Myeloid cells in cardiovascular organs.

Myeloid cells assume a wide range of phenotypes, some of which are protective against injury and infection whilst others promote cardiovascular disease. This heterogeneity is partially caused by switching of cell sources from local tissue-resident macrophage proliferation to recruitment of circulating cells, and partially due to macrophages' phenotypic plasticity. While long-lived tissue-resident macrophages support development, tissue homoeostasis and cardiac conduction, monocyte-derived cells may promote destruction of the arterial wall and the myocardium, leading to organ ischaemia and heart failure. Influencing myeloid cell flux and phenotype shifts emerges as a therapeutic opportunity in many disease areas, including atherosclerosis, acute myocardial infarction, heart failure and stroke. However, it is currently unclear which cell subsets and drug targets are the most efficient and safest options. Here I review the neutrophil and macrophage supply chain and the cells' emerging heterogeneity in the setting of atherosclerosis and ischaemic heart disease.

Detecting the vulnerable plaque in patients.

Atherosclerosis is a systemic condition that eventually evolves into vulnerable plaques and cardiovascular events. Pathology studies reveal that rupture-prone atherosclerotic plaques have a distinct morphology, namely a thin, inflamed fibrous cap covering a large lipidic and necrotic core. With the fast development of imaging techniques in the last decades, detecting vulnerable plaques thereby identifying individuals at high risk for cardiovascular events has become of major interest. Yet, in current clinical practice, there is no routine use of any vascular imaging modality to assess plaque characteristics as each unique technique has its pros and cons. This review describes the techniques that may evolve into screening tool for the detection of the vulnerable plaque. Finally, it seems that plaque morphology has been changing in the last decades leading to a higher prevalence of 'stable' atherosclerotic plaques, possibly due to the implementation of primary prevention strategies or other approaches. Therefore, the nomenclature of vulnerable plaque lesions should be very carefully defined in all studies.

[Advances in cardiovascular medicine through molecular imaging]. / Von vulnerablem Plaque bis Infarktheilung - neue Perspektiven in der Kardiologie mit molekularer Bildgebung.

We will witness a change of paradigm in cardiovascular imaging, which is empowered by advances in imaging technology, biochemistry, molecular biology and nanotechnology. Instead of simply following the physical distribution of established contrast agents, we now have the opportunity to noninvasively image biological processes such as enzyme activity, interaction with cell surface markers, gene expression and cell migration. These advancements open up new avenues in basic cardiovascular research and will greatly speed up the pace of discovery. Patient management will profit as well: cardiovascular molecular imaging will strengthen personlized and prophylactic medicine through timely and precise diagnostics. In our review we describe selected molecular imaging strategies in atherosclerosis, myocardial ischemia and healing.

23Na microscopy of the mouse heart in vivo using density-weighted chemical shift imaging.

The mouse has become an important animal model for human cardiac disease, and the development of techniques for non-invasive imaging of the mouse heart in vivo is, therefore, of great potential interest. Previous magnetic resonance imaging studies have concentrated on pathologically induced changes in cardiac structure and dynamics by acquiring proton images. Further information can be gained by studying cardiac function and physiology using other nuclei, for example, sodium. Sodium imaging of such a small structure presents considerable technical challenges. In this work we show the first sodium images of the mouse heart, with an isotropic spatial resolution of 1 x 1 x 1 mm, acquired in a time of 1.5 h. The ventricles, septum and myocardium are readily distinguishable in these images, which were acquired through the combination of 3D density-weighted chemical shift imaging, optimized instrumentation, and a high magnetic field strength (17.6 T). Measurements of the myocardial:blood sodium concentration in the left and right ventricles agree well with theoretical values.

Cardiac magnetic resonance imaging in small animal models of human heart failure.

