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.

Lack of Impact of Presence of Positive C4d Staining in Capillaries in Myocardial Biopsies on Long-term Survival of Heart Transplant Patients.

BACKGROUND: The long-term survival of 209 consecutive patients (mean age, 46 ± 15 years) from a single center with ≥1 diagnostic myocardial biopsy after heart transplantation was analyzed. METHODS: Patients were considered as C4d positive if a capillary staining (immunohistochemistry in paraffin samples) was observed in ≥1 myocardial biopsy. Data were analyzed according to pathologic consensus of antibody mediated rejection definition of C4d+ positivity: 2004 definition in group A and the 2013 definition in group B and compared with their respective controls, composed of patients who do not meet those criteria. Age, follow-up time, and number of biopsies were comparable between patients with C4d+ and controls in both groups. Follow-up was 100% complete with mean of observation time 2143 days. RESULTS: During the follow-up period, 62 patients died (group A: C4d+ 32% vs controls 29%; group B: C4d+ 36% vs controls 29% [P = NS]). There were no differences in survival between patients with positive staining and without C4d+ staining when Kaplan-Meier survival curves were compared. CONCLUSIONS: The presence of C4d positive staining in myocardial capillaries of heart biopsies of patients after heart transplantation, as an isolated finding, was not related to worse long-term survival.

Traumatic tricuspid valve insufficiency: case report.

A 30-year old man underwent a head-on motor accident and was admitted to hospital, where he was successfully treated for several injuries. He was discharged home with slight tricuspid regurgitation, without signs of hemodynamic decompensation, and required no further treatment. Five years later he was admitted to the National Institute of Cardiology due to overt right ventricular failure secondary to tricuspid valve regurgitation. After several unsuccessful attempts at papillary muscle and chordal repair, a 33-mm SJM Biocor valve was implanted. This case history underlines the value of echocardiography, even after blunt chest trauma without cardiac symptoms. A good functional result can be achieved years after onset of traumatic valve insufficiency, but early diagnosis and surgical treatment increases the feasibility of tricuspid valve repair rather than replacement, and also prevents progressive deterioration of right ventricular function.

Clinical characteristics of patients with resistant hypertension: the RESIST-POL study.

Recent studies indicate that resistant hypertension (RHTN) is present in about 12% of the treated hypertensive population. However, patients with true RHTN (confirmed out of the office) have not been widely studied. We prospectively studied 204 patients (123 male, 81 female, mean age 48.4 years, range 19-65 years) with truly RHTN (ambulatory daytime mean blood pressure >135/85 mm Hg). We evaluated the frequency of obstructive sleep apnea (OSA), renal artery stenosis (RAS), primary aldosteronism (PA) and other secondary forms of hypertension (HTN) and conditions. Mild, moderate and severe OSA were present in 55 (27.0%), 38 (18.6%) and 54 (26.5%) patients, respectively. Secondary forms of HTN were diagnosed in 49 patients (24.0%), the most frequent being PA (15.7%) and RAS (5.4%). Metabolic syndrome (MS) was present in 65.7% of patients. Excessive sodium excretion was evident in 33.3% of patients and depression in 36.8% patients. In patients with RHTN, OSA and MS were the most frequent conditions, frequently overlapping with each other and also with PA. Our data indicate that in the vast majority of patients with truly RHTN, at least one of three co-morbidities-OSA, MS and PA-is present. Other conditions, even though less frequent, should also be taken into the consideration.

Pheochromocytoma-related 'classic' takotsubo cardiomyopathy.

We report a case of a 53-year-old hypertensive male with takotsubo cardiomyopathy in the setting of pheochromocytoma. Pheochromocytoma presenting as takotsubo cardiomyopathy is a recognized but uncommon occurrence with recently increasing number of published cases. We present typical apical ballooning syndrome, with transient left ventricular apical ballooning in contrast to several reports, in which patients with pheochromocytoma-induced cardiomyopathy had so called 'inverted'takotsubo cardiomyopathy. In patients being diagnosed with acute coronary syndrome symptoms without coronary artery stenosis or spasm, and pronounced blood pressure variability, pheochromocytoma-induced takotsubo or 'inverted' takotsubo cardiomyopathy should be kept in mind.

[Assessment of myocardial function at infarct zone after PTCA infarct-related artery--a study with tissue Doppler echocardiography]. / Ocena wplywu PTCA tetnicy odpowiedzialnej za zawal na funkcje miesnia sercowego w strefie zawalu metoda tkankowej echokardiografii dopplerowskiej (TDE).

