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AimsDiabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure.Methods and resultsWe enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models.ConclusionDiabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable.

BackgroundExtracellular matrix expansion may be a fundamental feature of adverse myocardial remodeling, it appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and extracellular matrix is not clear because of difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance techniques to quantify the full spectrum of extracellular matrix expansion not readily detectable by conventional cardiovascular magnetic resonance.Methods and resultsWe recruited 793 consecutive patients at the time of cardiovascular magnetic resonance without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20-50 years). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction. ECV uses gadolinium contrast as an extracellular space marker based on T1 measures of blood and myocardium pre- and post-gadolinium contrast and hematocrit measurement. In volunteers, ECV ranged from 21.7% to 26.2%, but in patients it ranged from 21.0% to 45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (interquartile range 0.5-1.2 years), and 43 individuals who experienced the composite end point of death/cardiac transplant/left ventricular assist device implantation. In Cox regression models, ECV related to all-cause mortality and the composite end point (hazard ratio, 1.55; 95% confidence interval, 1.27-1.88 and hazard ratio, 1.48; 95% confidence interval, 1.23-1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and myocardial infarction size.ConclusionsECV measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation).

The goal of the present study was to assess the effects of left ventricular (LV) pacing sites (apex vs. free wall) on radial synchrony and global LV performance in a canine model of contraction dyssynchrony. Ultrasound tissue Doppler imaging and hemodynamic (LV pressure-volume) data were collected in seven anesthetized, opened-chest dogs. Right atrial (RA) pacing served as the control, and contraction dyssynchrony was created by simultaneous RA and fight ventricular (RV) pacing to induce a left bundle-branch block-like contraction pattern. Cardiac resynchronization therapy (CRT) was implemented by adding simultaneous LV pacing to the RV pacing mode at either the LV apex (CRTa) or free wall (CRTf). A new index of synchrony was developed via pair-wise cross-correlation analysis of tissue Doppler radial strain from six midrnyocardial cross-sectional regions, with a value of 15 indicating perfect synchrony. Compared with RA pacing, RV pacing significantly decreased radial synchrony (11.1 [+ or -] 0.8 vs. 4.8 [+ or -] 1.2, P < 0.01) and global LV performance (cardiac output: 2.0 [+ or -] 0.3 vs. 1.4 - 0.1 l/rain and stroke work: 137 [+ or -] 22 vs. 60 [+ or -] 14 mJ, P < 0.05). Although both CRTa and CRTf significantly improved radial synchrony, only CRTa markedly improved global function (cardiac output: 2.1 [+ or -] 0.2 l/rain and stroke work: 113 [+ or -] 13 mJ, P < 0.01 vs. RV pacing). Furthermore, CRTa decreased LV end-systolic volume compared with RV pacing without any change in LV end-systolic pressure, indicating an augmented global LV contractile state. Thus, LV apical pacing appears to be a superior pacing site in the context of CRT. The dissociation between changes in synchrony and global LV performance with CRTf suggests that regional analysis from a single plane may not be sufficient to adequately characterize contraction synchrony. cardiac resynchronization therapy; left ventricular global performance; myocardial strain; tissue Doppler imaging

Embryonic myocardium has a high rate of cell proliferation and regulates cellular proliferation, contractile function, and myocardial architecture in response to changes in external mechanical loads. However, the small and complex three-dimensional (3D) structure of the embryonic myocardium limits our ability to directly investigate detailed relationships between mechanical load, contractile function, and cardiomyocyte proliferation. We developed a novel 3D engineered early embryonic cardiac tissue (EEECT) from early embryonic ventricular cells to test the hypothesis that EEECT retains the proliferative and contractile properties of embryonic myocardium. We combined freshly isolated White Leghorn chicken embryonic ventricular cells at Hamburger-Hamilton (HH) stage 31 (day 7 of a 46-stage, 21-day incubation period), collagen type I, and matrix factors to construct cylindrical-shaped EEECTs. We studied tissue architecture, cell proliferation patterns, and contractile function. We then generated engineered fetal cardiac tissue (EFCT) from HH stage 40 (day 14) fetal ventricular cells for direct comparison with EEECT. Tissue architecture was similar in EEECT and EFCT. EEECT maintained high cell proliferation patterns by culture day 12, whereas EFCT decreased cell proliferation rate by culture day 9 (P < 0.05). EEECT increased active contractile force from culture day 7 to day 12. The culture day 12 EEECT contractile response to the [beta]-adrenergic stimulation was less than culture day 9 EFCT (P < 0.05). Cyclic mechanical stretch stimulation induced myocardial hyperplasia in EEECT. Results indicate that EEECT retains the proliferative and contractile properties of developing embryonic myocardium and shows potential as a robust in vitro model of developing embryonic myocardium. cardiomyocyte; morphogenesis; growth and development; hyperplasia; tissue engineering