The aim of this study was to test the feasibility of cine magnetic resonance imaging (MRI) for assessment of the infarcted rat and mouse heart and to compare the results with established methods. These models have been proven to predict genesis and prevention of heart failure in patients. The value of cine MRI was tested in studies investigating interventions to change the course of the remodeling process. MRI was performed for determination of left ventricular (LV) volumes and mass, myocardial infarct (MI) size and cardiac output. LV wet weight was determined after MRI. Rats underwent conventional hemodynamic measurements for determination of cardiac output and LV volumes by electromagnetic flowmeter and pressure-volume curves. Infarct size was determined by histology. MRI-acquired MI-size (18.5+/-2%) was smaller than that found by histology (22.8+/-2.5%, p<0.05) with close correlation (r=0.97). There was agreement in LV mass between MRI and wet weight (r=0.97, p<0.05) and in the MRI- and flowmeter measurements of cardiac output (r=0.80, p<0.05). Volume by MRI differed from pressure-volume curves with good correlation (r=0.96, p<0.05). In a serial study of mice after coronary ligation, LV hypertrophy at 8 weeks was detected (Sham 105.1+/-7.9 mg, MI 144.4+/-11.7 mg, p<0.05). Left ventricles were enlarged in infarcted mice (end-diastolic volume, week 8: Sham 63.5+/-4 microl, MI 94.2 microl, p<0.05). In conclusion, cine MRI is a valuable diagnostic tool applicable to the rat and mouse model of MI. Being non-invasive and exact it offers new insights into the remodeling process after MI because serial measurements are possible. The technique was applied to study several interventions and proved its usefulness.

Serial cine-magnetic resonance imaging of left ventricular remodeling after myocardial infarction in rats.

The purpose of the present study was the serial investigation of morphological and functional changes after left coronary artery ligation in the intact rat using cine-magnetic resonance imaging (MRI). MRI studies were performed 4, 8, 12, and 16 weeks after myocardial infarction (MI) with an echocardiogram (ECG)-triggered cine-fast low-angle shot (FLASH)-sequence in a 7-Tesla magnet. MI-size, left ventricular (LV) mass and volumes, cardiac index, ejection fraction (EF), and remote wall and scar thickness of 11 Wistar rats were compared to four sham-operated rats. Stress MRI with dobutamine (10 microl/kg x minute) was performed at 16 weeks. In MI groups (small MI < 30%, N = 5, large MI > 30%, N = 6), there was significant increase of LV mass (small MI + 47.8% increase, large MI + 74.1%) and wall thickness (large MI 1.21 +/- 0.03 to 1.84 +/- 0.07 mm). Scar thickness declined from four to 16 weeks (large MI 0.92 +/- 0.06 to 0.38 +/- 0.02 mm, P < 0.05). End-diastolic volume of both MI groups was significantly elevated but increased further only in animals with large MI from four to 16 weeks (657.1 +/- 38.6 to 869.7 +/- 60.7 microL, P < 0.05). Compared to sham, EF was significantly depressed in MI (large MI 31.5 +/- 2.0%). Wall thickening declined from four to 16 weeks post-MI (large MI 50.9 +/- 9.9 to 28.9 +/- 4.4%, P < 0.05). During stress, sham and MI rats increased wall thickening from 66.5 +/- 8.2 to 111.2 +/- 6.7% and from 30.8 +/- 4.3 to 47.5 +/- 5.8%, respectively (P < 0.05). Hypertrophy was found in all animals with MI throughout the entire period of observation, whereas dilatation after four weeks was only detected in animals with large MI. These morphologic changes were accompanied by an early decline of EF; myocardial function characterized by wall thickening deteriorated later.

Serial magnetic resonance imaging of microvascular remodeling in the infarcted rat heart.

BACKGROUND: Alterations in the coronary circulation are important determinants of myocardial function. Few data are available, however, about microvascular changes in reactive hypertrophy. With MRI, serial determination of myocardial microcirculation after myocardial infarction (MI) is feasible. METHODS AND RESULTS: We quantitatively determined myocardial perfusion and relative intracapillary blood volume using an MRI technique. Infarct size, myocardial mass, and left ventricular volumes were determined with cine MRI. Rats were investigated at 8, 12, and 16 weeks after MI (mean MI size 24.1+/-2.0%) or sham operation. Vasodilation was induced by adenosine. In the infarcted group, maximum perfusion decreased significantly from 8 to 16 weeks (5.6+/-0.3 versus 3.5+/-0.2 mL. g(-1). min(-1), P<0.01) compared with sham animals (5.5+/-0.3 versus 5.0+/-0.2 mL. g(-1). min(-1), P=0.17). Myocardial mass increased significantly (559.1+/-20.8 mg at 8 weeks versus 690.9+/-42.7 mg at 16 weeks, P<0.05) compared with sham-operated animals (516.3+/-41.7 versus 549.2+/-32.3 mg). Basal relative intracapillary blood volume increased significantly to 15.7+/-0.5 vol% at 8 weeks after MI and remained elevated (16.8+/-0.6 vol%) at 16 weeks compared with 12.1+/-0.3 vol% (P<0.01) in sham-operated rats. CONCLUSIONS: Our results indicate that significant microvascular changes occur during cardiac remodeling. Hypoperfusion in the hypertrophied myocardium is related to an increase in vascular capacity, suggesting a compensatory vasodilatory response at the capillary level. These microvascular changes may therefore contribute to the development of heart failure.

