Quantitative myocardial contrast echocardiography: a new method for the non-invasive detection of chronic heart transplant rejection

Chronic heart transplant rejection, i.e. cardiac allograft vasculopathy (CAV) is a major adverse prognostic factor after heart transplantation (HTx). This study tested the hypothesis that the relative myocardial blood volume (rBV) as quantified by myocardial contrast echocardiography accurately detects severe CAV as defined by coronary intravascular ultrasound (IVUS).

Effect of pressure-controlled intermittent coronary sinus occlusion (PICSO) on myocardial ischaemia and reperfusion in a closed-chest porcine model

AIMS To investigate a pressure-controlled intermittent coronary sinus occlusion (PICSO) system in an ischaemia/reperfusion model. METHODS AND RESULTS We randomly assigned 18 pigs subjected to 60 minutes ischaemia by left anterior descending (LAD) coronary artery balloon occlusion to PICSO (n=12, groups A and B) or to controls (n=6, group C). PICSO started 10 minutes before (group A), or 10 minutes after (group B) reperfusion and was maintained for 180 minutes. A continuous drop of distal LAD pressure was observed in group C. At 180 minutes of reperfusion, LAD diastolic pressure was significantly lower in group C compared to groups A and B (p=0.02). LAD mean pressure was significantly less than the systemic arterial mean pressure in group C (p=0.02), and the diastolic flow slope was flat, compared to groups A and B (p=0.03). IgG and IgM antibody deposition was significantly higher in ischaemic compared to non-ischaemic tissue in group C (p<0.05). Significantly more haemorrhagic lesions were seen in the ischaemic myocardium of group C, compared to groups A and B (p=0.002). The necrotic area differed non-significantly among groups. CONCLUSIONS PICSO was safe and effective in improving coronary perfusion pressure and reducing antibody deposition consistent with reduced microvascular obstruction and ischaemia/reperfusion injury.

Computational and experimental methodology for site-matched investigations of the influence of mineral mass fraction and collagen orientation on the axial indentation modulus of lamellar bone

Relationships between mineralization, collagen orientation and indentation modulus were investigated in bone structural units from the mid-shaft of human femora using a site-matched design. Mineral mass fraction, collagen fibril angle and indentation moduli were measured in registered anatomical sites using backscattered electron imaging, polarized light microscopy and nano-indentation, respectively. Theoretical indentation moduli were calculated with a homogenization model from the quantified mineral densities and mean collagen fibril orientations. The average indentation moduli predicted based on local mineralization and collagen fibers arrangement were not significantly different from the average measured experimentally with nanoindentation (p=0.9). Surprisingly, no substantial correlation of the measured indentation moduli with tissue mineralization and/or collagen fiber arrangement was found. Nano-porosity, micro-damage, collagen cross-links, non-collagenous proteins or other parameters affect the indentation measurements. Additional testing/simulation methods need to be considered to properly understand the variability of indentation moduli, beyond the mineralization and collagen arrangement in bone structural units.

Edema is a sign of early acute myocardial infarction on post-mortem magnetic resonance imaging

The aim of this study was to investigate if acute myocardial infarction can be detected by post-mortem cardiac magnetic resonance (PMMR) at an earlier stage than by traditional autopsy, i.e., within less than 4 h after onset of ischemia; and if so, to determine the characteristics of PMMR findings in early acute infarcts. Twenty-one ex vivo porcine hearts with acute myocardial infarction underwent T2-weighted cardiac PMMR imaging within 3 h of onset of iatrogenic ischemia. PMMR imaging findings were compared to macroscopic findings. Myocardial edema induced by ischemia and reperfusion was visible on PMMR in all cases. Typical findings of early acute ischemic injury on PMMR consist of a central zone of intermediate signal intensity bordered by a rim of increased signal intensity. Myocardial edema can be detected on cardiac PMMR within the first 3 h after the onset of ischemia in porcine hearts. The size of myocardial edema reflects the area of ischemic injury in early acute (per-acute) myocardial infarction. This study provides evidence that cardiac PMMR is able to detect acute myocardial infarcts at an earlier stage than traditional autopsy and routine histology.

