Computational modeling of left heart diastolic function: examination of ventricular dysfunction

A computational model that accounts for blood-tissue interaction under physiological flow conditions was developed and applied to a thin-walled model of the left heart. This model consisted of the left ventricle, left atrium, and pulmonary vein flow. The input functions for the model included the pulmonary vein driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The Immersed Boundary Method was used for the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology, and the fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). This model was used to examine the flow fields in the left heart under abnormal diastolic conditions of delayed ventricular relaxation, delayed ventricular relaxation with increased ventricular stiffness, and delayed ventricular relaxation with an increased atrial contraction. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions, and to the results from simulations of normal diastolic function in this model [1]. Cases involving impairment of diastolic function were modeled with changes to the input functions for fiber relaxation/contraction of the chambers. The three cases of diastolic dysfunction investigated agreed with the changes in diastolic flow fields seen clinically. The effect of delayed relaxation was to decrease the early filling magnitude, and this decrease was larger when the stiffness of the ventricle was increased. Also, increasing the contraction of the atrium during atrial systole resulted in a higher late filling velocity and atrial pressure. The results show that dysfunction can be modeled by changing the relationships for fiber resting-length and/or stiffness. This provides confidence in future modeling of disease, especially changes to chamber properties to examine the effect of local dysfunction on global flow fields.     

Molecular mechanism of the E99K mutation in cardiac actin (ACTC Gene) that causes apical hypertrophy in man and mouse

We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to β-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.     

Thermodynamic phase plane analysis of ventricular contraction and relaxation

Background  

Ventricular function has conventionally been characterized using indexes of systolic (contractile) or diastolic (relaxation/stiffness) function. Systolic indexes include maximum elastance or equivalently the end-systolic pressure volume relation and left ventricular ejection fraction. Diastolic indexes include the time constant of isovolumic relaxation - and the end-diastolic pressure-volume relation. Conceptualization of ventricular contraction/relaxation coupling presents a challenge when mechanical events of the cardiac cycle are depicted in conventional pressure, P, or volume, V, terms. Additional conceptual difficulty arises when ventricular/vascular coupling is considered using P, V variables.     

Cell-intrinsic functional effects of the α-cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy

Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in β-cardiac myosin. Mice heterozygous for this mutation in the α-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy.     

Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse

Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice (P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively (P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies.     

Diabetic kidney disease in FVB/NJ Akita mice: temporal pattern of kidney injury and urinary nephrin excretion

Akita mice are a genetic model of type 1 diabetes. In the present studies, we investigated the phenotype of Akita mice on the FVB/NJ background and examined urinary nephrin excretion as a marker of kidney injury. Male Akita mice were compared with non-diabetic controls for functional and structural characteristics of renal and cardiac disease. Podocyte number and apoptosis as well as urinary nephrin excretion were determined in both groups. Male FVB/NJ Akita mice developed sustained hyperglycemia and albuminuria by 4 and 8 weeks of age, respectively. These abnormalities were accompanied by a significant increase in systolic blood pressure in 10-week old Akita mice, which was associated with functional, structural and molecular characteristics of cardiac hypertrophy. By 20 weeks of age, Akita mice developed a 10-fold increase in albuminuria, renal and glomerular hypertrophy and a decrease in the number of podocytes. Mild-to-moderate glomerular mesangial expansion was observed in Akita mice at 30 weeks of age. In 4-week old Akita mice, the onset of hyperglycemia was accompanied by increased podocyte apoptosis and enhanced excretion of nephrin in urine before the development of albuminuria. Urinary nephrin excretion was also significantly increased in albuminuric Akita mice at 16 and 20 weeks of age and correlated with the albumin excretion rate. These data suggest that: 1. FVB/NJ Akita mice have phenotypic characteristics that may be useful for studying the mechanisms of kidney and cardiac injury in diabetes, and 2. Enhanced urinary nephrin excretion is associated with kidney injury in FVB/NJ Akita mice and is detectable early in the disease process.     

Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(min)) decreased by 25 +/- 2% (P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 +/- 5% and 25 +/- 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) increased by 62 +/- 10% (P < 0.05) and the stiffness constant (k) increased by 66 +/- 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 +/- 25% and 63 +/- 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.     

Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure

Aging is associated with profound changes in the structure and function of the heart. A fundamental understanding of these processes, using relevant animal models, is required for effective prevention and treatment of cardiovascular disease in the elderly. Here, we studied cardiac performance in 4- to 5-mo-old (young) and 24- to 26-mo-old (old) Fischer 344 male rats using the Millar pressure-volume (P-V) conductance catheter system. We evaluated systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), maximal slope of the systolic pressure increment (+dP/dt), and its relation to end-diastolic volume (+dP/dt-EDV) as well as the time constant of left ventricular pressure decay, as an index of relaxation. The slope of the end-diastolic P-V relation (EDPVR), an index of left ventricular stiffness, was also calculated. Aging was associated with decrease in left ventricular systolic pressure, +dP/dt, maximal slope of the diastolic pressure decrement, +dP/dt-EDV, PRSW, ejection fraction, stroke volume, cardiac and stroke work indexes, and efficiency. In contrast, total peripheral resistance, left ventricular end-diastolic volume, left ventricular end-diastolic pressure, and EDPVR were greater in aging than in young animals. Taken together, these data suggest that advanced aging is characterized by decreased systolic performance accompanied by delayed relaxation and increased diastolic stiffness of the heart in male Fischer 344 rats. P-V analysis is a sensitive method to determine cardiac function in rats.     

Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein alpha-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy, with death ensuing by 6 mo. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric alpha-/beta-TM protein that decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the FHC mutation. These double-transgenic mice "rescue" the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.     

Mechanics of left ventricular relaxation, early diastolic lengthening, and suction investigated in a mathematical model

We investigated the determinants of ventricular early diastolic lengthening and mechanics of suction using a mathematical model of the left ventricle (LV). The model was based on a force balance between the force represented by LV pressure (LVP) and active and passive myocardial forces. The predicted lengthening velocity (e') from the model agreed well with measurements from 10 dogs during 5 different interventions (R = 0.69, P < 0.001). The model showed that e' was increased when relaxation rate and systolic shortening increased, when passive stiffness was decreased, and when the rate of fall of LVP during early filling was decreased relative to the rate of fall of active stress. We first defined suction as the work the myocardium performed to pull blood into the ventricle. This occurred when contractile active forces decayed below and became weaker than restoring forces, producing a negative LVP. An alternative definition of suction is filling during falling pressure, commonly believed to be caused by release of restoring forces. However, the model showed that this phenomenon also occurred when there had been no systolic compression below unstressed length and therefore in the absence of restoring forces. In conclusion, relaxation rate, LVP, systolic shortening, and passive stiffness were all independent determinants of e'. The model generated a suction effect seen as lengthening occurring during falling pressure. However, this was not equivalent with the myocardium performing pulling work on the blood, which was performed only when restoring forces were higher than remaining active fiber force, corresponding to a negative transmural pressure.     

Dissociation between myocardial relaxation and diastolic stiffness in the stunned heart: its prevention by ischemic preconditioning

The effects of myocardial stunning and ischemic preconditioning on left-ventricular developed pressure and end-diastolic pressure (diastolic stiffness) as well as on coronary-perfusion pressure were examined in isolated isovolumic rabbit hearts. The isovolumic relaxation was evaluated, and the time constant of pressure decay during the isovolumic period was calculated. Our experimental protocol comprised: 1) myocardial stunning-global ischemia (15 min) followed by reperfusion (30 min); 2) myocardial stunning-global ischemia (20 min) followed by reperfusion (30 min); and 3) ischemic preconditioning — a single cycle of brief global ischemia and reperfusion (5 min each), before a second ischemic period, of 20-min duration. There was no effect upon systolic and diastolic parameters when 15 and 20 minutes of ischemia were evaluated. In both stunned groups the left ventricular developed pressure first recovered to near control values, but then stabilized at only 60% of the control values. Whereas the isovolumic relaxation time constant was increased after 5 min of reperfusion, and return to control values at late reperfusion, the end diastolic pressure remained elevated during the entire period. Values of dP/dV calculated at common pressure levels, were used as a second index of diastolic stiffness. They were increased after stunning, as also was the coronary perfusion pressure. When the heart was preconditioned with a single episode of ischemia, the systolic and diastolic alterations were completely abolished. We thus concluded that diastolic abnormalities incurred by myocardial stunning consist in both an increase in diastolic stiffness and an early impairment of isovolumic relaxation. The increase in stiffness cannot result from incomplete relaxation since these two parameters become temporally dissociated during the reperfusion period.     

