Cardiac function of the leopard shark,Triakis semifasciata

Summary The pressure difference between the cardinal sinus and the pericardium, and the transmural ventricular diastolic pressure at rest and during swimming in the leopard shark, Triakis semifasciata, was measured to characterize the mechanism of cardiac filling in chronically-instrumented fish and to evaluate cardiac responses to swimming. Echo-Doppler and radiographic imaging were also used to fully describe the cardiac cycle. Swimming induces an increase in preload as manifested by a large increment of cardinal sinus pressure (0.26/0.20 [systolic/diastolic] to 0.49/0.32 kPa) which always exceeds pericardial pressure. Increases in both mean ventricular diastolic transmural pressure (0.30–0.77 kPa) and cardinal sinus pressure during swimming suggest increased cardiac filling by vis a tergo as the mechanism for augmenting cardiac output. In contrast to mammals, the fluid-filled pericardial space of elasmobranchs is considerably larger and the pericardium itself does not move in concert with the heart throughout the cardiac cycle. Also, modest increases in heart rate drastically curtail the duration of diastole, which becomes much less than that of systole, a phenomenon not found in mammals. In the absence of tachycardia (<40 bpm), ventricular filling is characterized by a period of early rapid filling, and a late period of filling owing to atrial systole, separated by a period of diastasis. Ventricular filling in elasmobranchs is thus biphasic and is not solely dependent on atrial systole. Atrial diastole is characterized by three filling periods associated with atrial relaxation, ventricular ejection, and sinus venosus contraction. The estimated ventricular ejection fraction of Triakis (80%) exceeds that of the mammalian left ventricle.     

Estimation of left ventricular operating stiffness from Doppler early filling deceleration time in humans

Shortened early transmitral deceleration times (E(DT)) have been qualitatively associated with increased filling pressure and reduced survival in patients with cardiac disease and increased left ventricular operating stiffness (K(LV)). An equation relating K(LV) quantitatively to E(DT) has previously been described in a canine model but not in humans. During several varying hemodynamic conditions, we studied 18 patients undergoing open-heart surgery. Transesophageal echocardiographic two-dimensional volumes and Doppler flows were combined with high-fidelity left atrial (LA) and left ventricular (LV) pressures to determine K(LV). From digitized Doppler recordings, E(DT) was measured and compared against changes in LV and LA diastolic volumes and pressures. E(DT) (180 +/- 39 ms) was inversely associated with LV end-diastolic pressures (r = -0.56, P = 0.004) and net atrioventricular stiffness (r = -0.55, P = 0.006) but had its strongest association with K(LV) (r = -0.81, P < 0.001). K(LV) was predicted assuming a nonrestrictive orifice (K(nonrest)) from E(DT) as K(nonrest) = (0.07/E(DT))(2) with K(LV) = 1.01 K(nonrest) - 0.02; r = 0.86, P < 0.001, DeltaK (K(nonrest) - K(LV)) = 0.02 +/- 0.06 mm Hg/ml. In adults with cardiac disease, E(DT) provides an accurate estimate of LV operating stiffness and supports its application as a practical noninvasive index in the evaluation of diastolic function.     

Characterization of Regional Left Ventricular Function in Nonhuman Primates Using Magnetic Resonance Imaging Biomarkers: A Test-Retest Repeatability and Inter-Subject Variability Study