Non-acute myocardial infarction-related causes of elevated high-sensitive troponin T in the emergency room: a cross-sectional analysis

To systematically investigate putative causes of non-coronary high-sensitive troponin elevations in patients presenting to a tertiary care emergency department. In this cross-sectional analysis, patients who received serial measurements of high-sensitive troponin T between 1 August 2010 and 31 October 2012 at the Department of Emergency Medicine were included. The following putative causes were considered to be associated with non-acute coronary syndrome-related increases in high-sensitive troponin T: acute pulmonary embolism, renal insufficiency, aortic dissection, heart failure, peri-/myocarditis, strenuous exercise, rhabdomyolysis, cardiotoxic chemotherapy, high-frequency ablation therapy, defibrillator shocks, cardiac infiltrative disorders (e.g., amyloidosis), chest trauma, sepsis, shock, exacerbation of chronic obstructive pulmonary disease, and diabetic ketoacidosis. During the study period a total of 1,573 patients received serial measurements of high-sensitive troponin T. Of these, 175 patients were found to have acute coronary syndrome leaving 1,398 patients for inclusion in the study. In 222 (30 %) of patients, no putative cause described in the literature could be attributed to the elevation in high-sensitive troponin T observed. The most commonly encountered mechanism underlying the troponin T elevation was renal insufficiency that was present in 286 patients (57 %), followed by cerebral ischemia in 95 patients (19 %), trauma in 75 patients (15 %) and heart failure in 41 patients (8 %). Non-acute coronary syndrome-associated elevation of high-sensitive troponin T levels is commonly observed in the emergency department. Renal insufficiency and acute cerebral events are the most common conditions associated with high-sensitive troponin T elevation.

Myocardial Infarction - Stress PRevention INTervention (MI-SPRINT) to reduce the incidence of posttraumatic stress after acute myocardial infarction through trauma-focused psychological counseling: study protocol for a randomized controlled trial

BACKGROUND Posttraumatic Stress Disorder (PTSD) may occur in patients after exposure to a life-threatening illness. About one out of six patients develop clinically relevant levels of PTSD symptoms after acute myocardial infarction (MI). Symptoms of PTSD are associated with impaired quality of life and increase the risk of recurrent cardiovascular events. The main hypothesis of the MI-SPRINT study is that trauma-focused psychological counseling is more effective than non-trauma focused counseling in preventing posttraumatic stress after acute MI. METHODS/DESIGN The study is a single-center, randomized controlled psychological trial with two active intervention arms. The sample consists of 426 patients aged 18 years or older who are at 'high risk' to develop clinically relevant posttraumatic stress symptoms. 'High risk' patients are identified with three single-item questions with a numeric rating scale (0 to 10) asking about 'pain during MI', 'fear of dying until admission' and/or 'worrying and feeling helpless when being told about having MI'. Exclusion criteria are emergency heart surgery, severe comorbidities, current severe depression, disorientation, cognitive impairment and suicidal ideation. Patients will be randomly allocated to a single 45-minute counseling session targeting either specific MI-triggered traumatic reactions (that is, the verum intervention) or the general role of psychosocial stress in coronary heart disease (that is, the control intervention). The session will take place in the coronary care unit within 48 hours, by the bedside, after patients have reached stable circulatory conditions. Each patient will additionally receive an illustrated information booklet as study material. Sociodemographic factors, psychosocial and medical data, and cardiometabolic risk factors will be assessed during hospitalization. The primary outcome is the interviewer-rated posttraumatic stress level at three-month follow-up, which is hypothesized to be at least 20% lower in the verum group than in the control group using the t-test. Secondary outcomes are posttraumatic stress levels at 12-month follow-up, and psychosocial functioning and cardiometabolic risk factors at both follow-up assessments. DISCUSSION If the verum intervention proves to be effective, the study will be the first to show that a brief trauma-focused psychological intervention delivered within a somatic health care setting can reduce the incidence of posttraumatic stress in acute MI patients. TRIAL REGISTRATION ClinicalTrials.gov: NCT01781247.

Long-term outcomes of biodegradable versus durable polymer drug-eluting stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of individual patient data from three randomised trials

Aims: Arterial plaque rupture and thrombus characterise ST-elevation myocardial infarction (STEMI) and may aggravate delayed arterial healing following durable polymer drug-eluting stent (DP-DES) implantation. Biodegradable polymer (BP) may improve biocompatibility. We compared long-term outcomes in STEMI patients receiving BP-DES vs. durable polymer sirolimus-eluting stents (DP-SES). Methods and results: We pooled individual patient-level data from three randomised clinical trials (ISAR-TEST-3, ISAR-TEST-4 and LEADERS) comparing outcomes from BP-DES with DP-SES at four years. The primary endpoint (MACE) comprised cardiac death, MI, or target lesion revascularisation (TLR). Secondary endpoints were TLR, cardiac death or MI, and definite or probable stent thrombosis. Of 497 patients with STEMI, 291 received BP-DES and 206 DP-SES. At four years, MACE was significantly reduced following treatment with BP-DES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced TLR (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09). Conclusions: In STEMI, BP-DES demonstrated superior clinical outcomes to DP-SES at four years. Trends towards reduced cardiac death or myocardial infarction and reduced stent thrombosis require corroboration in specifically powered trials.

