Markus Vosseler

Area at Risk and Viability after Myocardial Ischemia and Reperfusion Can Be Determined by Contrast-Enhanced Cardiac Magnetic Resonance Imaging

Background/Aims: Clinical differentiation between infarcted and viable myocardium in the ischemic area at risk is controversial. We investigated the potential of contrast-enhanced cardiac magnetic resonance imaging (ceCMRI) in determining the area at risk 24 h after ischemia. Methods: Myocardial ischemia was induced by percutaneous coronary intervention of the left anterior descending coronary artery in pigs. Coronary occlusion time was 30 min in group A, which caused little myocardial infarction and 45 min in group B, which led to irreversible damage. 24 h after reperfusion ceCMRI was performed at 2 and 15 min after administration of gadolinium-diethylenetriamine pentaacetic acid. The area at risk was determined by intravenous injection of Evans blue and myocardial viability by triphenyltetrazolium-chloride staining. Results: The signal-intense areas at 2 and 15 min after contrast administration matched the area at risk in groups A and B. Nonviable myocardium in group A was overestimated (14–15%) while good agreement was present in group B. Conclusion: The area at risk of reperfused ischemic myocardium can be determined by ceCMRI 24 h after coronary recanalization. This type of information might have relevant clinical implications in the treatment and stratification of patients with acute coronary syndrome in particular after surgical interventions.

Resistance of the Internal Mammary Artery to Restenosis : A Histomorphologic Study of Various Porcine Arteries

Background/Aims: Restenosis after percutaneous transluminal angioplasty (PTA) of the internal mammary artery (IMA) grafts is much less pronounced than in other arteries and venous grafts. The aim of the study was to test whether various arteries respond differently to dilatation. Methods: PTA of the IMA, carotid, renal and circumflex coronary (RCx) arteries was performed in 9 pigs (balloon to artery ratio of 1:1.5). After 8 weeks, angiography was repeated and vessels prepared for histological analysis. Immunohistochemical staining was done to examine proliferative activity (Ki67) and to identify the vasa vasorum of the adventitia (F VIII-RA). Results: The intima-media ratio after PTA was lowest in the IMA (0.06), followed by the carotid (0.27) and renal arteries (0.49) and the RCx (0.69). Proliferation of the intima was seen at 287° of the vessel circumference in the RCx, at 286° in the renal and at 166° in the carotid artery. No proliferative activity was seen in the IMA. The intima-adventitia ratio was lower in the IMA than in the RCx and renal arteries (p < 0.05). Conclusion: Intima proliferation after PTA varies between the different vessels, with best results seen in the IMA. There are differences in remodeling after PTA between muscular, muscular/elastic and elastic arteries.

Parameters of blood viscosity do not correlate with the extent of coronary and carotid atherosclerosis and with endothelial function in patients undergoing coronary angiography

While the role of physical forces on the control of atherogenesis and the modulation of endothelial function is well known, studies investigating the impact of shear stress on the extent of central atherosclerosis and flow-mediated dilation in humans produced controversial results. We investigated the relationship between viscosity, coronary atherosclerosis, carotid intima-media thickness and flow-mediated dilation in patients undergoing coronary angiography. 451 patients (306 males, mean age 66 ± 10) were enrolled. Viscosity, which was calculated using a validated formula, showed a positive association with platelet activation (P = 0.01), leukocyte counts (P = 0.006) and C-reactive protein (P = 0.03), a marker of inflammation; surprisingly, visocsity showed a negative association with FMD (FMD decreased 0.14 ± 0.05% per each cPoise increase in viscosity) but only in patients without coronary artery disease. Viscosity showed no association with the extent of coronary or carotid artery disease. We provide cross-sectional data on the relationship between whole blood viscosity and parameters of vascular structure and function. While viscosity correlated with parameters of vascular inflammation, it showed no relationship with the presence and severity of central atherosclerosis.

Critical single proximal left arterial descending coronary artery stenosis to mimic chronic myocardial ischemia: a new model induced by minimal invasive technology.

Background/Aims: The present report examines a new pig model for progressive induction of high-grade stenosis, for the study of chronic myocardial ischemia and the dynamics of collateral vessel growth. Methods: Thirty-nine Landrace pigs were instrumented with a novel experimental stent (GVD stent) in the left anterior descending coronary artery. Eight animals underwent transthoracic echocardiography at rest and under low-dose dobutamine. Seven animals were examined by nuclear PET and SPECT analysis. Epi-, mid- and endocardial fibrosis and the numbers of arterial vessels were examined by histology. Results: Functional analysis showed a significant decrease in global left ventricular ejection fraction (24.5 ± 1.6%) 3 weeks after implantation. There was a trend to increased left ventricular ejection fraction after low-dose dobutamine stress (36.0 ± 6.6%) and a significant improvement of the impaired regional anterior wall motion. PET and SPECT imaging documented chronic hibernation. Myocardial fibrosis increased significantly in the ischemic area with a gradient from epi- to endocardial. The number of arterial vessels in the ischemic area increased and coronary angiography showed abundant collateral vessels of Rentrop class 1. Conclusion: The presented experimental model mimics the clinical situation of chronic myocardial ischemia secondary to 1-vessel coronary disease.

Low IL-10/TNFα ratio in patients with coronary artery disease and reduced left ventricular ejection fraction with a poor prognosis after 10 years.