Pre-clinical animal models are important to study the fundamental biological and functional mechanisms involved in the longitudinal evolution of heart failure (HF). Particularly, large animal models, like nonhuman primates (NHPs), that possess greater physiological, biochemical, and phylogenetic similarity to humans are gaining interest. To assess the translatability of these models into human diseases, imaging biomarkers play a significant role in non-invasive phenotyping, prediction of downstream remodeling, and evaluation of novel experimental therapeutics. This paper sheds insight into NHP cardiac function through the quantification of magnetic resonance (MR) imaging biomarkers that comprehensively characterize the spatiotemporal dynamics of left ventricular (LV) systolic pumping and LV diastolic relaxation. MR tagging and phase contrast (PC) imaging were used to quantify NHP cardiac strain and flow. Temporal inter-relationships between rotational mechanics, myocardial strain and LV chamber flow are presented, and functional biomarkers are evaluated through test-retest repeatability and inter subject variability analyses. The temporal trends observed in strain and flow was similar to published data in humans. Our results indicate a dominant dimension based pumping during early systole, followed by a torsion dominant pumping action during late systole. Early diastole is characterized by close to 65% of untwist, the remainder of which likely contributes to efficient filling during atrial kick. Our data reveal that moderate to good intra-subject repeatability was observed for peak strain, strain-rates, E/circumferential strain-rate (CSR) ratio, E/longitudinal strain-rate (LSR) ratio, and deceleration time. The inter-subject variability was high for strain dyssynchrony, diastolic strain-rates, peak torsion and peak untwist rate. We have successfully characterized cardiac function in NHPs using MR imaging. Peak strain, average systolic strain-rate, diastolic E/CSR and E/LSR ratios, and deceleration time were identified as robust biomarkers that could potentially be applied to future pre-clinical drug studies.     

Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets

Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 +/- 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 +/- 2 vs. 21 +/- 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/dt(max): 2,476 +/- 203 vs. 2,330 +/- 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/dt(min): -2,466 +/- 190 vs. -2,076 +/- 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 +/- 2 vs. 43 +/- 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 +/- 33 vs. 244 +/- 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer (P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload (P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.     

Acute hypothyroidism slows the rate of left ventricular diastolic relaxation

The effect of acute thyroid hormone deficiency on left ventricular diastolic filling was studied by radionuclide ventriculography with simultaneous right heart catheterization in nine athyreotic patients without cardiovascular disease. The patients were studied when they were hypothyroid and when they were euthyroid on replacement therapy. Peak filling rate and the time to peak filling were used to characterize diastolic function. The time to peak filling was defined as the interval from end-systole on the radionuclide time-volume curve to the time of occurrence of peak filling. The peak filling rate was determined in absolute terms from the normalized radionuclide peak filling rate and from the end-diastolic volume, which was derived from the radionuclide ejection fraction and from the thermodilution stroke volume. In all patients, the values for peak filling rate were lower in the hypothyroid than in the euthyroid state (287 +/- 91 mL/s vs. 400 +/- 118 mL/s, delta = 41 +/- 13%, p less than 0.01). Peak filling always occurred during the first half of the diastolic interval. The time to peak filling was not significantly affected by the thyroid state (170 +/- 10 ms vs. 159 +/- 21 ms, delta = 7 +/- 10%). Left ventricular filling pressure as reflected by the pulmonary capillary wedge pressure and end-systolic volume were similar in both thyroid states (6 +/- 2 mmHg vs. 8 +/- 2 mmHg (1 mmHg = 133.32 Pa) and 32 +/- 11 mL vs. 32 +/- 7 mL, respectively). The data suggest that the rate of active diastolic relaxation is decreased in short-duration hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Training-specific changes in cardiac structure and function: a prospective and longitudinal assessment of competitive athletes.

This prospective, longitudinal study examined the effects of participation in team-based exercise training on cardiac structure and function. Competitive endurance athletes (EA, n = 40) and strength athletes (SA, n = 24) were studied with echocardiography at baseline and after 90 days of team training. Left ventricular (LV) mass increased by 11% in EA (116 +/- 18 vs. 130 +/- 19 g/m(2); P < 0.001) and by 12% in SA (115 +/- 14 vs. 132 +/- 11 g/m(2); P < 0.001; P value for the compared Delta = NS). EA experienced LV dilation (end-diastolic volume: 66.6 +/- 10.0 vs. 74.7 +/- 9.8 ml/m(2), Delta = 8.0 +/- 4.2 ml/m(2); P < 0.001), enhanced diastolic function (lateral E': 10.9 +/- 0.8 vs. 12.4 +/- 0.9 cm/s, P < 0.001), and biatrial enlargement, while SA experience LV hypertrophy (posterior wall: 4.5 +/- 0.5 vs. 5.2 +/- 0.5 mm/m(2), P < 0.001) and diminished diastolic function (E' basal lateral LV: 11.6 +/- 1.3 vs. 10.2 +/- 1.4 cm/s, P < 0.001). Further, EA experienced right ventricular (RV) dilation (end-diastolic area: 1,460 +/- 220 vs. 1,650 +/- 200 mm/m(2), P < 0.001) coupled with enhanced systolic and diastolic function (E' basal RV: 10.3 +/- 1.5 vs. 11.4 +/- 1.7 cm/s, P < 0.001), while SA had no change in RV parameters. We conclude that participation in 90 days of competitive athletics produces significant training-specific changes in cardiac structure and function. EA develop biventricular dilation with enhanced diastolic function, while SA develop isolated, concentric left ventricular hypertrophy with diminished diastolic relaxation.     

