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.

Renal artery aneurysms: presentation of five cases.

We are presenting clinical characteristics, management and follow-up of five consecutive patients with renal artery aneurysm. Renal artery aneurysms are relatively uncommon, they rarely give rise to clinical manifestations and they are usually found incidentally. However with the introduction of Doppler ultrasound, computed tomography (CT) and magnetic resonance (MR) imaging, the diagnosis of renal artery aneurysms became more frequent.

Moderate exercise training reduces arterial chemoreceptor reflex drive in mild hypertension.

The aim of our study was to check the responsiveness the chemoreceptor reflex in 28 young mildly hypertensive men (HTS), aged 18-32 years and 25 normotensive male subjects (NTS) aged 19-32 years, before and after 3-months dynamic exercise training. We tested the hypothesis that dynamic training reduces arterial chemoreceptor drive in mild hypertension. Circulatory response to 3-min hyperoxic inactivation of arterial chemoreceptors induced by 70% oxygen breathing was measured before and after training. Arterial blood pressure (BP) was recorded continuously by Finapres method, stroke volume and arm blood flow were registered by impedance reography, heart rate by ECG. Both groups were submitted to moderate 3-months dynamic exercise training. Before training the hyperoxic breathing caused in HTS a significant decrease in systolic BP by 6+/-1 mmHg p<0.01, in diastolic BP by 2+/-0.6 mmHg p<0.01, and in total peripheral vascular resistance (TPR) by 0.24+/-0.04 TPRU (p<0.01). After training hyperoxia augmented systolic BP by 2.64+/-1.9 mmHg (NS), diastolic BP by 2+/-1 mmHg p<0.05, and TPR by 0.043+/-0.05 TPRU (ANOVA). In NTS before training brief hyperoxia produced insignificant change in BP and TPR. In NTS after training hyperoxia increased systolic BP by 4.2 mm Hg+/-1.23 p<0.01 and diastolic BP by 3.1+/-0.6 mmHg p<0.01 respectively and TPR by 0.053+/-0.02 TPRU. Our results confirm earlier finding on the enhanced arterial chemoreceptor reflex drive in mild human hypertension. We conclude that normalizing arterial blood pressure in subjects with mild hypertension which occurred after 3-months dynamical exercise training is due to attenuation of the sympathoexcitatory chemoreceptor reflex drive by exercise training. The mechanism of this effect requires further study.

Effects of moderate physical training on blood pressure variability and hemodynamic pattern in mildly hypertensive subjects.

The objective of our study was to compare the cardiovascular effects of moderate exercise training in healthy young (NTS, n=18, 22.9+/-0.44 years) and in hypertensive human subjects (HTS, n=30, 23+/-1.1). The VO(2max) did not significantly differ between groups. HTS of systolic blood pressure (SBP) 148+/-3.6 mmHg and diastolic blood pressure(DBP) 88+/-2.2 mmHg, and NTS of SBP: 128.8 +/- 4 mmHg and DBP: 72 +/- 2.9 mmHg were submitted to moderate dynamic exercise training, at about 50% VO(2max) 3 times per week for one hour, over 3 months. VO(2max) was measured by Astrand's test. Arterial blood pressure was measured with Finapres technique, the stroke volume, cardiac output and arm blood flow were assessed by impedance reography. Variability of SBP and pulse interval values (PI) were estimated by computing the variance and power spectra according to FFT algorithm. After training period significant improvements in VO(2max) were observed in NTS- by 1.92 +/-0.76 and in HTS by 3+/-0.68 ml/kg/min). In HTS significantly decreased: SBP by 19 +/-2.9 mmHg, in DBP by 10.7+/-2 mmHg total peripheral resistance (TPR) by 0.28 +/-0.05 TPR units. The pretraining value of low frequency component power spectra SBP (LF(SPB)) was significantly greater in HTS, compared to NTS. PI variance was lower in HTS, compared to NTS. After physical training, in HTS PI variance increased suggesting a decrease in frequency modulated sympathetic activity and increase in vagal modulation of heart rate in mild hypertension. A major finding of the study is the significant decrease of resting low frequency component SBP power spectrum after training in HTS. The value of LF(SPB) in trained hypertensive subjects normalized to the resting level of LF(SPB) in NTS. Our findings suggest that antihypertensive hemodynamic effects of moderate dynamic physical training are associated with readjustment of the autonomic cardiovascular control system.