Paracrine or virus-mediated induction of decorin expression by endothelial cells contributes to tube formation and prevention of apoptosis in collagen lattices

Resting endothelial cells express the small proteoglycan biglycan, whereas sprouting endothelial cells also synthesize decorin, a related proteoglycan. Here we show that decorin is expressed in endothelial cells in human granulomatous tissue. For in vitro investigations, the human endothelium-derived cell line, EA.hy 926, was cultured for 6 or more days in the presence of 1% fetal calf serum on top of or within floating collagen lattices which were also populated by a small number of rat fibroblasts. Endothelial cells aligned in cord-like structures and developed cavities that were surrounded by human decorin. About 14% and 20% of endothelial cells became apoptotic after 6 and 12 days of co-culture, respectively. In the absence of fibroblasts, however, the extent of apoptosis was about 60% after 12 days, and cord-like structures were not formed nor could decorin production be induced. This was also the case when lattices populated by EA.hy 926 cells were maintained under one of the following conditions: 1) 10% fetal calf serum; 2) fibroblast-conditioned media; 3) exogenous decorin; or 4) treatment with individual growth factors known to be involved in angiogenesis. The mechanism(s) by which fibroblasts induce an angiogenic phenotype in EA.hy 926 cells is (are) not known, but a causal relationship between decorin expression and endothelial cell phenotype was suggested by transducing human decorin cDNA into EA.hy 926 cells using a replication-deficient adenovirus. When the transduced cells were cultured in collagen lattices, there was no requirement of fibroblasts for the formation of capillary-like structures and apoptosis was reduced. Thus, decorin expression seems to be of special importance for the survival of EA.hy 926 cells as well as for cord and tube formation in this angiogenesis model.

Quantitative Myocardial Contrast Echocardiography during Pharmacological Stress for Diagnosis of Coronary Artery Disease: A Systematic Review and Meta-analysis of Diagnostic Accuracy Studies

AIMS: We conducted a meta-analysis to evaluate the accuracy of quantitative stress myocardial contrast echocardiography (MCE) in coronary artery disease (CAD). METHODS AND RESULTS: Database search was performed through January 2008. We included studies evaluating accuracy of quantitative stress MCE for detection of CAD compared with coronary angiography or single-photon emission computed tomography (SPECT) and measuring reserve parameters of A, beta, and Abeta. Data from studies were verified and supplemented by the authors of each study. Using random effects meta-analysis, we estimated weighted mean difference (WMD), likelihood ratios (LRs), diagnostic odds ratios (DORs), and summary area under curve (AUC), all with 95% confidence interval (CI). Of 1443 studies, 13 including 627 patients (age range, 38-75 years) and comparing MCE with angiography (n = 10), SPECT (n = 1), or both (n = 2) were eligible. WMD (95% CI) were significantly less in CAD group than no-CAD group: 0.12 (0.06-0.18) (P < 0.001), 1.38 (1.28-1.52) (P < 0.001), and 1.47 (1.18-1.76) (P < 0.001) for A, beta, and Abeta reserves, respectively. Pooled LRs for positive test were 1.33 (1.13-1.57), 3.76 (2.43-5.80), and 3.64 (2.87-4.78) and LRs for negative test were 0.68 (0.55-0.83), 0.30 (0.24-0.38), and 0.27 (0.22-0.34) for A, beta, and Abeta reserves, respectively. Pooled DORs were 2.09 (1.42-3.07), 15.11 (7.90-28.91), and 14.73 (9.61-22.57) and AUCs were 0.637 (0.594-0.677), 0.851 (0.828-0.872), and 0.859 (0.842-0.750) for A, beta, and Abeta reserves, respectively. CONCLUSION: Evidence supports the use of quantitative MCE as a non-invasive test for detection of CAD. Standardizing MCE quantification analysis and adherence to reporting standards for diagnostic tests could enhance the quality of evidence in this field.