UNLABELLED: Angioplasty of an infarct-related artery (IRA) performed several weeks or months after myocardial infarction (MI) may improve myocardial function. It is still unclear though, how soon wall function is restored following the procedure. This study was designed to assess quantitatively changes of regional left ventricular function after PTCA of IRA by means of tissue Doppler echocardiography (TDE). Thirty nine patients (30 male, mean age 53.4 +/- 8.4 yrs) who had MI 13 +/- 6 weeks earlier were qualified for IRA angioplasty on the basis of dobutamine stress echocardiography (DSE) if a viable myocardium was demonstrated. Regional wall function at infarct zone was assessed by TDE one day before PTCA (exam 1), 1-3 days (exam 2) and 28-30 days (exam 3) after successful angioplasty. Myocardial velocities and time--derived TDE intervals were calculated both in systole (systolic peak velocity--S, pre-ejection period--PEP, contraction time--CT), and diastole (E and A velocity waves, E/A ratio, isovolumic relaxation time--IVRT, rapid filling time--RFT, atrial filling time--AFT). All parameters were measured in longitudinal direction (annulus, basal and medial segments) of posterior (20 pts), anterior (17 pts) and lateral (2 pts) walls. S wave velocity increased between exam 1 and 2 (4.9 +/- 1.2 cm/s vs 5.6 +/- 1.3 cm/s, p < 0.02), whereas E wave decreased between examinations. Pre-PTCA E/A ratio was significantly lower than in exam 2 and 3. PEP decreased between exam 1 and 2 (96 +/- 23 ms vs 84 +/- 16 ms, p < 0.01). Significant correlation was found in IVRT and RFT prior and immediately after PTCA (103 +/- 21 ms vs 87 +/- 20 ms, p < 0.001, 151 +/- 39 ms, vs 170 +/- 30 ms p < 0.01 respectively). CONCLUSIONS: Patients after infarction with persisted viable myocardium may benefit from late angioplasty of IRA. In regional wall function assessment TDE seems to be more sensitive technique than visual wall motion analysis alone. TDE parameters demonstrated a rapid initial improvement. Changes of myocardial velocities (S, E) and time--derived TDE intervals (IVRT, PEP, RFT) are sensitive markers of restored myocardial function.

[Usefulness of dobutamine stress echocardiography in qualification of patients to angioplasty of infarct related artery]. / Przydatnosc echokardiograficznego testu dobutaminowego w kwalifikacji chorych do zabiegu udroznienia tetnicy odpowiedzialnej za zawal.

UNLABELLED: Late angioplasty of an infarct-related artery (IRA) performed weeks or months after myocardial infarction (MI) may restore blood flow in IRA and would result in improvement of regional wall motion. This study was designed to assess dobutamine stress echocardiography (DSE) in predicting the improvement of regional left ventricular (LV) function in patients after late PTCA of IRA. MATERIAL AND METHODS: 44 patients (36 M 8 F, mean age 54 +/- 7 year) who had a MI 15 +/- +/- 8 weeks earlier, were qualified to angioplasty of IRA when DSE showed the change in wall motion at the infarct zone--improved during low dose infusion (5-10 micrograms/kg/min) and/or worsened during a high dose dobutamine (up to 40 micrograms/kg/min). Regional wall motion was assessed by DSE performed at 2-7 days and 6-month after successful angioplasty. Wall motion score index (WMSI) decreased from 1.51 +/- 0.29 at rest to 1.31 +/- 0.28 at low-dose dobutamine infusion (p > 0.001) before angioplasty. Early after PTCA regional wall motion improves and baseline, exercise and rest values of WMSI decreased, compared with values before angioplasty. At baseline echocardiography 248 of segments were dyssynergic (112 hypokinetic, 125 akinetic and 10 dyskinetic). Viability during DSE was more frequent in segments with biphasic reaction during DSE than in segments showed monophasic reaction. In 34 patients control angiography (CA) was performed 6 month after successful PTCA. In this selected group CA showed significant restenosis of IRA in 12 pts (35% =, 9 of them showed positive DSE. Their base WMSI increased from 1.36 +/- 0.28 to 1.47 +/- 0.30 and peak stress WMSI from 1.32 +/- 0.29 to 1.60 +/- 0.30 (p < 0.001), respectively, between the exam just after PTCA comparing with the exam which detected restenosis. CONCLUSIONS: In some patients with infarction and a narrowed or occluded IRA the myocardium remains viable for a prolonged period. Improvement of wall motion during low-dose DSE and/or worsened during high dose DSE at infarct zone is a very useful tool in predicting of viable myocardium at infarct zone. DSE is an excellent method to demonstrate an immediate improvement in regional LV dysfunction after angioplasty of IRA. At 6 months' follow-up restenosis of IRA is often seen.

Sub-Optimal Management of Type 2 Diabetes Mellitus - A Local Audit

Background: Despite increased awareness of risk factors for coronary artery disease and randomized trial data supporting comprehensive diabetic care; these risk factors continue to be largely ignored in patients with type 2 diabetes mellitus. Objective: Cross-sectional study to determine the level of control in patients with type 2 diabetes in tertiary diabetes clinics. Methods: Patient demographic; diabetes and cardiovascular disease related (CVD) data was collected from 150 (F:M; 98:52) randomly selected patients with type 2 diabetes mellitus attending the diabetes clinics at the three academic teaching hospitals served by the University of the Witwatersrand. Blood pressure; height; weight; body mass index and waist circumference were measured. Glycated haemoglobin and fasting serum lipid levels were obtained from patient records. Black patients contributed 68; White 12; 7; Indian 10; 7and Coloured 8; 7. Results: Mean HbA1c for the whole cohort was 8; 7. Obesity was present in 37; 3; hypercholesterolaemia in 29; 3and hypertriglyceridaemia in 45; 3. Waist circumference was = 80 cm in 98of the females and = 94 cm in 69of the males. 127 patients out of 150 (85) were hypertensive and 74of these had a systolic blood pressure = 130 mmHg and 84a diastolic blood pressure = 80 mmHg. 43of the patients did minimal exercise; 6smoked and only 51were on aspirin. Conclusion: Comprehensive diabetic care is still largely lacking despite clinical trial data documenting improved outcomes associated not only with glycaemic control but also with use of antihypertensive; lipid lowering and anti-platelet therapy