[Takayasu's arteritis: underestimated cause of hypertension]. / Choroba takayasu--niedoceniana przyczyna nadcisnienia tetniczego.

UNLABELLED: Takaysu's arteritis (TA) is regarded to be a frequent cause of hypertension in Asian population. However some reports have recently informed about increasing frequency of its also in non Asian people. The aim of this study was to evaluated own experiences on diagnosis and treatment of TA as well as prevalence of TA in hypertensive patients in Caucasian population. MATERIALS AND METHODS: During last 15 years we examined 4190 hypertensive patients hospitalized in our department. Renovascular hypertension was recognized in 139 cases. The diagnosis of TA was based on angiographically proven vascular changes and its inflammatory phase on estimation increased (> 40 mm/h) sedimentation rate and immunoglobulins above normal level. The patients with acute phase of TA initially received typical immunosuppressive therapy (prednisone in monotherapy or combined with azatioprine or cyclophosphamide), followed by chronic administration of prednisone. In every case, if it was possible, we proposed angio-corrective procedure. All patients have received hypotensive and antiplatelet therapy. RESULTS: TA was recognized in 15 patients--4 men and 11 women, average age 36.3 +/- 9.8 y. The patients with TA represented 0.37% hypertensive and 10.9% cases of renovascular hypertension. Significant stenosis of renal artery and various degree of lesions in aorta and some arteries was discovered in all persons. In the observed group hypertension was effectively controlled with 2-3 hypotensive drugs, including ACE inhibitors, diuretics and Ca antagonists. The acute phase of TA was diagnosed in 11 patients and it was treated successfully (except one case) with immunosuppressive therapy. After discontinuation of the treatment (4 patients) progression of the disease was observed. In 6 patients, characterised by clinical and biochemical remission of acute phase percutaneous angioplasty renal artery was performed. A good result in long-term follow-up period was observed in 4 cases (in 2 after repeated procedure). Surgical procedure was performed in 4 cases--in 2 on carotid and in 1 on renal and the next one on coronary artery. In first 3 cases the procedures were unsuccessful (reocclusion ?). CONCLUSIONS: Our observation suggested that 1. The incidence of TA in hypertensive (especially renovascular hypertension) population is more frequent than expected. 2. Acute phase of the disease is indication to long-term the immunosuppressive therapy. 3. Angiocorrective procedure is necessary reflected in every case in period of remission of acute phase.

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.

[Accelerated and malignant hypertension--clinical observation]. / Nadcisnienie tetnicze przyspieszone i zlosliew--obserwacja kliniczna.

There were 101 (4.6%) cases of malignant and accelerated hypertension among 2195 hypertensives patients treated in Department of Hypertension of National Institute of Cardiology between 1981 and 1990. Almost 30% of these patients were diagnosed as having secondary cause of hypertension. Comparison with control group of patients with moderate or mild hypertension revealed that malignant hypertensives had a shorter history of illness, lower level of education, higher evidence of smoking and over-consumption of alcohol. The systolic and diastolic blood pressure values were significantly higher in this group. The patients with malignant hypertension had significantly higher blood concentration of urea, creatinine and uric acid. Mild anemia was also present. Severe cardiovascular complications (myocardial infarction, stroke, encephalopathy, left ventricular failure) were observed in 44% cases of malignant hypertension. Due to efficacious hypotensive treatment blood pressure decreased significantly and biochemical indicators of renal function improved. Withdrawal of characteristic for malignant hypertension changes in fundoscopy was also observed. Results of this study indicate that prompt and aggressive treatment with normalization of blood pressure results in reversal of vascular lesions and permits recovery of cerebral and renal function.

[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)

[Malignant arterial hypertension--clinical picture, prognosis, management]. / Nadcisnienie tetnicze zlosliwe--obraz kliniczny, rokowanie, leczenie.

