The angiotensin-converting enzyme insertion/deletion polymorphism and its associations with carotid artery wall thickness and coronary heart disease: The atherosclerosis risk in communities study

Coronary heart disease (CHD) is the leading cause of death in the United States. Recently, renin-angiotensin system (RAS) was found associated with atherosclerosis formation, with angiotensin II inducing vascular smooth muscle cell growth and migration, platelet activation and aggregation, and stimulation of plasminogen activator inhibitor-1. Angiotensin II is converted from angiotensin I by angiotensin I-converting enzyme (ACE) and this enzyme is mainly genetically determined. The ACE gene has been assigned to chromosome 17q23 and an insertion/deletion (I/D)polymorphism has been characterized by the presence/absence of a 287 bp fragment in intron 16 of the gene. The two alleles form three genotypes, namely, DD, ID and II and the DD genotype has been linked to higher plasma ACE levels and cell ACE activity.^ In this study, the association between the ACE I/D polymorphism and carotid artery wall thickness measured by B-mode ultrasound was investigated in a biracial sample, and the association between the gene and incident CHD was investigated in whites and if the gene-CHD association in whites, if any, was due to the gene effect on atherosclerosis. The study participants are from the prospective Atherosclerosis Risk in Communities (ARIC) Study, including adults aged 45 to 65 years. The present dissertation used a matched case-control design for studying the associations of the ACE gene with carotid artery atherosclerosis and an unmatched case-control design for the association of the gene with CHD. A significant recessive effect of the D allele on carotid artery thickness was found in blacks (OR = 3.06, 95% C.I: 1.11-8.47, DD vs. ID and II) adjusting for age, gender, cigarette smoking, LDL-cholesterol and diabetes. No similar associations were found in whites. The ACE I/D polymorphism is significantly associated with coronary heart disease in whites, and while stratifying data by carotid artery wall thickness, the significant associations were only observed in thin-walled subgroups. Assuming a recessive effect of the D allele, odds ratio was 2.84 (95% C.I:1.17-6.90, DD vs. ID and II) and it was 2.30 (95% C.I:1.22-4.35, DD vs. ID vs. II) assuming a codominant effect of the D allele. No significant associations were observed while comparing thick-walled CHD cases with thin-walled controls. Following conclusions could be drawn: (1) The ACE I/D polymorphism is unlikely to confer appreciable increase in the risk of carotid atherosclerosis in US whites, but may increases the risk of carotid atherosclerosis in blacks. (2) ACE I/D polymorphism is a genetic risk factor for incident CHD in US whites and this effect is separate from the chronic process of atherosclerosis development. Finally, the associations observed here are not causal, since the I/D polymorphism is in an intron, where no ACE proteins are encoded. ^

Imaging findings in uncorrected tetralogy of Fallot and pulmonary atresia with major aortopulmonary collateral arteries and septic embolism.

Tetralogy of Fallot (TOF) is one of the most common congenital heart malformations comprising a ventricular septal defect, right ventricular outflow tract obstruction, right ventricular hypertrophy, and overriding aorta. A rare variant includes pulmonary atresia and major aortopulmonary collateral arteries. Altered hemodynamics within the functional single-ventricle results in turbulent flow and predisposes to endocardial vegetation formation which may consequently lead to thromboembolic events. We present a rare case of an adult survivor of uncorrected TOF with pulmonary atresia.

Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study

AIM The effect of long-term high-intensity statin therapy on coronary atherosclerosis among patients with acute ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to quantify the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of STEMI patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS Between September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-IVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients were treated with high-intensity rosuvastatin (40 mg/day) throughout 13 months and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRA. The primary IVUS end-point was the change in per cent atheroma volume (PAV). After 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 3.29 to 1.89 mmol/L (P < 0.001), and high-density lipoprotein cholesterol (HDL-C) levels had increased from 1.10 to 1.20 mmol/L (P < 0.001). PAV of the non-IRA decreased by -0.9% (95% CI: -1.56 to -0.25, P = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Per cent necrotic core remained unchanged (-0.05%, 95% CI: -1.05 to 0.96%, P = 0.93) as did the number of RF-IVUS defined thin cap fibroatheromas (124 vs. 116, P = 0.15). CONCLUSION High-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-infarct-related arteries without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