Diastolic time – frequency relation in the stress echo lab: filling timing and flow at different heart rates

 

A cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been recently validated. Second heart sound can be simultaneously recorded in order to quantify both systole and diastole duration.

Aims

1- To assess the feasibility and extra-value of operator-independent, force sensor-based, diastolic time recording during stress.

Methods

We enrolled 161 patients referred for stress echocardiography (exercise 115, dipyridamole 40, pacing 6 patients). The sensor was fastened in the precordial region by a standard ECG electrode. The acceleration signal was converted into digital and recorded together with ECG signal. Both systolic and diastolic times were acquired continuously during stress and were displayed by plotting times vs. heart rate. Diastolic filling rate was calculated as echo-measured mitral filling volume/sensor-monitored diastolic time.

Results

Diastolic time decreased during stress more markedly than systolic time. At peak stress 62 of the 161 pts showed reversal of the systolic/diastolic ratio with the duration of systole longer than diastole. In the exercise group, at 100 bpm HR, systolic/diastolic time ratio was lower in the 17 controls (0.74 ± 0.12) than in patients (0.86 ± 0.10, p < 0.05 vs. controls). Diastolic filling rate increased from 101 ± 36 (rest) to 219 ± 92 ml/m²* s^-1 at peak stress (p < 0.5 vs. rest).

Conclusion

Cardiological systolic and diastolic duration can be monitored during stress by using an acceleration force sensor. Simultaneous calculation of stroke volume allows monitoring diastolic filling rate. Stress-induced "systolic-diastolic mismatch" can be easily quantified and is associated to several cardiac diseases, possibly expanding the spectrum of information obtainable during stress.     

ECG-synchronized thoracic vest inflation during autonomic blockade, myocardial ischemia, or cardiac arrest.

To evaluate, in the absence of lung inflation, the cardiovascular effects of single and repetitive pleural pressure increments induced by thoracic vest inflations and timed to occur during specific portions of the cardiac cycle, seven chronically instrumented dogs were studied. Reflexes and left ventricular (LV) performance were varied by autonomic blockade, circumflex coronary occlusion (with and without beta-blockade), or cardiac arrest. Single late systolic, but not early systolic, vest inflations significantly increased LV stroke volume both before (+12.4%) and after myocardial depression by coronary occlusion+beta-blockade (+18.5%) when performed after a period of apnea to control preload and rate. During vest inflations, LV and aortic pressures increased to a greater degree than esophageal pressure (by 51 vs. 39 mmHg, P = 0.0001). Lung inflations (26 trials in 3 dogs) during early or late systole failed to increase stroke volume, despite peak esophageal pressures of 11-26 mmHg. With autonomic reflexes intact, repetitive vest inflations coupled to early systole, late systole, or diastole induced a large (40%) but unspecific systemic flow increase. In contrast, during autonomic blockade, flow increased slightly (7.5%, P < 0.05) with late systolic compared with diastolic inflations but not relative to baseline. During coronary occlusion (with or without beta-blockade), no cycle-specific differences were seen, whereas matched vest inflations during cardiac arrest generated 20-30% of normal systemic flow. Thus only single late systolic thoracic vest inflations associated with large increments in pleural pressure increased LV emptying, presumably by decreasing LV afterload and/or focal cardiac compression. However, during myocardial ischemia and depression, coupling of vest inflation to specific parts of the cardiac cycle revealed no hemodynamic improvement, suggesting that benefits of this circulatory assist method, if any, are minor and may be restricted to conditions of cardiac arrest.     