We explored the relationship between left ventricular (LV) pressure and intracellular free calcium concentration ([[Ca].sub.i]) in the isolated perfused mouse heart. [[Ca].sub.i] (rhod-2) and LV pressure were recorded simultaneously. In response to increases in LV volume (Frank-Starling, FS, protocol), there were increases in developed pressure (up to 250%), with no changes in pressure morphology (rise or relaxation time) or [[Ca].sub.i] (magnitude and morphology) for up to 10 min. During transient increases in the stimulus interval at a fixed LV volume (mechanical restitution, MR, protocol), developed pressure increased significantly (31.3 [+ or -] 1.2%), with relatively small changes in peak systolic [[Ca].sub.i] (7.4 [+ or -] 1.4%). The relaxation of [[Ca].sub.i], however, was prolonged (30.0 [+ or -] 5.5%), resulting in prolonged pressure relaxation (21.2 [+ or -] 1.9%) and increased area under the calcium transient that paralleled the increase in developed pressure (1:1 ratio). A model-based analysis showed that changes in LV pressure during the MR protocol could be completely explained by altered [[Ca].sub.i]; it was not necessary to invoke any changes in model parameters (i.e., dynamic processes that link calcium to pressure). For the FS data, the model predicted only a change in the gain parameter: however, this change alone cannot reproduce well-established length-dependent changes in the steady-state force-pCa relationship. In summary, the mouse myocardium appears to be unique in that significant changes in peak developed pressure can occur with little or no change in the peak [[Ca].sub.i]. Additionally, unlike other mammalian species, load-dependent prolongation of pressure relaxation is absent in the mouse heart, and pressure relaxation is primarily governed by intracellular free calcium relaxation. murine heart: length-dependent activation: load-dependent relaxation: excitation-contraction coupling: model-based analysis

Research suggests that left ventricular isovolumic relaxation is influenced by ejection in different ways. Positive and negative inotropic effects are observed. Experiments using isolated adult male rabbit hearts are described. Left ventricular pressure and volume measurements are reported in relation to active stress and isovolumic relaxation time.

Fluid resuscitation during treatment of septic shock may have some negative effects on systemic arterial mechanical properties, which are already compromised by bacterial endotoxins. Rabbits treated with endotoxin alone had elevated total peripheral resistance (TPR), lowered cardiac output and increased cardiac impedance. Rabbits treated with both endotoxin and and fluid resuscitation had decreased TPR, somewhat increased cardiac output and a lesser rise in cardiac impendence.

The asymmetric T-tube model of systemic arterial circulation may correctly measure root aortic flow and descending aortic flow under many conditions, and can differentiate between proximal and distal arterial mechanical properties. In dogs with a balloon inflated in the left external iliac artery and injected with vasoactive agents, nitroprusside initially influenced the distal properties of the model, whereas phenylephrine affected both the distal and tube parameters.

Atomic force microscopy (AFM) of cultured rat atrial myocytes shows an eight fold variation of quiescent cells over the cell surface, such that the lowest stiffness was at nuclear region and increased towards the periphery. Cell contractile activity alteration with physiological perturbations and dynamic variations in cell stiffness is revealed in every single contraction. Thus the relationship among the localized cell mechanical behavior and the associated biochemical and structural environment, is directly observed using AFM.

Computer software supplements laboratory studies by simulating the functions of multiple organ systems. Studies using live animals and computers enhance understanding of the basic concepts by interactive demonstrations. Limitations of time and other factors in animal experiments can be overcome by computer simulations, although teaching using computers is sometimes artificial in nature.