Cognitive and emotional effects of carotid stenosis

PRINCIPLES Patients with carotid artery stenosis (CAS) are at risk of ipsilateral stroke and chronic compromise of cerebral blood flow. It is under debate whether the hypo-perfusion or embolism in CAS is directly related to cognitive impairment. Alternatively, CAS may be a marker for underlying risk factors, which themselves influence cognition. We aimed to determine cognitive performance level and the emotional state of patients with CAS. We hypothesised that patients with high grade stenosis, bilateral stenosis, symptomatic patients and/or those with relevant risk factors would suffer impairment of their cognitive performance and emotional state. METHODS A total of 68 patients with CAS of ≥70% were included in a prospective exploratory study design. All patients underwent structured assessment of executive functions, language, verbal and visual memory, motor speed, anxiety and depression. RESULTS Significantly more patients with CAS showed cognitive impairments (executive functions, word production, verbal and visual memory, motor speed) and anxiety than expected in a normative sample. Bilateral and symptomatic stenosis was associated with slower processing speed. Cognitive performance and anxiety level were not influenced by the side and the degree of stenosis or the presence of collaterals. Factors associated with less cognitive impairment included higher education level, female gender, ambidexterity and treated hypercholesterolemia. CONCLUSIONS Cognitive impairment and increased level of anxiety are frequent in patients with carotid stenosis. The lack of a correlation between cognitive functioning and degree of stenosis or the presence of collaterals, challenges the view that CAS per se leads to cognitive impairment.

Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients

BACKGROUND AND PURPOSE The use of thrombolysis in patients with minor neurological deficits and large vessel occlusion is controversial. METHODS We compared the outcome of patients with low National Institutes of Health Stroke Scale (NIHSS) scores and large vessel occlusions between thrombolysed and non-thrombolysed patients. RESULTS 88 (1.7%) of 5312 consecutive patients with acute (within 24 h) ischaemic stroke had occlusions of the internal carotid or the main stem of the middle cerebral artery and baseline NIHSS scores ≤5.47 (53.4%) were treated without thrombolysis, and 41 (46.6%) received intravenous thrombolysis, endovascular therapy or both. Successful recanalisation on MR or CT angiography at 24 h was more often observed in thrombolysed than in non-thrombolysed patients (78.9% versus 10.5%; p<0.001). Neurological deterioration (increase of NIHSS score ≥1 compared to baseline) was observed in 22.7% of non-thrombolysed versus 10.3% of thrombolysed after 24 h (p=0.002), in 33.3% versus 12.5% at hospital discharge (p=0.015) and in 41.4% versus 15% at 3 months (p<0.001). Symptomatic intracerebral haemorrhage occurred in two (asymptomatic in five) thrombolysed and in none (asymptomatic in three) non-thrombolysed. Thrombolysis was an independent predictor of favourable outcome (p=0.030) but not survival (p=0.606) at 3 months. CONCLUSIONS Non-thrombolysed patients with mild deficits and large vessel occlusion deteriorated significantly more often within 3 months than thrombolysed patients. Symptomatic intracerebral haemorrhages occurred in less than 5% of patients in both groups. These data suggest that thrombolysis is safe and effective in these patients. Therefore, randomised trials in patients with large vessel occlusions and mild or rapidly improving symptoms are needed.

Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion.

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point. © 2015 Wiley Periodicals, Inc.

Electrical carotid baroreceptor stimulation

The Barostim neo ™ system is a novel implantable device that activates the carotid baroreflex. It decreases the sympathetic activity and inhibits the renin system, which results in reduced blood pressure and heart rate. In patients with resistant hypertension, electrically activation of the baroreflex leads to an average decrease in systolic blood pressure of 38, 36, 40 and 53 mmHg at 1, 2, 3 and 4 years, respectively. Additionally, cardiac remodelling with reduced left ventricular mass and posterior wall thickness has been observed in long-term studies. In a limited number of patients with heart failure, baroreflex activation therapy leads to a decrease in muscle sympathetic nerve activity and to improved quality of life and functional capacities. The implantation procedure is safe and associated with risks comparable with those of other active implantable devices. Barostim neo is currently available in several European countries.

Prevalence of potential retrograde embolization pathways in the proximal descending aorta in stroke patients and controls.