General anesthesia with sevoflurane decreases myocardial blood volume and hyperemic blood flow in healthy humans

BACKGROUND Preservation of myocardial perfusion during general anesthesia is likely important in patients at risk for perioperative cardiac complications. Data related to the influence of general anesthesia on the normal myocardial circulation are limited. In this study, we investigated myocardial microcirculatory responses to pharmacological vasodilation and sympathetic stimulation during general anesthesia with sevoflurane in healthy humans immediately before surgical stimulation. METHODS Six female and 7 male subjects (mean age 43 years, range 28-61) were studied at baseline while awake and during the administration of 1 minimum alveolar concentration sevoflurane. Using myocardial contrast echocardiography, myocardial blood flow (MBF) and microcirculatory variables were assessed at rest, during adenosine-induced hyperemia, and after cold pressor test-induced sympathetic stimulation. MBF was calculated from the relative myocardial blood volume multiplied by its exchange frequency (β) divided by myocardial tissue density (ρT), which was set at 1.05 g·mL(-1). RESULTS During sevoflurane anesthesia, MBF at rest was similar to baseline values (1.05 ± 0.28 vs 1.05 ± 0.32 mL·min(-1)·g(-1); P = 0.98; 95% confidence interval [CI], -0.18 to 0.18). Myocardial blood volume decreased (P = 0.0044; 95% CI, 0.01-0.04) while its exchange frequency (β) increased under sevoflurane anesthesia when compared with baseline. In contrast, hyperemic MBF was reduced during anesthesia compared with baseline (2.25 ± 0.5 vs 3.53 ± 0.7 mL·min(-1)·g(-1); P = 0.0003; 95% CI, 0.72-1.84). Sympathetic stimulation during sevoflurane anesthesia resulted in a similar MBF compared to baseline (1.53 ± 0.53 and 1.55 ± 0.49 mL·min(-1)·g(-1); P = 0.74; 95% CI, -0.47 to 0.35). CONCLUSIONS In otherwise healthy subjects who are not subjected to surgical stimulation, MBF at rest and after sympathetic stimulation is preserved during sevoflurane anesthesia despite a decrease in myocardial blood volume. However, sevoflurane anesthesia reduces hyperemic MBF, and thus MBF reserve, in these subjects.

Heart rate is a prognostic risk factor for myocardial infarction: a post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) study population

BACKGROUND Elevated resting heart rate is known to be detrimental to morbidity and mortality in cardiovascular disease, though its effect in patients with ischemic stroke is unclear. We analyzed the effect of baseline resting heart rate on myocardial infarction (MI) in patients with a recent noncardioembolic cerebral ischemic event participating in PERFORM. METHODS We compared fatal or nonfatal MI using adjusted Cox proportional hazards models for PERFORM patients with baseline heart rate <70 bpm (n=8178) or ≥70 bpm (n=10,802). In addition, heart rate was analyzed as a continuous variable. Other cerebrovascular and cardiovascular outcomes were also explored. RESULTS Heart rate ≥70 bpm was associated with increased relative risk for fatal or nonfatal MI (HR 1.32, 95% CI 1.03-1.69, P=0.029). For every 5-bpm increase in heart rate, there was an increase in relative risk for fatal and nonfatal MI (11.3%, P=0.0002). Heart rate ≥70 bpm was also associated with increased relative risk for a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (excluding hemorrhagic death) (P<0001); vascular death (P<0001); all-cause mortality (P<0001); and fatal or nonfatal stroke (P=0.04). For every 5-bpm increase in heart rate, there were increases in relative risk for fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (4.7%, P<0.0001), vascular death (11.0%, P<0.0001), all-cause mortality (8.0%, P<0.0001), and fatal and nonfatal stroke (2.4%, P=0.057). CONCLUSION Elevated heart rate ≥70 bpm places patients with a noncardioembolic cerebral ischemic event at increased risk for MI.

The MI SYNTAX score for risk stratification in patients undergoing primary percutaneous coronary intervention for treatment of acute myocardial infarction: A substudy of the COMFORTABLE AMI trial.

