Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations.

BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD. METHODS: 51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery. RESULTS AND DISCUSSION: In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group). CONCLUSIONS: This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.

Persistent dissection of carotid artery in patients operated on for type A acute aortic dissection--carotid ultrasound follow-up.

Over a period of 5 years, 124 patients were operated on at the National Institute of Cardiology in Warsaw for acute aortic dissection, 27 of whom died. The 97 patients discharged from the hospital were included in the present analysis. The age of the patients ranged from 25 to 73 years with a mean of 50+/-10 years. Ultrasound examination of carotid arteries was performed with the patient lying on his back using a Toshiba 340A color Doppler system with a linear array probe of 7.5 MHz. Of the 97 patients examined, 15 (15%) had a dissection of at least one of the common carotid arteries (CCA). Two had Marfan syndrome. In 11 patients the dissection involved the right common carotid artery and in four it involved both the left and right common carotid arteries. The flow in the true lumen of CCA and ICA was preserved in all patients and the degree of narrowing ranged from 30 to -70%. Only one of the 15 patients with CCA dissection had an ipsilateral neurological deficit which was already present before the aortic aneurysm operation. Ultrasound follow-up was performed in all patients with the CCA dissection found on first examination. The mean duration of follow-up was 21 months. In 14 patients the degree and extent of the dissection as well as the narrowing of the true lumen was comparable, and in one patient the false channel closed spontaneously. During follow-up there were no new major neurological events despite the persistence of the CCA dissection with different degrees of narrowing of the true lumen. Doppler ultrasound examination of the carotid arteries can supply additional information about the extent of the dissection, and help to assess the flow in the persisting 'double channel' common carotid artery during the follow-up of patients.

[Doxazosin (alpha 1-adrenoreceptor antagonist) used in primary hypertension and it's beneficial effect on lipid metabolism]. / Doksazosyna (bloker alfa 1-receptorów) skuteczny lek w nadcisnieniu pierwotnym o korzystnym wplywie na gospodarke lipidowa.

The aim of the study was to investigate the effect of a new selective alpha 1-adrenoreceptor blocker doxazosin on blood pressure, serum lipids and lipoproteins in patients with essential hypertension. The study was done in 32 out-patients with mild-to-moderate hypertension (22 men and 10 women, mean age 45.6 +/- 10.1). After 2-week placebo period the patients were given doxazosin in increasing doses from 1 to 8 mg daily for 6 to 14 weeks (mean daily dose 2.24 +/- 1.6 mg). Twenty-nine patients completed the study. The active treatment caused highly significant drop in systolic and diastolic blood pressure both in supine and standing positions. No orthostatic hypertension was noted. There was also a statistically significant decrease in serum total cholesterol, VLDL-cholesterol, and triglyceride levels and increase in the positive prognostic lipid indicators. HDL3-cholesterol and apolipoprotein AI levels as well as HDL/total cholesterol ratio. Accordingly, the statistically significant decrease of the so called atherogenic index was noted. The drug was well tolerated and only one patient dropped from the study because of side effects. The authors conclude that doxazosin appears to be an effective and well tolerated antihypertensive drug with a favorable effect on lipid metabolism. It may be particularly useful in hypertensive patients with coexisting lipid abnormalities.

[Renovascular hypertension--clinical observations and long-term follow-up]. / Nadcisnienie naczyniowo-nerkowe--obserwacja kliniczna i odlegle wyniki leczenia.

Renovascular hypertension is one of the most common causes of secondary hypertension. Its early diagnosis is particularly important, firstly because it is one of the few potentially reversible causes of chronic renal failure. In many centers, including our own, renal angioplasty (PTA) or surgery is the treatment of choice for patients with renovascular hypertension. The aim of the study was the evaluation of the early and late results of PTA versus renovascular surgery. The diagnostic procedures and clinical course of renovascular hypertension were also analyzed. Among patients with renovascular hypertension treated in our Department during the 1981-1993 years, 89 patients (46 men, 43 women) were diagnosed and having renovascular hypertension (3% of all hypertensive patients). The average duration of hypertension in this group was 5 years. High incidence of accelerated hypertension (18%) and cardiovascular complications were observed: myocardial infarction in 20.2% of cases and stroke in 4.5%. The presence of renal failure was found in 22.5% of cases, hypokalemia in 11.2%, 38.3% of patients had changes in other arteries. Renal angioscintigraphy and captopril renal scintigraphy were performed in accordance with renal arteriography in 80% of patients. Arteriography showed unilateral renal artery stenosis in 78.7% of patients and bilateral - in 21.3%. The most common cause of renovascular hypertension in our material was atherosclerosis (65.2%). Fibromuscular dysplasia and Takayasu arteritis were diagnosed less frequently (25.8% and 9.0% respectively). Forty four patients were treated with PTA, 15 underwent surgical revascularization and 11 - unilateral nephrectomy. Early beneficial therapeutic effect (normalization or improvement of blood pressure control) was observed in 88.6% for PTA and 66.7% for surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