Quantification of left and right ventricular kinetic energy using four-dimensional intracardiac magnetic resonance imaging flow measurements

We aimed to quantify kinetic energy (KE) during the entire cardiac cycle of the left ventricle (LV) and right ventricle (RV) using four-dimensional phase-contrast magnetic resonance imaging (MRI). KE was quantified in healthy volunteers (n = 9) using an in-house developed software. Mean KE through the cardiac cycle of the LV and the RV were highly correlated (r(2) = 0.96). Mean KE was related to end-diastolic volume (r(2) = 0.66 for LV and r(2) = 0.74 for RV), end-systolic volume (r(2) = 0.59 and 0.68), and stroke volume (r(2) = 0.55 and 0.60), but not to ejection fraction (r(2) < 0.01, P = not significant for both). Three KE peaks were found in both ventricles, in systole, early diastole, and late diastole. In systole, peak KE in the LV was lower (4.9 ± 0.4 mJ, P = 0.004) compared with the RV (7.5 ± 0.8 mJ). In contrast, KE during early diastole was higher in the LV (6.0 ± 0.6 mJ, P = 0.004) compared with the RV (3.6 ± 0.4 mJ). The late diastolic peaks were smaller than the systolic and early diastolic peaks (1.3 ± 0.2 and 1.2 ± 0.2 mJ). Modeling estimated the proportion of KE to total external work, which comprised ～0.3% of LV external work and 3% of RV energy at rest and 3 vs. 24% during peak exercise. The higher early diastolic KE in the LV indicates that LV filling is more dependent on ventricular suction compared with the RV. RV early diastolic filling, on the other hand, may be caused to a higher degree of the return of the atrioventricular plane toward the base of the heart. The difference in ventricular geometry with a longer outflow tract in the RV compared with the LV explains the higher systolic KE in the RV.     

Sub-clinical left ventricular diastolic dysfunction in early stage of chronic obstructive pulmonary disease

Sub-clinical cardiac dysfunction may be significantly associated with chronic obstructive pulmonary disease (COPD) with a different degree of severity. In a cross-sectional design we aimed to evaluate the frequency of left ventricular diastolic dysfunction (LVdd) and its correlation with lung function, pulmonary arterial pressure and systemic inflammation in a selected population of COPD at an early stage of their disease. Fifty-five COPD patients with no clinical signs of cardiovascular dysfunction were recruited and compared to 40 matched healthy controls. All the subjects underwent pulmonary function testing, doppler echocardiography, and interleukin-6 blood sampling. Presence of LVdd was defined according to the significant change in both the ratio between early and late diastolic transmitral flow velocity (E/A ratio), isovolumetric relaxation time (IVRT), and deceleration time (DT). The frequency of LVdd was higher in the COPD group (70.9 percent) compared to controls (27.5 percent). In these patients decreased E/A ratio, and prolonged IVRT and DT clearly pointed to left ventricular filling impairment, a condition we found to be especially severe in those patients suffering from lung static hyperinflation as expressed by inspiratory-to-total lung capacity ratio (IC/TLC) <0.25. Circulating levels of interleukin-6 were also higher among COPD patients compared to controls. The results of the present study suggest that subclinical left ventricular filling impairment is frequently found in COPD patients at the earlier stage of the disease even in the absence of any other cardiovascular dysfunction. Doppler echocardiography may help the early identification of LVdd in COPD patients.     

Cardiovascular system of normal aged subjects. Cardiovascular senescence

The cardiovascular system of the elderly is characterised by (i) an increased characteristic impedance of the big vessels, without hypertension; (ii) a cardiac index unchanged at rest and during submaximal exercising, despite a diminished VO2 max; (iii) a diastolic dysfunction with reduced rapid early filling (E wave at echo) and enhanced atrial systole (A wave); (iv) benign arrhythmias; (v) a reduced coronary reserve and an increased sensitivity to ischemia; (vi) an efficacy of converting enzyme inhibitors remaining unchanged, despite an altered renin-agiotensin system.     

