains patient characteristics, procedural details, and follow-up data on all RDN procedures performed in Sweden. Consecutive procedures between 2011 and 2015 were included. RESULTS: The data analysis consists of 252 patients (mean age 61 ±â€Š10 years, 38% women; mean 4.5 ±â€Š1.5 antihypertensive drugs). Office SBP and DBP and 24-h ambulatory blood pressure (BP) decreased 6 months after RDN (176 ±â€Š23/97 ±â€Š17 to 161 ±â€Š26/91 ±â€Š16 mmHg, both P < 0.001; and 155 ±â€Š17/89 ±â€Š14 to 147 ±â€Š18/82 ±â€Š12 mmHg, both P < 0.001). Significant office and ambulatory BP reductions persisted throughout the observation period of 36 months. Major procedure-related vascular complications occurred in four patients. Renal function and number of antihypertensive drugs were unchanged during follow-up. CONCLUSION: In this complete national cohort, RDN was associated with a sustained reduction in office and ambulatory BP in patients with resistant hypertension. The procedure proved to be feasible and associated with a low-complication rate, including long-term adverse events.

Impaired endothelial function of forearm resistance arteries in CADASIL patients.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy, which mainly involves the brain causing stroke and dementia. Mice expressing the mutated protein display early dysfunction in vasoreactivity in resistance arteries, but studies of patients have been inconclusive so far. METHODS: We examined peripheral endothelium-dependent vasodilatation in 10 CADASIL-patients and 20 controls using 3 methods: venous occlusion plethysmography of forearm blood flow with intraarterial acetylcholine and sodium nitroprusside infusions for evaluation of resistance arteries, ultrasound with flow mediated vasodilatation (FMD) of the brachial artery for evaluation of a conduit artery, and the pulse wave method with measurements before and after terbutaline for evaluation of systemic endothelium-dependent vasodilation. RESULTS: The CADASIL patients displayed reductions in both basal (P=0.034) and stimulated blood flow (P=0.023 for the highest dose of acetylcholine) and an impaired endothelium-dependent vasodilation when investigated in forearm resistance arteries (P=0.019). The FMD and the pulse wave method did not show any reduction in endothelium-dependent vasodilation in the patients. CONCLUSIONS: Endothelium-dependent vasodilation was impaired in resistance arteries, but not in a conduit artery, in the forearm of CADASIL patients.

A comparison of three different methods to determine arterial compliance in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

BACKGROUND: Several different techniques to evaluate arterial compliance have been described but have not been simultaneously tested in a large-scale, population-based setting. This study aimed to evaluate the feasibility and relation to cardiac risk of three of these techniques in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS AND RESULTS: In the population-based PIVUS study (1016 participants aged 70), assessment of arterial distensibility by ultrasound in the carotid artery, by pulse wave analysis (augmentation index) and the stroke volume to pulse pressure ratio by echocardiography were successfully employed in 86, 92, 91 and 77% of the sample, respectively. All three indices of arterial compliance were inter-related (r = 0.19-0.34, P < 0.0001 for all). Although all three indices were significantly related to the Framingham risk score (r = 0.12-0.32, P = 0.0005-0.0001), only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently associated with the Framingham score in multiple regression analysis (P < 0.0001 for both). CONCLUSIONS: All three indices to evaluate arterial compliance were feasible to obtain in a general elderly population and were inter-related. Although all of the techniques were correlated to Framingham risk score, only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently related to coronary risk, suggesting complementary use of these two indices of arterial compliance in the future.

Coexistence of microhemorrhages and acute spontaneous brain hemorrhage: correlation with signs of microangiopathy and clinical data.