[Blood pressure and levels of catecholamines during physical exertion in patients with essential hypertension]. / Cisnienie tetnicze krwi i stezenie amin katecholowych w warunkach wysilku fizycznego u chorych z nadcisnieniem tetniczym pierwotnym.

UNLABELLED: Material of the study consisted of 30 patients with borderline (BH) and 30 with (EH) established essential uncomplicated hypertension in age 18-50 years and 30 healthy men (N) in age 20-46 years. The patients did not receive treatment at least 14 days before the study. In all subjects the submaximal exercise ergometer test was performed. Blood pressure was measured in sitting position using mercury sphygmomanometer five times: before the test, in first and third minute of exercise, at the moment of submaximal exercise and after 30 minutes recovery. Blood samples were taken three times: before the test, at the moment of submaximal exercise and in 30th minute of recovery. Plasma concentrations of adrenaline and noradrenaline were assessed. In all groups significant increase was seen of systolic and diastolic blood pressure as well as plasma catecholamine concentrations at the maximal level of exercise in comparison to the basal values. The noradrenaline exercise concentrations was highest in patients with borderline hypertension. The adrenaline concentration was higher in hypertensive subjects than in controls. These differences were statistically significant. The degree of increase of noradrenaline during the test was significantly greater in patients with borderline hypertension than in other groups. CONCLUSION: different catecholamines reaction on exercise in examined groups suggest the involvement of sympathetic system in pathogenesis of essential hypertension.

[Hormonal contraceptives and arterial hypertension]. / Hormonalne srodki antykoncepcyjne a nadcisnienie tetnicze.

PIP: A literature review is presented to show that oral contraceptives (OCs) can cause arterial hypertension in women. The occurrence of this side effect varies over the broad range of 1-15%. Thus, in a Polish study of 100 women, the occurrence of hypertension after 1, 3, and 4 years of OC use was 1%, 8%, and 16%, respectively. Most studies on hypertension caused by OCs were performed with pills containing 50-100 mc of estrogens and 1-4 mg of gestagen. Through these studies, a strong correlation was established between the occurrence of hypertension and the dose of estrogens. Normal blood pressure was observed over 3 years in women using pills containing 20-30 ug of estrogens and 150-250 mc of gestagen. Most OCs are combinations of synthetic estrogens with progesterone. Estrogens appear to dominate in the pathogenesis of hypertension caused by OCs. The mechanism of action of estrogens on arterial blood pressure is not clear. Several hypotheses have been proposed, and some of them are briefly discussed. Numerous studies prove that the occurrence of hypertension increases with the age of the woman using OCs. From this review, the conclusion is drawn that physicians should not recommend hormonal agents to women with hypertensive cardiovascular disorders or susceptibility to contraceptive-induced hypertension. Changing from high-to low-dose steroid preparations could become an important step in the future development of OCs.^ieng

[Evaluation of selected parameters of zinc metabolism in patients with primary hypertension]. / Ocena wybranych parametrów gospodarki cynkowej u chorych z pierwotnym nadcisnieniem tetniczym.

UNLABELLED: The aim of the study was to investigate the role of zinc (Zn) in essential hypertension (EH). PATIENTS AND METHODS: Material of the study consisted of 31 patients (12 female, 19 male) with mild and moderate EH and 20 healthy persons (NT) (7 female, 13 male). Erythrocyte (ZnE) and serum (ZnS) zinc as well as 24 hour urinary zinc excretion (ZuU) were assessed in both groups. Zn parameters were measured by atomic absorption spectrophotomery. RESULTS: ZnS was lower and ZnE was higher in EH (p < 0.001) than in normotensives. ZnU did not differ between EH and NT. ZnE and ZnS negatively correlated with age in NT but not in EH, ZnU negatively correlated with age only in EH. BP positively correlated with ZnS in EH but not in NT. In both groups negative correlations were found between BP and ZnU. CONCLUSIONS: 1. Zinc probably plays a role in pathogenesis of essential hypertension.