The role of displacement of the mitral annulus in left atrial filling and emptying in the intact dog

The variations in ventricular-atrial mitral annular position during the cardiac cycle and the simultaneous changes in left atrial silhouette area (obtained by angiography after injections of contrast material into the main pulmonary artery) were investigated in six experiments on intact dogs with chronically implanted intracardiac markers. Frame-by-frame measurements of the angiograms (120 frames/s) were used to determine, under various hemodynamic conditions, the duration, magnitude, and average rate of the mitral annular motion and of the simultaneous changes in left atrial area during atrial filling (ventricular systole) and atrial emptying (early in ventricular diastole). The mitral annulus was seen to move towards the ventricular apex during systole and towards the atrium early in diastole with the duration, average rate, and magnitude of displacement (although varying widely) showing good statistical correlations (P less than 0.0005-0.005) with the changes in projected left atrial area. These findings suggest that the duration, rate, and magnitude of atrial filling and emptying may be, in the intact heart, determined by the movements of the atrioventricular junction.     

Experimental cardiac tamponade: correlation of pressure, flow velocity, and echocardiographic changes

Seven episodes of experimental cardiac tamponade were induced in five anesthetized closed-chest dogs. Simultaneous pericardial and intracavitary pressures were synchronized with superior vena caval and transvalvular pulsed-Doppler flow tracings. The earliest indication of tamponade was the development of a negative transmural right atrial pressure that occurred during early ventricular diastole and was associated with echocardiographic evidence of right atrial collapse. This was also associated with reversal of diastolic flow in the superior vena cava and with diminished early diastolic flow velocity across the tricuspid as well as the mitral valve. During more advanced cardiac tamponade, the transmural right atrial pressure became negative during both early and late ventricular diastole as well as during isovolumic ventricular systole. This was associated with a disappearance of early diastolic ventricular filling and right ventricular diastolic collapse as observed on two-dimensional echocardiography. In hypotensive cardiac tamponade (cardiac output diminished by 70%), the decreased transmural right atrial pressure that developed during ventricular systole was accompanied by diminished antegrade flow in the superior vena cava. In advanced and hypotensive tamponade, ventricular filling occurred mainly during atrial contraction.     

Titin isoform switching is a major cardiac adaptive response in hibernating grizzly bears

The hibernation phenomenon captures biological as well as clinical interests to understand how organs adapt. Here we studied how hibernating grizzly bears (Ursus arctos horribilis) tolerate extremely low heart rates without developing cardiac chamber dilation. We evaluated cardiac filling function in unanesthetized grizzly bears by echocardiography during the active and hibernating period. Because both collagen and titin are involved in altering diastolic function, we investigated both in the myocardium of active and hibernating grizzly bears. Heart rates were reduced from 84 beats/min in active bears to 19 beats/min in hibernating bears. Diastolic volume, stroke volume, and left ventricular ejection fraction were not different. However, left ventricular muscle mass was significantly lower (300 +/- 12 compared with 402 +/- 14 g; P = 0.003) in the hibernating bears, and as a result the diastolic volume-to-left ventricular muscle mass ratio was significantly greater. Early ventricular filling deceleration times (106.4 +/- 14 compared with 143.2 +/- 20 ms; P = 0.002) were shorter during hibernation, suggesting increased ventricular stiffness. Restrictive pulmonary venous flow patterns supported this conclusion. Collagen type I and III comparisons did not reveal differences between the two groups of bears. In contrast, the expression of titin was altered by a significant upregulation of the stiffer N2B isoform at the expense of the more compliant N2BA isoform. The mean ratio of N2BA to N2B titin was 0.73 +/- 0.07 in the active bears and decreased to 0.42 +/- 0.03 (P = 0.006) in the hibernating bears. The upregulation of stiff N2B cardiac titin is a likely explanation for the increased ventricular stiffness that was revealed by echocardiography, and we propose that it plays a role in preventing chamber dilation in hibernating grizzly bears. Thus our work identified changes in the alternative splicing of cardiac titin as a major adaptive response in hibernating grizzly bears.     