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Cardiac troponin I (TnI) knockout mice exhibit a phenotype of sudden death at 17-18 days after birth due to a progressive loss of TnI. The objective of this study was to gain insight into the physiological consequences of TnI depletion and the cause of death in these mice. Cardiac function was monitored serially between 12 and 17 days of age by using high-resolution ultrasonic imaging and Doppler echocardiography. Two-dimensional B-mode and anatomical M-mode imaging and Doppler echocardiography were performed using a high-frequency ( approximately 20-45 MHz) ultrasound imaging system on homozygous cardiac TnI mutant mice (cTnI(-/-)) and wild-type littermates. On day 12, cTnI(-/-) mice were indistinguishable from wild-type mice in terms of heart rate, atrial and LV (LV) chamber dimensions, LV posterior wall thickness, and body weight. By days 16 through 17, wild-type mice showed up to a 40% increase in chamber dimensions due to normal growth, whereas cTnI(-/-) mice showed increases in atrial dimensions of up to 97% but decreases in ventricular dimensions of up to 70%. Mitral Doppler analysis revealed prolonged isovolumic relaxation time and pronounced inversion of the mitral E/A ratio (early ventricular filling wave-to-late atrial contraction filling wave) only in cTnI(-/-) mice indicative of impaired LV relaxation. cTnI(-/-) mouse hearts showed clear signs of failure on day 17, characterized by >50% declines in cardiac output, ejection fraction, and fractional shortening. B-mode echocardiography showed a profoundly narrowed tube-like LV and enlarged atria at this time. Our data are consistent with TnI deficiency causing impaired LV relaxation, which leads to diastolic heart failure in this model.     

Isovolumic pressure-to-early rapid filling decay rate relation: model-based derivation and validation via simultaneous catheterization echocardiography.

Transmitral Doppler echocardiography is the preferred method of noninvasive diastolic function assessment. Correlations between catheterization-based measures of isovolumic relaxation (IVR) and transmitral, early rapid filling (Doppler E-wave)-derived parameters have been observed, but no model-based, causal explanation has been offered. IVR has also been characterized in terms of its duration as IVR time (IVRT) and by tau, the time-constant of IVR, by approximating the terminal left ventricular IVR pressure contour as Pt= Pinfinity + P(o)e(-t/tau), where Pt is the continuity of pressure, Pinfinity and Po are constants, t is time, and tau is the time constant of IVR. To characterize the relation between IVR and early rapid filling more fully, simultaneous (micromanometric) left ventricular pressure and transmitral Doppler E-wave data from 25 subjects undergoing elective cardiac catheterization and having normal physiology were analyzed. The time constant tau was determined from the dP/dt vs. P (phase) plane and, simultaneous Doppler E-waves provided global indexes of chamber viscosity/relaxation (c), chamber stiffness (k), and load (xo). We hypothesize that temporal continuity of pressure decay at mitral valve opening and physiological constraints permit the algebraic derivation of linear relations relating 1/tau to both peak atrioventricular pressure gradient (kxo) and E-wave-derived viscosity/relaxation (c) but does not support a similar, causal (linear) relation between deceleration time and tau or IVRT. Both predicted linear relations were observed: kxo to 1/tau (r = 0.71) and viscosity/relaxation to 1/tau (r = 0.71). Similarly, as anticipated, only a weak linear correlation between deceleration time and IVRT or tau was observed (r = 0.41). The observed in vivo relationship provides insight into the isovolumic mechanism of relaxation and the changing-volume mechanism of early rapid filling via a link of the respective relaxation properties.     

Cardiac structural and functional responses to salt loading in SHR

Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (V(E)/V(A)), and slower propagation velocity of E wave (V(P)). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased V(E)/V(P), an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.     

cTnT^R92Q转基因小鼠肥厚型心肌病模型的建立

目的建立cTnT^R92Q肥厚型心肌病的转基因小鼠模型。方法把cTnT^R92Q基因插入-αMHC启动子下游,构建转基因表达载体,通过显微注射法建立cTnT^R92Q转基因C57BL/6J小鼠。PCR鉴定cTnT^R92Q转基因小鼠的基因表型,RT-PCR检测基因表达,光学显微镜和超声检测cTnT^R92Q转基因小鼠心脏的病理改变。结果建立了3个不同表达水平的cTnT^R92Q转基因小鼠品系。转入的cTnT^R92Q基因在心脏组织的表达水平高于内源性cTnT。组织学分析显示cTnT^R92Q转基因小鼠心脏变大,心室壁肥厚,心腔变小,心肌细胞排列紊乱,心肌间质纤维增多。超声检查显示心室壁变厚,收缩期容积和舒张期容积显著缩小,射血分数、短轴缩短率明显增加。结论cTnT^R92Q转基因小鼠心脏变大,室壁变厚,心腔变小,心肌细胞排列紊乱,间质纤维化以及心肌舒张功能失调,说明成功建立了cTnT^R92Q转基因小鼠肥厚型心肌病模型,为研究肥厚型心肌病发病机制和药物研发提供了有价值的动物模型。     

Dyschalasia: A Variant or Early Phase of Achalasia?: A Review of Motor Disturbances in Achalasia with Reference to Late Relaxation of the Lower Esophageal Sphincter

One of the characteristic motor abnormalities in achalasia of the esophagus is the lack of relaxation of the lower esophageal sphincter during swallowing. In a subject with a clinical history and radiologic evidence of early achalasia all the typical motor abnormalities of the disease were observed in the course of pressure studies, but the sphincter exhibited a fall of pressure in response to a contraction of the body of the esophagus. This relaxation occurred later than would be expected in the normal esophagus and, therefore, this unusual condition was named dyschalasia.The relationship of dyschalasia to classical achalasia is discussed and several theories are advanced. The authors believe that dyschalasia is possibly an early stage of achalasia.     