BACKGROUND Retrograde diastolic blood flow in the proximal descending aorta (DAo) connecting complex plaques (≥4 mm thick) with brain-supplying supra-aortic arteries may constitute a source of stroke. Yet, data only from high-risk populations (cryptogenic stroke patients with aortic atheroma≥3 mm) regarding the prevalence of this potential stroke mechanism are available. We aimed to quantify the frequency of this mechanism in unselected patients with cryptogenic stroke after routine diagnostics and controls without a history of stroke. METHODS 88 patients (67 stroke patients, 21 cardiac controls) were prospectively included. 3D T1-weighted bright blood MRI of the aorta was applied for the detection of complex DAo atheroma. ECG-triggered and navigator-gated 4D flow MRI allowed measuring time-resolved 3D blood flow in vivo. Potential retrograde embolization pathways were defined as the co-occurrence of complex plaques and retrograde blood flow in the DAo reaching the outlet of (a) the left subclavian artery, (b) the left common carotid artery, or/and (c) the brachiocephalic trunk. The frequency of these pathways was analyzed by importing 2D plaque images into 3D blood flow visualization software. RESULTS Complex DAo plaques were more frequent in stroke patients (44 in 31/67 patients (46.3%) vs. 5 in 4/21 controls (19.1%); p=0.039), especially in older patients (29/46 (63.04%) patients≥60 years of age with 41 plaques vs. 2/21 (9.14%) patients<60 years of age with 3 plaques; p<0.001). Contrary to our assumption, retrograde diastolic blood flow at the DAo occurred in every patient irrespective of the existence of plaques with a similar extent in both groups (26±14 vs. 32±18 mm; p=0.114). Therefore, only the higher prevalence of complex DAo plaques in stroke patients resulted in a three times higher frequency of potential retrograde embolization pathways compared to controls (22/67 (32.8%) vs. 2/21 (9.5%) controls; p=0.048). CONCLUSIONS This study revealed that retrograde flow in the descending aorta is a common phenomenon not only in stroke patients. The existence of potential retrograde embolization pathways depends mainly on the occurrence of complex plaques in the area 0 to ∼30 mm behind the outlet of the left subclavian artery, which is exposed to flow reversal. In conclusion, we have shown that the frequency of potential retrograde embolization pathways was significantly higher in stroke patients suggesting that this mechanism may play a role in retrograde brain embolism.

Dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection.

BACKGROUND We prospectively investigated temporal and spatial evolution of intramural hematomas in patients with acute spontaneous internal carotid artery dissection using repeated magnetic resonance imaging over six-months. AIM The aim of the present study was to assess dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection at multiple follow-up time-points with T1w, PD/T2w, and magnetic resonance angiography. METHODS We performed serial multiparametric magnetic resonance imaging in 10 patients with spontaneous internal carotid artery dissection on admission, at days 1, 3, 7-14 and at months 1·5, 3, and 6. We calculated the volume and extension of the hyperintense intramural hematoma using T1w and PD/T2w fat suppressed sequences and assessed the degree of stenosis due to the hematoma using magnetic resonance angiography. RESULTS Mean interval from symptom onset to first magnetic resonance imaging was two-days (SD 2·7). Two patients presented with ischemic stroke, three with transient ischemic attacks, and five with pain and local symptoms only. Nine patients had a transient increase of the intramural hematoma volume, mainly up to day 10 after symptom onset. Fifty percent had a transient increase in the degree of the internal carotid artery stenosis on MRA, one resulting in a temporary occlusion. Lesions older than one-week were predominantly characterized by a shift from iso- to hyperintese signal on T2w images. At three-month follow-up, intramural hematoma was no longer detectable in 80% of patients and had completely resolved in all patients after six-months. CONCLUSIONS Spatial and temporal dynamics of intramural hematomas after spontaneous internal carotid artery dissection showed an early volume increase with concomitant progression of the internal carotid artery stenosis in 5 of 10 patients. Although spontaneous internal carotid artery dissection overall carries a good prognosis with spontaneous hematoma resorption in all our patients, early follow-up imaging may be considered, especially in case of new clinical symptoms.

Cognitive improvement in patients with carotid stenosis is independent of treatment type

Treatment of carotid artery stenosis decreases the long-term risk of stroke and may enhance cerebral blood flow. It is therefore expected to have the potential to prevent cognitive decline or even improve cognition over the long-term. However, intervention itself can cause peri-interventional cerebral infarcts, possibly resulting in a decline of cognitive performance, at least for a short time. We investigated the long-term effects of three treatment methods on cognition and the emotional state one year after intervention. In this prospective observational cohort study, 58 patients with extracranial carotid artery stenosis (≥70%) underwent magnetic resonance imaging and assessment of cognition, mood and motor speed before carotid endarterectomy (n = 20), carotid stenting (n = 10) or best medical treatment (n = 28) (i.e., time-point 1 [TP1]), and at one-year follow-up (TP2). Gain scores, reflecting cognitive change after treatment, were built according to performance as (TP2 -TP1)/TP1. Independent of the treatment type, significant improvement in frontal lobe functions, visual memory and motor speed was found. Performance level, motor speed and mood at TP1 were negatively correlated with gain scores, with greater improvement in patients with low performance before treatment. Active therapy, whether conservative or interventional, produces significant improvement of frontal lobe functions and memory in patients with carotid artery disease, independent of treatment type. This effect was particularly pronounced in patients with low cognitive performance prior to treatment.

