In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke.
300 patients (age >49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (<70% NASCET) internal carotid artery plaques will be enrolled in the prospective multicenter study CAPIAS. Carotid plaque characteristics will be determined by high-resolution black-blood carotid MRI at baseline and 12 month follow up. Primary outcome is the prevalence of complicated AHA-LT VI plaques in cryptogenic stroke patients ipsilateral to the ischemic stroke compared to the contralateral side and to patients with defined stroke etiology. Secondary outcomes include the association of AHA-LT VI plaques with the recurrence rates of ischemic events up to 36 months, rates of new ischemic lesions on cerebral MRI (including clinically silent lesions) after 12 months and the influence of specific AHA-LT VI plaque features on the progression of atherosclerotic disease burden, on specific infarct patterns, biomarkers and aortic arch plaques.
CAPIAS will provide important insights into the role of non-stenosing carotid artery plaques in cryptogenic stroke. The results might have implications for our understanding of stroke mechanism, offer new diagnostic options and provide the basis for the planning of targeted interventional studies.
Atherosclerosis; Cryptogenic stroke; Internal carotid artery; Plaque imaging; MRI
GLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study.
GLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain.
GLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 – 6.08; p = 0.03).
Circulating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.
GLP-1; Atherosclerosis; Coronary CT angiography
Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.
Coronary artery calcifications (CAC) are markers of coronary atherosclerosis, but do not correlate well with stenosis severity. This study intended to evaluate clinical situations where a combined approach of coronary calcium scoring (CS) and nuclear stress test (SPECT-MPI) is useful for the detection of relevant CAD.
Patients with clinical indication for invasive coronary angiography (ICA) were included into our study during 08/2005-09/2008. At first all patients underwent CS procedure as part of the study protocol performed by either using a multidetector computed tomography (CT) scanner or a dual-source CT imager. CAC were automatically defined by dedicated software and the Agatston score was semi-automatically calculated. A stress-rest SPECT-MPI study was performed afterwards and scintigraphic images were evaluated quantitatively. Then all patients underwent ICA. Thereby significant CAD was defined as luminal stenosis ≥75% in quantitative coronary analysis (QCA) in ≥1 epicardial vessel. To compare data lacking Gaussian distribution an unpaired Wilcoxon-Test (Mann–Whitney) was used. Otherwise a Students t-test for unpaired samples was applied. Calculations were considered to be significant at a p-value of <0.05.
We consecutively included 351 symptomatic patients (mean age: 61.2±12.3 years; range: 18–94 years; male: n=240) with a mean Agatston score of 258.5±512.2 (range: 0–4214). ICA verified exclusion of significant CAD in 66/67 (98.5%) patients without CAC. CAC was detected in remaining 284 patients. In 132/284 patients (46.5%) with CS>0 significant CAD was confirmed by ICA, and excluded in 152/284 (53.5%) patients. Sensitivity for CAD detection by CS alone was calculated as 99.2%, specificity was 30.3%, and negative predictive value was 98.5%. An additional SPECT in patients with CS>0 increased specificity to 80.9% while reducing sensitivity to 87.9%. Diagnostic accuracy was 84.2%.
In patients without CS=0 significant CAD can be excluded with a high negative predictive value by CS alone. An additional SPECT-MPI in those patients with CS>0 leads to a high diagnostic accuracy for the detection of CAD while reducing the number of patients needing invasive diagnostic procedure.
Computed tomography coronary calcium scoring; Single photon emission computed tomography myocardial perfusion imaging; Invasive coronary angiography; Coronary artery disease
The heavy metals silver, gold, and mercury can strongly inhibit aquaporin-mediated water flow across plant cell membranes, but critical examinations of their side effects are rare. Here, the short-lived radiotracer 42K is used to demonstrate that these metals, especially silver, profoundly change potassium homeostasis in roots of intact barley (Hordeum vulgare L.) plants, by altering unidirectional K+ fluxes. Doses as low as 5 μM AgNO3 rapidly reduced K+ influx to 5% that of controls, and brought about pronounced and immediate increases in K+ efflux, while higher doses of Au3+ and Hg2+ were required to produce similar responses. Reduced influx and enhanced efflux of K+ resulted in a net loss of >40% of root tissue K+ during a 15 min application of 500 μM AgNO3, comprising the entire cytosolic potassium pool and about a third of the vacuolar pool. Silver also brought about major losses of UV-absorbing compounds, total electrolytes, and NH4+. Co-application, with silver, of the channel blockers Cs+, TEA+, or Ca2+, did not affect the enhanced efflux, ruling out the involvement of outwardly rectifying ion channels. Taken together with an examination of propidium iodide staining under confocal microscopy, the results indicate that silver ions affect K+ homeostasis by directly inhibiting K+ influx at lower concentrations, and indirectly inhibiting K+ influx and enhancing K+ efflux, via membrane destruction, at higher concentrations. Ni2+, Cd2+, and Pb2+, three heavy metals not generally known to affect aquaporins, did not enhance K+ efflux or cause propidium iodide incorporation. The study reveals strong and previously unknown effects of major aquaporin inhibitors and recommends caution in their application.