Malignant hypertension is the most severe form of hypertension. Untreated--quickly leads to target organs damage and death. The most important things are early diagnosis and treatment, which can improve prognosis in the group of patients with malignant hypertension. Pathogenesis of malignant hypertension is not completely established, although histopathological changes are well known. The article presents recent opinions on etiopathogenesis, clinical course and treatment of malignant hypertension.

[Comparative studies on the effects of propranolol and acebutolol on blood pressure, serum lipids and lipoproteins in patients with primary hypertension]. / Porównawcze badania nad wplywem propranololu i acebutololu na cisnienie tetnicze oraz lipidy i lipoproteiny surowicy w nadcisnieniu tetniczym pierwotnym.

A comparative studies on the effect of propranolol and acebutolol on blood pressure, cardiac function, blood serum lipids and lipoproteins were carried out in 48 patients with the primary hypertension double-blind method was applied. Tested drugs were given for 12 weeks. It was found, that both drugs are potent and comparable hypotensive agents normalizing blood pressure in the majority of treated patients. No significant difference in the effect on heart rate and adverse reactions has been noted. Acebutolol did not change lipid metabolism parameters whereas propranolol slightly but statistically significantly increased serum triglycerides.

[Ambulatory 24-hour blood pressure monitoring in patients with resistant hypertension]. / Rejestracja 24-godzinna cisnienia tetniczego krwi u chorych z tzw. Opornym nadcisnieniem tetniczym.

The aim of the study was to assess the usefulness of 24-hour blood pressure (BP) and heart rate (HR) monitoring in patients with "resistant" hypertension. 30 patients (44.1 +/- 9.9 years) with diastolic BP 100 mm Hg or more in spite of treatment with three or more antihypertensive drugs were studied. Ambulatory recording of BP and HR was performed by means of Del Mar Avionics monitoring system 9000. Mean recording time was 21.5 hours and mean number of measurements during one recording--56.7. Mean ambulatory systolic and diastolic BP values were significantly lower than mean value of three casual measurements (146.0 +/- 24.6 vs 171.5 +/- 21.2 mm Hg for systolic and 97.2 +/- 11.3 vs 110.4 +/- 7.5 mm Hg for diastolic BP p less than 0.01) In 14 (46.6%) systolic BP and in 10 patients (33.3%) diastolic BP were normal. The patients with normal and abnormal ambulatory BP recordings did not differ in regard to age and mean clinic BP levels. However, patients with abnormal ambulatory BP recordings were more often overweight and showed a greater frequency of left ventricular hypertrophy and family history of hypertension and its complications. The results of the study show that ambulatory BP monitoring may be of value in assessing the response to antihypertensive treatment in patients with so called resistant hypertension as judged on the basis of clinic pressure.

[Twenty-four hour automatic recording of blood pressure and cardiac rhythm in patients with borderline hypertension]. / Calodobowa automatyczna rejestracja cisnienia tetniczego krwi i rytmu serca u chorych z granicznym nadcisnieniem tetniczym.

The aim of the study was to evaluate the usefulness of 24-hour automatic recording of blood pressure and cardiac rhythm in patients with borderline hypertension. The study was performed in 50 patients aged 38.8 +/- 13.1 using the Del Mar Avionics device. Mean time of recordings was 21.3 hours, and the mean number of blood pressure measurements per one patient was 52.4. Great fluctuations of systolic blood pressure (from 92.1 +/- 12.6 to 191 +/- 37.0 mm Hg) and diastolic one (from 57.3 +/- 11.4 to 118.9 +/- 13.8 mm Hg) were observed. Mean systolic blood pressure (125.6 +/- 10.6 mm Hg) was significantly lower than the mean value of last three ambulatory measurements (141.9 +/- 9.8; p less than 0.001). Also mean diastolic pressure was lower than that obtained in the out patient clinic (84.7 +/- 9.7 vs 91.9 +/- 3.2 mm Hg; p less than 0.001). Mean heart rate during the day was 86.2 +/- 10.7 and at night 69.7 +/- 10.5 beats per minute. Ventricular and/or supraventricular cardiac arrhythmias were observed in 14 (28%) of examined patients. Results of the study indicate, that 24-hour automatic blood pressure recording is the valuable method, affording possibilities for more precise estimation of blood pressure and its 24-hour fluctuations in patients with borderline hypertension.