PURPOSE: To evaluate prospectively with magnetic resonance (MR) imaging the coexistence of microhemorrhages (MHs) in white patients with acute spontaneous intraparenchymal hemorrhage (IPH) and acute ischemic stroke and to study the association with imaging findings of microangiopathy and various clinical data. MATERIALS AND METHODS: Before examinations, informed consents were signed by either the patient or a relative. The study was carried out with the approval of the local ethics committee. MR imaging was performed in 90 patients with acute stroke: 45 with acute spontaneous IPHs (24 men and 21 women; median age, 65 and 68 years, respectively) and 45 age-matched control subjects without intracranial hemorrhages (26 men and 19 women; median age for both, 67 years), as determined at computed tomography. MR imaging included transverse T1- and T2-weighted spin-echo, transverse fluid-attenuated inversion recovery, transverse and coronal T2*-weighted gradient-echo, and, in 50 patients, diffusion-weighted sequences. Presence of MHs and signs of microangiopathy, such as T2 hyperintensities or lacunae, were recorded in the white and deep gray matter. The relationships between MH and IPH and between MH and T2 hyperintensities were analyzed by means of regression analysis. Different clinical features, such as arterial hypertension or diabetes, were registered and correlated with the image findings by means of regression analysis. RESULTS: MHs were found in 64% of patients with IPH (29 of 45) and 18% of control subjects (eight of 45). A statistically significant relationship between MH and IPH was determined (P < .001). Among the 29 patients with IPH and MH, 24 (83%) had T2 hyperintensities and 13 (45%) had lacunae; among the 16 patients without MH, seven (44%) had T2 hyperintensities and three (19%) had lacunae. A relationship between MH and occurrence and extent of T2 hyperintensities was also identified (P < .001). There was no clear relationship with the clinical data studied. CONCLUSION: The results support a correlation between the presence of imaging signs of cerebral microangiopathy, clinically silent MHs, and acute IPHs.

A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

BACKGROUND: Three different techniques to evaluate endothelium-dependent vasodilation in the peripheral circulation have been described but not simultaneously tested in a large-scale population-based setting. This study aimed to evaluate the feasibility and usefulness of these techniques in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS AND RESULTS: In the population-based PIVUS study (1016 subjects aged 70 years), the invasive forearm technique with acetylcholine given in the brachial artery (EDV), the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD), and the pulse wave analysis method with beta-2-agonist (terbutaline) provocation were successfully used in 87%, 97%, and 86% of the sample, respectively. The results of EDV and pulse wave analysis were interrelated (r=0.12, P=0.0013), but no relationships were found with FMD measurements. All 3 techniques were correlated to the Framingham risk score (r=0.10 to 0.12, P=0.0007 to 0.001). In multiple regression analysis, however, only EDV and FMD were independently associated with the Framingham score. CONCLUSIONS: All 3 evaluated techniques were feasible to perform in a general elderly population. Both the invasive forearm technique and FMD were independently associated with increased coronary risk, suggesting that information on conduit artery and resistance artery endothelial function carry different, but important, information in the elderly. If the invasive technique cannot be used, the pulse wave based technique is an alternative.

Cost-effectiveness of preoperative radiotherapy in rectal cancer: results from the Swedish Rectal Cancer Trial.

PURPOSE: The Swedish Rectal Cancer Trial (SRCT) demonstrated that a short-term regimen of high-dose fractionated preoperative radiotherapy (5 x 5 Gy) reduced the local recurrence rates and improved overall survival. This has had an impact on the primary treatment of rectal cancer. The current study investigated the cost-effectiveness of the new combined approach. METHODS AND MATERIALS: After an 8-year follow-up, in-hospital and outpatient costs related to the treatment of rectal cancer and its complications were analyzed for 98 randomly allocated patients who participated in the SRCT from a single Swedish health care region. The costs were then related to the clinical data from the SRCT regarding complications, local and distant recurrences, and survival. RESULTS: The total cost for a nonirradiated patient was US$30,080 compared with US$35,268 for an irradiated patient. The surgery-alone group had increased costs related to local recurrences, and the radiotherapy group had increased costs for irradiation and complications. With a survival benefit of 21 months (retrieved from the SRCT), the cost for a saved year was US$3654. Sensitivity analyses for different rates of local recurrences, the costs related to complications and less marked survival benefit showed that this figure could vary up to US$15,228. CONCLUSION: The cost for a life-year saved in these data was US$3654. This figure could reach US$15,228 in the most pessimistic setting of the sensitivity tests, a cost still comparable with other well-accepted medical interventions.