Aquaporins; barley (Hordeum vulgare L.); heavy metals; ion transport; membrane integrity
Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload despite similar average load result in different phenotypes.
Methods and Results
Afterload and preload were compared in mice with transversal aortic constriction (TAC) and aorto-caval shunt (Shunt). When compared to sham mice, six hours after surgery, systolic wall stress (afterload) was increased in TAC (+40%, P<0.05), diastolic wall stress (preload) was increased in Shunt (+277%, P<0.05) and TAC (+74%, P<0.05) and mean total wall stress was similarly increased in TAC (69%) and Shunt (67%) (TAC vs. Shunt: not significant (n.s.), each P<0.05 vs. Sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in Shunt (n.s. TAC vs. Shunt). After 24 hours and 1 week, calcium/calmodulin dependent protein kinase II (CaMKII) signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional SR release and calcium spark frequency. In Shunt, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis and cardiomyocyte apoptosis. The latter was significantly reduced in CaMKIIδ-KO TAC mice. 157 mRNAs and 13 microRNAs were differentially regulated in TAC vs. Shunt. After 8 weeks, fractional shortening was lower and mortality higher in TAC
Afterload results in maladaptive fibrotic hypertrophy with CaMKII-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function and lower mortality. This indicates that different loads result in distinct phenotype differences which may require specific pharmacological interventions.
heart failure; preload; afterload; CaM kinase II; hemodynamic; remodeling; apoptosis
Left coronary artery arising from the right sinus of Valsalva is an uncommon congenital coro-nary anomaly that seems to be associated with sudden death in young patients.
We report a case of cardiac arrest in a 59-year-old patient after sexual intercourse and Silde-nafil ingestion. A coronary arteriography and an angiographic computed tomography scan subsequently revealed a LCA origin from the right aortic sinus along with an intramural course of the left main stem. In addition a distal stenosis of the right coronary artery was detected. After successful resuscitation without neurological deficits coronary artery bypass surgery was performed.
To our knowledge, this is the first report demonstrating sudden cardiac arrest associated with Sildenafil ingestion in a patient with this type of coronary anomaly. The question arises, whether a cardiac screening is necessary before a Sildenafil therapy is initiated.
Coronary artery anomalies (CAAs) are currently undergoing profound changes in understanding potentially pathophysiological mechanisms of disease. Aim of this study was to investigate the prevalence of anomalous origin and course of coronary arteries in consecutive symptomatic patients, who underwent cardiac 64-slice multidetector-row computed tomography angiography (MDCTA).
Imaging datasets of 748 consecutive symptomatic patients referred for cardiac MDCTA were analyzed and CAAs of origin and further vessel course were grouped according to a recently suggested classification scheme by Angelini et al.
An overall of 17/748 patients (2.3%) showed CAA of origin and further vessel course. According to aforementioned classification scheme no Subgroup 1- (absent left main trunk) and Subgroup 2- (anomalous location of coronary ostium within aortic root or near proper aortic sinus of Valsalva) CAA were found. Subgroup 3 (anomalous location of coronary ostium outside normal "coronary" aortic sinuses) consisted of one patient with high anterior origin of both coronary arteries. The remaining 16 patients showed a coronary ostium at improper sinus (Subgroup 4). Latter group was subdivided into a right coronary artery arising from left anterior sinus with separate ostium (subgroup 4a; n = 7) and common ostium with left main coronary artery (subgroup 4b; n = 1). Subgroup 4c consisted of one patient with a single coronary artery arising from the right anterior sinus (RAS) without left circumflex coronary artery (LCX). In subgroup 4d, LCX arose from RAS (n = 7).
Prevalence of CAA of origin and further vessel course in a symptomatic consecutive patient population was similar to large angiographic series, although these patients do not reflect general population. However, our study supports the use of 64-slice MDCTA for the identification and definition of CAA.
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
Hymenoptera venoms contain thrombogenic substances that might be responsible for cardiovascular events independent of anaphylactic reactions.
We report a 55-year-old man who experienced an acute ST-elevation myocardial infarction after wasp sting. The patient presented without signs of anaphylaxis or shock. The coronary angiography showed an acute stent thrombosis of the right coronary artery. Percutanous coronary intervention was performed immediately and this is an example for a cardiovascular complication associated with a hymenoptera sting, since the vasoactive, inflammatory, and thrombogenic substances of hymenoptera venoms potentially cause stent thrombosis and myocardial ischemia. To the best of our knowledge this is the first report of acute stent thrombosis in a sirolimus-eluting stent following hymenoptera sting.
Stent thrombosis is a possible complication after wasp sting induced by thrombogenic substances of the hymenoptera venom.
Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined.