Rapamycin impairs endothelial cell function in human internal thoracic arteries.

BACKGROUND Definitive fate of the coronary endothelium after implantation of a drug-eluting stent remains unclear, but evidence has accumulated that treatment with rapamycin-eluting stents impairs endothelial function in human coronary arteries. The aim of our study was to demonstrate this phenomenon on functional, morphological and biochemical level in human internal thoracic arteries (ITA) serving as coronary artery model. METHODS After exposure to rapamycin for 20 h, functional activity of ITA rings was investigated using the organ bath technique. Morphological analysis was performed by scanning electron microscopy and evaluated by two independent observers in blinded fashion. For measurement of endothelial nitric oxide synthase (eNOS) release, mammalian target of rapamycin (mTOR) and protein kinase B (PKB) (Akt) activation, Western blotting on human mammary epithelial cells-1 and on ITA homogenates was performed. RESULTS Comparison of the acetylcholine-induced relaxation revealed a significant concentration-dependent decrease to 66 ± 7 % and 36 ± 7 % (mean ± SEM) after 20-h incubation with 1 and 10 μM rapamycin. Electron microscopic evaluation of the endothelial layer showed no differences between controls and samples exposed to 10 μM rapamycin. Western blots after 20-h incubation with rapamycin (10 nM-1 μM) revealed a significant and concentration-dependent reduction of p (Ser 1177)-eNOS (down to 38 ± 8 %) in human mammary epithelial cells (Hmec)-1. Furthermore, 1 μM rapamycin significantly reduced activation of p (Ser2481)-mTOR (58 ± 11 %), p (Ser2481)-mTOR (23 ± 4 %) and p (Ser473)-Akt (38 ± 6 %) in ITA homogenates leaving Akt protein levels unchanged. CONCLUSIONS The present data suggests that 20-h exposure of ITA rings to rapamycin reduces endothelium-mediated relaxation through down-regulation of Akt-phosphorylation via the mTOR signalling axis within the ITA tissue without injuring the endothelial cell layer.

Investigation of hemodynamics in an in vitro system simulating left ventricular support through the right subclavian artery using 4-dimensional flow magnetic resonance imaging.

OBJECTIVES Left ventricular assist devices are an important treatment option for patients with heart failure alter the hemodynamics in the heart and great vessels. Because in vivo magnetic resonance studies of patients with ventricular assist devices are not possible, in vitro models represent an important tool to investigate flow alterations caused by these systems. By using an in vitro magnetic resonance-compatible model that mimics physiologic conditions as close as possible, this work investigated the flow characteristics using 4-dimensional flow-sensitive magnetic resonance imaging of a left ventricular assist device with outflow via the right subclavian artery as commonly used in cardiothoracic surgery in the recent past. METHODS An in vitro model was developed consisting of an aorta with its supra-aortic branches connected to a left ventricular assist device simulating the pulsatile flow of the native failing heart. A second left ventricular assist device supplied the aorta with continuous flow via the right subclavian artery. Four-dimensional flow-sensitive magnetic resonance imaging was performed for different flow rates of the left ventricular assist device simulating the native heart and the left ventricular assist device providing the continuous flow. Flow characteristics were qualitatively and quantitatively evaluated in the entire vessel system. RESULTS Flow characteristics inside the aorta and its upper branching vessels revealed that the right subclavian artery and the right carotid artery were solely supported by the continuous-flow left ventricular assist device for all flow rates. The flow rates in the brain-supplying arteries are only marginally affected by different operating conditions. The qualitative analysis revealed only minor effects on the flow characteristics, such as weakly pronounced vortex flow caused by the retrograde flow via the brachiocephalic artery. CONCLUSIONS The results indicate that, despite the massive alterations in natural hemodynamics due to the retrograde flow via the right subclavian and brachiocephalic arteries, there are no drastic consequences on the flow in the brain-feeding arteries and the flow characteristics in the ascending and descending aortas. It may be beneficial to adjust the operating condition of the left ventricular assist device to the residual function of the failing heart.