Monocytes and dendritic cells (DC) produce tumour necrosis factor (TNF)α during inflammatory processes, but secrete interleukin (IL)-10 simultaneously in order to balance the pro-inflammation. In the present study, we investigated the expression of TNFα and IL-10 by monocytes and DC in patients with a poor cardiovascular prognosis after 10 years. Peripheral blood monocytes were isolated from 30 patients with coronary artery disease (CAD) with stable angina pectoris (SAP), or with an acute coronary syndrome (ACS). Monocytes were differentiated over 7 days to DC. Intracellular accumulation of TNFα and IL-10 in monocytes and DC was analysed by flow cytometry and correlated with the heart function, total and cardiovascular (CV) mortality, as well as with cardiovascular event rate over 10 years. We observed a decreased left ventricular function (LV-EF) for both SAP and ACS patients (p < 0.01), as well as a reduced IL-10/TNFα ratio for monocytes (p = 0.01) and DC (p < 0.01) for both patient groups in comparison to age-matched control group. Only the IL-10/TNFα ratio for monocytes correlated with LV-EF (r = 0.4302; p < 0.01). Patients with a low LV-EF as well as patients with a low IL-10/TNFα ratio showed an increased cardiovascular mortality over 10 years (both p < 0.05). The IL-10/TNFα ratio is decreased in patients with low ejection fraction and poor prognosis. The reduced heart function correlates with an increased proinflammatory state (low monocytic IL-10/TNFα ratio) in patients with CAD. This observed imbalance of IL-10 and TNFα in monocytes might explain pathophysiological processes in atherosclerosis and heart failure.

Gene therapy with iNOS enhances regional contractility and reduces delayed contrast enhancement in a model of postischemic congestive heart failure.

AIMS The purpose of this study was to evaluate the effect of transient local myocardial gene transfer of iNOS on cardiac function in a large mammal animal model of heart failure induced by chronic ischemia. METHODS Chronic myocardial ischemia was induced using a minimally invasive model in 16 landrace pigs. Upon demonstration of heart failure, eight animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection; eight animals received a sham procedure to serve as control. RESULTS The transmurality of late enhancement (control: 46.4%, iNOS: 35.9%; p < 0.05) was significantly decreased in the ischemic area in the iNOS-treated group. Wall thickness at end-systole (6.8 mm vs. 5.9 mm, p < 0.001) and at end-diastole (5.4 mm vs. 4.2 mm, p < 0.001) were significantly higher in the therapy group. Additionally, the regional wall motion at the level of the ischemic region was 3.5 mm in the therapy group while it was significantly less (3.0 mm, p < 0.001) in the control group. CONCLUSIONS Our findings demonstrate that transient iNOS overexpression potentially leads to a significant decrease of regional late enhancement with a positive effect on regional cardiac function in the ischemic area in a large animal model of postischemic heart failure.

Local transient myocardial liposomal gene transfer of inducible nitric oxide synthase does not aggravate myocardial function and fibrosis and leads to moderate neovascularization in chronic myocardial ischemia in pigs.

Microcirculation (2010) 17, 69–78. doi: 10.1111/j.1549‐8719.2010.00002.x

Serial assessments of microvascular obstruction by contrast-enhanced magnetic resonance predict contractile recovery and clinical outcome after reperfused acute myocardial infarction

AIMS The purpose of the study was to investigate, using cardiac magnetic resonance (CMR), the presence and time course of microvascular obstruction (MO) in patients with acute myocardial infarction (AMI), and to test its relationship with cardiac remodeling and clinical outcomes. METHODS AND RESULTS 53 patients with AMI and successful percutaneous reperfusion underwent CMR examination at four separate timepoints: within the first 48 hours, at 10 days, at six and twelve months after infarction. MO was quantified immediately (early imaging) and 10 minutes (late imaging) after contrast administration in each session. The extent of MO decreased from early to late imaging at both the first and the second CMR exam (p≤0.001). Early MO was absent in 18(36%) patients both at 48 hours and 10 days after AMI. At 1 year follow-up, LVEF in these patients improved to normal (median = 62% (53-70)). Early MO was present in the first but not in the second CMR in 13 (26%) patients; LVEF at one year in these patients reached a median = 52% (47-61). Finally, Early MO was present in both exams in 19 (38%) patients, who at 1 year after infarction had a LVEF of median = 49% (42-54, P≤0.001 across groups). The time course of MO was a predictor of prognosis upon Kaplan-Meier analysis (P = 0.035). The presence of MO at 10 days after AMI was associated with a higher risk of MACE during a 5-years follow-up. CONCLUSIONS The presence of MO within 48 hours after AMI, and its time course in the following ten days, provides complementary information on both functional myocardial recovery and long-term outcome.

A 34-year-old man with cardiac arrhythmias and lymphadenopathy.

A 34-year-old Caucasian male physician was admitted in June 2008 to our emergency department with complaints of palpitations. The symptoms had appeared the day before. The patient had had an ECG recorded at a peripheral hospital, showing monomorphic ventricular extrasystole and trigeminism (Fig. 1a); markers of cardiac necrosis were negative. Episodes of mild cough, that lasted 4– 5 days, and sporadic palpitations, had been present in the last 3 weeks, although these symptoms did not limit normal life and physical activities. He had a history of mildly elevated liver enzymes, was a former smoker, and had a positive family history of cardiovascular disease. Physical examination was absolutely negative except for the presence of swollen lymph nodes in neck and inguinal region. Laboratory showed elevated markers of liver function (GPT-ALT:69U/l, GOT-AST:41U/l, gamma-GT:227U/l) and C-reactive-protein (7.8 mg/dl, reference \5 mg/dl). ECG showed negative T-waves in leads DII, DIII and aVF (Fig. 1b). Transthoracic echocardiography showed normal size and function of all heart chambers, no valvular disease, and no pericardial effusion. The patient was admitted for further workout. At cardiac magnetic resonance, after the administration of Gadolinium, a well-defined mid-myocardial and subepicardial area of contrast enhancement was detected in the inferior septum (Fig. 2a–c). The almost complete absence