We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = −0.21, p = 0.0004), mixed (r = −0.20, p = 0.0007) and non-calcified plaques (r = −0.18, p = 0.003). No correlation was seen with calcified plaques (r = −0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: −0.036, 95%CI: −0.052 to −0.020, p<0.0001), mixed (estimate: −0.087, 95%CI: −0.132 to −0.042, p = 0.0001) and non-calcified plaques (estimate: −0.076, 95%CI: −0.115 to −0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: −0.021, 95% CI: −0.043 to −0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden.
Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS.
To establish an efficient prophylaxis of coronary artery disease reliable risk stratification is crucial, especially in the high risk population of patients suffering from diabetes mellitus. This prospective study determined the predictive value of coronary calcifications for future cardiovascular events in asymptomatic patients with diabetes mellitus.
We included 716 patients suffering from diabetes mellitus (430 men, 286 women, age 55.2 ± 15.2 years) in this study. On study entry all patients were asymptomatic and had no history of coronary artery disease. In addition, all patients showed no signs of coronary artery disease in ECG, stress ECG or echocardiography. Coronary calcifications were determined with the Imatron C 150 XP electron beam computed tomograph. For quantification of coronary calcifications we calculated the Agatston score. After a mean observation period of 8.1 ± 1.1 years patients were contacted and the event rate of cardiac death (CD) and myocardial infarction (MI) was determined.
During the observation period 40 patients suffered from MI, 36 patients died from acute CD. The initial Agatston score in patients that suffered from MI or died from CD (475 ± 208) was significantly higher compared to those without cardiac events (236 ± 199, p < 0.01). An Agatston score above 400 was associated with a significantly higher annualised event rate for cardiovascular events (5.6% versus 0.7%, p < 0.01). No cardiac events were observed in patients with exclusion of coronary calcifications. Compared to the Framingham risk score and the UKPDS score the Agatston score showed a significantly higher diagnostic accuracy in the prediction of MI with an area under the ROC curve of 0.77 versus 0.68, and 0.71, respectively, p < 0.01.
By determination of coronary calcifications patients at risk for future MI and CD could be identified within an asymptomatic high risk group of patients suffering from diabetes mellitus. On the other hand future events could be excluded in patients without coronary calcifications.
Comprehensive CT angiography protocols offering a simultaneous evaluation of pulmonary embolism, coronary stenoses and aortic disease are gaining attractiveness with recent CT technology. The aim of this study was to assess the diagnostic accuracy of a specific dual-source CT protocol for chest pain assessment. One hundred nine patients suffering from acute chest pain were examined on a dual-source CT scanner with ECG gating at a temporal resolution of 83 ms using a body-weight-adapted contrast material injection regimen. The images were evaluated for the cause of chest pain, and the coronary findings were correlated to invasive coronary angiography in 29 patients (27%). The files of patients with negative CT examinations were reviewed for further diagnoses. Technical limitations were insufficient contrast opacification in six and artifacts from respiration in three patients. The most frequent diagnoses were coronary stenoses, valvular and myocardial disease, pulmonary embolism, aortic aneurysm and dissection. Overall sensitivity for the identification of the cause of chest pain was 98%. Correlation to invasive coronary angiography showed 100% sensitivity and negative predictive value for coronary stenoses. Dual-source CT offers a comprehensive, robust and fast chest pain assessment.
Chest pain; CT angiography; Coronary artery disease; Pulmonary; Embolism; Aortic dissection
The multiphasic regulation of the Wnt/β-catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/β-catenin signaling, tissue- and cell-specific coactivators and repressors need to be recruited. The identification of such factors may help to elucidate mechanisms leading to enhanced cardiac differentiation efficiency in vitro as well as promote regeneration in vivo. Using a yeast-two-hybrid screen, we identified four-and-a-half-LIM-domain 2 (FHL2) as a cardiac-specific β-catenin interaction partner and activator of Wnt/β-catenin-dependent transcription. We analyzed the role of this interaction for early cardiogenesis in an in vitro model by making use of embryoid body cultures from mouse embryonic stem cells (ESCs). In this model, stable FHL2 gain-of-function promoted mesodermal cell formation and cell proliferation while arresting cardiac differentiation in an early cardiogenic mesodermal progenitor state. Mechanistically, FHL2 overexpression enhanced nuclear accumulation of β-catenin and activated Wnt/β-catenin-dependent transcription leading to sustained upregulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/β-catenin-dependent transcription, but not sustained high-level of Igfbp5 expression. This resulted in enhanced cardiogenesis. We propose that early Wnt/β-catenin-dependent transcriptional activation mediated by FHL2 is important for the transition to and expansion of early cardiogenic mesodermal cells. Collectively, our findings offer mechanistic insight into the early cardiogenic code and may be further exploited to enhance cardiac progenitor cell activity in vitro and in vivo. Stem Cells
Four and a half LIM-domain 2; β-Catenin; Igfbp5; Mouse embryonic stem cell; Cardiogenesis