BACKGROUND To investigate the performance of the MI Sxscore in a multicentre randomised trial of patients undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS The MI Sxscore was prospectively determined among 1132 STEMI patients enrolled into the COMFORTABLE AMI trial, which randomised patients to treatment with bare-metal (BMS) or biolimus-eluting (BES) stents. Patient- (death, myocardial infarction, any revascularisation) and device-oriented (cardiac death, target-vessel MI, target lesion revascularisation) major adverse cardiac events (MACEs) were compared across MI Sxscore tertiles and according to stent type. The median MI SXscore was 14 (IQR: 9-21). Patients were divided into tertiles of Sxscorelow (≤10), Sxscoreintermediate (11-18) and Sxscorehigh (≥19). At 1year, patient-oriented MACE occurred in 15% of the Sxscorehigh, 9% of the Sxscoreintermediate and 5% of the Sxscorelow tertiles (p<0.001), whereas device-oriented MACE occurred in 8% of the Sxscorehigh, 6% of the Sxscoreintermediate and 4% of the Sxscorelow tertiles (p=0.03). Addition of the MI Sxscore to the TIMI risk score improved prediction of patient- (c-statistic value increase from 0.63 to 0.69) and device-oriented MACEs (c-statistic value increase from 0.65 to 0.70). Differences in the risk for device-oriented MACE between BMS and BES were evident among Sxscorehigh (13% vs. 4% HR 0.33 (0.15-0.74), p=0.007 rather than those in Sxscorelow: 4% vs. 3% HR 0.68 (0.24-1.97), p=0.48) tertiles. CONCLUSIONS The MI Sxscore allows risk stratification of patient- and device-oriented MACEs among patients undergoing PPCI. The addition of the MI Sxscore to the TIMI risk score is of incremental prognostic value among patients undergoing PPCI for treatment of STEMI.

Biolimus-Eluting Stents With Biodegradable Polymer Versus Bare-Metal Stents in Acute Myocardial Infarction: Two-Year Clinical Results of the COMFORTABLE AMI Trial

BACKGROUND This study sought to determine whether the 1-year differences in major adverse cardiac event between a stent eluting biolimus from a biodegradable polymer and bare-metal stents (BMSs) in the COMFORTABLE trial (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) were sustained during long-term follow-up. METHODS AND RESULTS A total of 1061 patients were randomly assigned to biolimus-eluting stent (BES) and BMS at 11 centers, and follow-up rates at 2 years were 96.3%. A subgroup of 103 patients underwent angiography at 13 months. At 2 years, differences in the primary end point of cardiac death, target-vessel myocardial infarction, and target lesion revascularization continued to diverge in favor of BES-treated patients (5.8%) compared with BMS-treated patients (11.9%; hazard ratio=0.48; 95% confidence interval, 0.31-0.72; P<0.001) with a significant risk reduction during the second year of follow-up (hazard ratio 1-2 years=0.45; 95% confidence interval, 0.20-1.00; P=0.049). Differences in the primary end point were driven by a reduction in target lesion revascularization (3.1% versus 8.2%; P<0.001) and target-vessel reinfarction (1.3% versus 3.4%; P=0.023). The composite of death, any reinfarction and revascularization (14.5% versus 19.3%; P=0.03), and cardiac death or target-vessel myocardial infarction (4.2% versus 7.2%; P=0.036) were less frequent among BES-treated patients compared with BMS-treated patients. The 13-month angiographic in-stent percent diameter stenosis amounted to 12.0±7.2 in BES- and 39.6±25.2 in BMS-treated lesions (P<0.001). CONCLUSIONS Among patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, BES continued to improve cardiovascular events compared with BMS beyond 1 year.

New insights into the pathobiology of Down syndrome--hyaluronan synthase-2 overexpression is regulated by collagen VI α2 chain.

Down syndrome (DS) is a common birth defect characterized by the trisomy of chromosome 21. DS-affected umbilical cords (UCs) of fetuses show altered architecture of the extracellular matrix. Overexpression of the chromosome 21 genes encoding the collagen type VI (COLVI) chains α1(VI) and α2(VI), COL6A1 and COL6A2, respectively, has also reported to occur in the nuchal skin of DS fetuses. The aim of this study was therefore to evaluate the COLVI content in euploid and DS-affected UCs and human skin fibroblasts, and to investigate the relationships between COLVI and hyaluronan (HA) and HA synthase-2 (HAS2). We found that the UCs of DS fetuses showed denser staining of COLVI and increased COL6A2 expression at both early and term gestational ages. In vitro expression studies in DS-derived fibroblasts showed similarly increased amounts of α1(VI) and α2(VI) chains at the protein and transcriptional level, supporting the hypothesis of the gene dosage effect. Furthermore, increased levels of HA and HAS2 were also found in DS-derived skin fibroblast cultures. Notably, silencing of COL6A2 in DS-derived cells resulted in downregulation of HAS2, with a simultaneous decrease in secreted HA. Exogenous addition of COLVI to normal fibroblasts did not have any effect on HAS2 expression. In conclusion, UCs and skin fibroblasts in DS show significant increases in COLVI and HA; the overexpression of COL6A2 in DS tissue and cells is closely related to the increased expression of HAS2. These data may explain the DS phenotypes and their effects in organ tissue maturation.