Noninvasive cardiovascular phenotyping in mice

With the growth of genetic engineering, mice have become common as models of human diseases, which in turn has stimulated the development of techniques to monitor and image the murine cardiovascular system. Invasive methods are often more quantitative, but noninvasive methods are preferred when measurements must be repeated serially on living animals during development or in response to pharmacological or surgical interventions. Because of the small size and high heart rates in mice, high spatial and temporal resolutions are required to preserve signal fidelity. Monitoring of body temperature and the electrocardiogram is essential when animals must be anesthetized for a measurement or other procedure. Several other groups have developed cardiovascular imaging modalities suitable for murine applications, and ultrasound is the most widely used. Our group has developed and applied high-resolution Doppler probes and signal processing for measuring blood velocity in the heart and peripheral vessels of anesthetized mice noninvasively. We can measure cardiac filling and ejection velocities as indices of systolic and diastolic ventricular function and for timing of cardiac events; velocity pulse arrival times for determining pulse-wave velocity and arterial stiffness; peripheral velocity waveforms as indices of arterial resistance, compliance, and wave reflections; stenotic velocities for estimation of pressure drop and detection of vorticity; and tail artery velocity for determining systolic and diastolic blood pressure using a pressure cuff. These noninvasive methods are convenient and easy to apply and have been used to detect and evaluate numerous cardiovascular phenotypes in mutant mice.     

Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction

The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca(2+) sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca(2+)-Mg(2+) binding site of HCRLC, which demonstrated no Ca(2+) binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca(2+) sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca(2+) binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.     

Myocardial diastolic elasticity in chronic adriamycin lesion

Isolated hearts of the majority of rats receiving 20 mg/kg adriamycin for 10 weeks exhibited normal pump function. Left ventricular diastolic stiffness of these hearts was approximately 1.5 times higher, as compared to control hearts, with the filling pressure in the range of 5 to 20 cm H2O and diastolic pause 23% longer due to bradycardia. Pacing-induced increase in the heart rate up to the control level resulted in further increase in left ventricular diastolic stiffness due to the rise in myocardial stiffness, associated with a fall in cardiac output by 36%. The heart and right atrial compliance determined in separate experiments did not differ significantly from the control. The results suggest that increased left ventricular diastolic stiffness of adriamycin-treated rats seems to be rather due to energy-dependent disturbance in myofibril relaxation than to usually arising myocardial fibrosis.     

Diastolic ventricular-vascular stiffness and relaxation relation: elucidation of coupling via pressure phase plane-derived indexes

Because systole and diastole are coupled and systolic ventricular-vascular coupling has been characterized, we hypothesize that diastolic ventricular-vascular coupling (DVVC) exists and can be characterized in terms of relaxation and stiffness. To characterize and elucidate DVVC mechanisms, we introduce time derivative of pressure (dP/dt) vs. time-varying pressure [P(t)] (pressure phase plane, PPP)-derived analogs of ventricular and vascular "stiffness" and relaxation parameters. Although volume change (dV) = 0 during isovolumic periods, and time-varying left ventricular (LV) stiffness, typically expressed as change in pressure per unit change in volume (dP/dV), is undefined, our formulation allows determination of a PPP-derived stiffness analog during isovolumic contraction and relaxation. Similarly, an aortic stiffness analog is also derivable from the PPP. LV relaxation was characterized via tau, the time constant of isovolumic relaxation, and vascular (aortic pressure decay) relaxation was characterized in terms of its equivalent (windkessel) exponential decay time constant kappa. The results show that PPP-derived systolic and diastolic ventricular and vascular stiffness are strongly coupled [K(Ao)(+)=1.71(K(LV)(+)) +154, r=0.86; K(Ao)(-)=0.677(K(LV)(-))-5.53, r=0.86]. In support of the DVVC hypothesis, a strong linear correlation between relaxation (rate of pressure decay) indexes kappa and tau (kappa = 9.89tau - 90.3, r = 0.81) was also observed. The correlations observed underscore the role of long-term, steady-state DVVC as a diastolic function determinant. Awareness of the PPP-derived DVVC parameters provides insight into mechanisms and facilitates quantification of arterial stiffening and associated increase in diastolic chamber stiffness. The PPP method provides a tool for quantitative assessment and determination of the functional coupling of the vasculature to diastolic function.