In vivo assessment of cardiac remodeling after myocardial infarction in rats by cine-magnetic resonance imaging.

The rat infarct model offers important parallels to the process of remodeling after myocardial infarction (MI) in humans. The aim of this study was to test the feasibility of cine fast low-angle shot (FLASH) magnetic resonance imaging (MRI) for assessment of the infarcted and noninfarcted rat heart and to compare the results with established methods. In group A, MRI was done 8-16 weeks after MI on a 7-T scanner using an electrocardiogram-triggered cine-FLASH sequence. We determined left ventricular (LV) volumes and mass, wall thickness, MI size, cardiac output, and ejection fraction. Afterward, MI size was histologically determined. In group B, after MRI eight controls and eight rats 16 weeks after MI underwent conventional hemodynamic measurements for determination of cardiac output, LV volumes, and ejection fraction by electromagnetic flowmeter and pressure-volume curves. LV wet weight was determined. In group A, MRI-acquired MI size (18.5 +/- 2%) was smaller than histology (22.8 +/- 2.5%, p < 0.05) with close correlation (r = 0.97). In group B, agreement in LV mass was found between MRI and wet weight (controls, 537.6 +/- 19.6 vs. 540.3 +/- 18.4 mg; MI, 865.1 +/- 39.2 vs. 865.1 +/- 41.3 mg; for the difference p = ns, r = 0.97, p < 0.05) and in the MRI and flowmeter measurements (cardiac output, controls 73.1 +/- 2.9 vs. 75.2 +/- 2.6 ml/min; MI 82.4 +/- 5.2 vs. 81.9 +/- 3.7 ml/min; for the difference p = ns, r = 0.80, p < 0.05). End-diastolic volume by MRI differed from pressure-volume curves with good correlation (controls, 343.9 +/- 8.4 vs. 262.7 +/- 12.8 microl; MI, 737.0 +/- 70.5 vs. 671.1 +/- 64.1 microl; p < 0.05 each, r = 0.96, p < 0.05). Cine-FLASH-MRI is a valuable diagnostic tool applicable to the rat model of MI. Being noninvasive and exact, it offers new insights in the remodeling process after MI because serial measurements are possible.

Myocardial perfusion and intracapillary blood volume in rats at rest and with coronary dilatation: MR imaging in vivo with use of a spin-labeling technique.

PURPOSE: To validate a magnetic resonance (MR) imaging technique that is not first pass and that reveals perfusion and regional blood volume (RBV) in the intact rat. MATERIALS AND METHODS: Measurement of perfusion was based on the perfusion-sensitive T1 relaxation after magnetic spin labeling of water protons. RBV was determined from steady-state measurements of T1 before and after administration of an intravascular contrast agent. The colored microsphere technique was used as a reference method for perfusion measurement. RBV and perfusion maps were obtained with the rats at rest and during administration of 3 mg of adenosine phosphate per kilogram of body weight per minute. RESULTS: At MR imaging, perfusion during resting conditions was 3.5 mL/g/min +/- 0.1 (SEM), and RBV was 11.6% +/- 0.6 (SEM). Adenosine phosphate significantly increased perfusion to 4.5 mL/g/min +/- 0.3 (SEM) and decreased mean arterial pressure from 120 mm Hg to 65 mm Hg, which implies a reduction of coronary resistance to 40% of baseline. RBV increased consistently to 23.8% +/- 0.6 (SEM). CONCLUSION: The study results show that quantitative mapping of perfusion and RBV may be performed noninvasively by means of MR imaging in the intact animal. The presented method allows determination of vasodilative and perfusion reserve, which reflects the in vivo regulation of coronary microcirculation for a given stimulus.

Chronic effects of early started angiotensin converting enzyme inhibition and angiotensin AT1-receptor subtype blockade in rats with myocardial infarction: role of bradykinin.

OBJECTIVE: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist. METHODS: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 micrograms/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks. RESULTS: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects. CONCLUSION: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.