Effects of wave reflection timing on left ventricular mechanics

The aim of this study was to evaluate how the timing of the pressure pulse produced by peripheral reflection affects the left ventricle (stroke volume, ventricular work, coronary driving pressure). Ten isolated perfused rabbit hearts were attached to rubber tubes of different lengths (0.5, 0.8 and 1 m) connected to a hydraulic resistance. The different lengths produced reflections at different times and the reflected pulse returned to the ventricle in early (at 84 ms), middle (at 134 ms) and late systole (at 168 ms) for the three tubes, respectively. The loading parameters (ventricular filling pressure and hydraulic resistance) were not changed during the procedure. Ventricular and aortic pressure and aortic flow were monitored continuously and recorded; cardiac cycle was fixed at 800 ms. An operator-independent procedure was used to calculate instantaneous and total systolic external work, mean diastolic aorto-ventricular pressure difference and ventricular stroke volume. RESULTS: The mean value of stroke volume for the three different length rubber tubes was 320 +/- 71, 348 +/- 77 and 368 +/- 87 microliters, respectively. The mean value of total external work was 20.3 +/- 8.3, 22.5 +/- 8.8 and 24.2 +/- 9.6 mJ, respectively. The mean aortoventricular pressure difference was 40 +/- 12, 46 +/- 13, 50 +/- 14 mmHg, respectively (1 mmHg = 133 Pa). The differences between the parameters measured in the three conditions were statistically significant (p < 0.05). A reduction of reflection timing, reduces, on a pure mechanical basis, cardiac output and external ventricular work and has a negative effect on coronary driving pressure.     

MRI-determined left ventricular "crescent effect": a consequence of the slight deviation of contents of the pericardial sack from the constant-volume state

During one cardiac cycle, the volume encompassed by the pericardial sack in healthy subjects remains nearly constant, with a transient +/-5% decrease in volume at end systole. This "constant-volume" attribute defines a constraint that the longitudinal versus radial pericardial contour dimension relationship must obey. Using cardiac MRI, we determined the extent to which the constant-volume attribute is valid from four-chamber slices (two-dimensional) compared with three-dimensional volumetric data. We also compared the relative percentage of longitudinal versus radial (short-axis) change in cross-sectional area (dimension) of the pericardial contour, thereby assessing the fate of the +/-5% end-systolic volume decrease. We analyzed images from 10 normal volunteers and 1 subject with congenital absence of the pericardium, obtained using a 1.5-T MR scanner. Short-axis cine loop stacks covering the entire heart were acquired, as were single four-chamber cine loops. In the short-axis and four-chamber slices, relative to midventricular end-diastolic location, end-systolic pericardial (left ventricular epicardial) displacement was observed to be radial and maximized at end systole. Longitudinal (apex to mediastinum) pericardial contour dimension change and pericardial area change on the four-chamber slice were negligible throughout the cardiac cycle. We conclude that the +/-5% end-systolic decrease in the volume encompassed by the pericardial sack is primarily accounted for by a "crescent effect" on short-axis views, manifesting as a nonisotropic radial diminution of the pericardial/epicardial contour of the left ventricle. This systolic drop in cardiac volume occurs primarily at the ventricular level and is made up during the subsequent diastole when blood crosses the pericardium in the pulmonary venous Doppler D wave during early rapid left ventricular filling.     

Developmental changes in left and right ventricular diastolic filling patterns in mice

Developmental changes in left and right ventricular diastolic filling patterns were determined noninvasively in isoflurane-anesthetized outbred ICR mice. Blood velocities in the mitral and tricuspid orifices were recorded in 16 embryos at days 14.5 (E14.5) and 17.5 of gestation (E17.5) using an ultrasound biomicroscope and also serially in three groups of postnatal mice aged 1-7 days (n = 23), 1-4 wk (n = 18), and 4-12 wk (n = 27) using 20-MHz pulsed Doppler. Postnatal body weight increased rapidly to 8 wk. Heart rate increased rapidly from approximately 180 beats/min at E14.5 to approximately 380 beats/min at 1 wk after birth and then more gradually to plateau at approximately 450 beats/min after 4 wk. Ventricular filling was quantified using the ratio of peak velocity of early ventricular filling due to active relaxation (E wave) to that of the late ventricular filling caused by atrial contraction (A wave) (peak E/A ratio) and the ratio of the peak E velocity to total time-velocity integral of E and A waves (peak E/total TVI ratio). Both ventricles had similar diastolic filling patterns in embryos (peak E/A ratio of 0.28 +/- 0.02 for mitral flow and 0.27 +/- 0.02 for tricuspid flow at E14.5). After birth, mitral peak E/A increased to >1 between the third and fifth day, continued to increase to 2.25 +/- 0.25 at approximately 3 wk, and then remained stable. The tricuspid peak E/A ratio increased much less but stabilized at the same age (increased to 0.79 +/- 0.03 at 3 wk). The peak E/total TVI ratio showed similar left-right differences and changes with development. Age-related changes were largely due to increases in peak E velocity. The results suggest that diastolic function matures approximately 3 wk postnatally, presumably in association with maturation of ventricular recoil and relaxation mechanisms.     

Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI(193His) mice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI(193His) mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.     

MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load?

Changes in diastolic indexes during normal aging, including reduced early filling velocity (E), lengthened E deceleration time (DT), augmented late filling (A), and prolonged isovolumic relaxation time (IVRT), have been attributed to slower left ventricular (LV) pressure (LVP) decay. Indeed, this constellation of findings is often referred to as the "abnormal relaxation" pattern. However, LV filling is determined by the atrioventricular pressure gradient, which depends on both LVP decline and left atrial (LA) pressure (LAP). To assess the relative influence of LVP decline and LAP, we studied 122 normal subjects aged 21-92 yr by Doppler echocardiography and MRI. LVP decline was assessed by color M-mode (V(p)) and the LV untwisting rate. Early diastolic LAP was evaluated using pulmonary vein flow systolic fraction, pulmonary vein flow diastolic DT, color M-mode (E/V(p)), and tissue Doppler (E/E(m)). Linear regression showed the expected reduction of E, increase in A, and prolongation of IVRT and DT with advancing age. There was no relation of age to parameters reflecting the rate of LVP decline. However, older age was associated with reduced E/V(p) (P = 0.008) and increased pulmonary vein systolic fraction (P < 0.001), pulmonary vein DT (P = 0.0026), and E/E(m) (P < 0.0001), all suggesting reduced early LAP. Therefore, reduced early filling in older adults may be more closely related to a reduced early diastolic LAP than to slower LVP decline. This effect also explains the prolonged IVRT. We postulate that changes in LA active or passive properties may contribute to development of the abnormal relaxation pattern during the aging process.     

Left ventricular diastolic filling in young persons with type 1 diabetes mellitus

The purpose of this study was to evaluate the influence of diabetes mellitus on left ventricular function. Using Doppler echocardiography we examined a group of 49 young (20-32 years old) persons with type 1 diabetes mellitus and a group of healthy age-matched men and evaluated the parameters of diastolic filling of the left ventricle (LV). We found significant differences in peak velocity of early filling of the left ventricle ((70.07+/-10.84 vers. 78.2+/-10.59 cm.s(-1), p+/-0. 01), peak velocity of late diastolic filling of LV (A = 47.74+/-11.6 vers. 43.15+/-7.48 cm.s(-1), p < or = 0.027), ratio E/A (1.53+/-0.4 vers. 1.84+/-0.33), time velocity integral of peak E (TVIE = 0.083+/-0.014 vers. 0.1+/-0.022 m, p < or = 0.001), time velocity integral of peak A (TVIA = 0.039+/-0.011 vers. 0.037+/-0.012 m, p < or = 0.3), ratio TVIE/TVIA (2.3+/-0.73 vers. 2.9+/-0.9, p < or = 0.001), time E (204.4+/-31.59 vers. 198.4+/-19.09 ms, p < or = 0.27), time A (126.9 < or = 23.0 vers. 113.5+/-15.59 ms, p < or = 0.002), time E/time A (1.64+/-0.3 vers. 1.76+/-0.22, p < or = 0.039) and duration of isovolumic relaxation period (IVRT = 88.2+/-10.8 vers. 71.13+/-8.4 ms, p < or = 0.0001). Despite significant differences all the results were in the range of values for the healthy population. However in detailed analysis we found that the values measured in young (20-32 years old) persons with type 1 diabetes mellitus corresponded with diastolic parameters of healthy men of the age of 50 years and more. Thus, diabetes mellitus can influence the relaxation properties of the left ventricle.