Diastolic Chamber Stiffness Research Articles

Catestatin Protects Against Diastolic Dysfunction by Attenuating Mitochondrial Reactive Oxygen Species Generation.

Background Catestatin has been reported as a pleiotropic cardioprotective peptide. Heart failure with preserved ejection fraction (HFpEF) was considered a heterogeneous syndrome with a complex cause. We sought to investigate the role of catestatin in HFpEF and diastolic dysfunction. METHODS AND RESULTS Administration of recombinant catestatin (1.5 mg/kg/d) improved diastolic dysfunction and left ventricular chamber stiffness in transverse aortic constriction mice with deoxycorticosterone acetate pellet implantation, as reflected by Doppler tissue imaging and pressure-volume loop catheter. Less cardiac hypertrophy and myocardial fibrosis was observed, and transcriptomic analysis revealed downregulation of mitochondrial electron transport chain components after catestatin treatment. Catestatin reversed mitochondrial structural and respiratory chain component abnormality, decreased mitochondrial proton leak, and reactive oxygen species generation in myocardium. Excessive oxidative stress induced by Ru360 abolished catestatin treatment effects on HFpEF-like cardiomyocytes in vitro, indicating the beneficial role of catestatin in HFpEF as a mitochondrial ETC modulator. The serum concentration of catestatin was tested among 81 patients with HFpEF and 76 non-heart failure controls. Compared with control subjects, serum catestatin concentration was higher in patients with HFpEF and positively correlated with E velocity to mitral annular e' velocity ratio, indicating a feedback compensation role of catestatin in HFpEF. Conclusions Catestatin protects against diastolic dysfunction in HFpEF through attenuating mitochondrial electron transport chain-derived reactive oxygen species generation. Serum catestatin concentration is elevated in patients with HFpEF, probably as a relatively insufficient but self-compensatory mechanism.

Predictive value of left ventricular diastolic chamber stiffness in patients with severe aortic stenosis undergoing aortic valve replacement.

Despite improvements in cardiac haemodynamics and symptoms, long-term mortality remains increased in some patients after aortic valve replacement (AVR). Limited data exist on the prognostic role of left ventricular (LV) chamber stiffening in these patients. We performed a retrospective analysis in 1893 patients with severe aortic stenosis (AS) referred for AVR. LV end-diastolic pressure-volume relations (EDPVR, P = αV^β) were reconstructed from echocardiographic measurements of end-diastolic volumes and estimates of end-diastolic pressure (EDP). The impact of EDPVR-derived LV chamber stiffness (CS30, at 30 mmHg EDP) on all-cause mortality after AVR was evaluated. Mean age was 76 ± 10 years, 39% were females, and ejection fraction (EF) was 61 ± 12%. The mean LV chamber stiffness (CS30) was 2.2 ± 1.3 mmHg/mL. A total of 877 (46%) patients had high LV stiffness (CS30 >2 mmHg/mL). In these patients, the EDPVR curves were steeper and shifted leftwards, indicating higher stiffness at all pressure levels. These patients were slightly older, more often female, and had more prevalent comorbidities compared to patients with low stiffness. At follow-up [median 4.2 (interquartile range 2.8-6.3) years; 675 deaths], a higher CS30 was associated with lower survival (hazard ratio: 2.7 for severe vs. mild LV stiffening; P < 0.0001), both in patients with normal or reduced EF. At multivariate analysis, CS30 remained an independent predictor, even after adjusting for age, sex, comorbidities, EF, LV remodelling, and diastolic dysfunction. Higher preoperative LV chamber stiffening in patients with severe AS is associated with poorer outcome despite successful AVR.

Myocardial Stiffness by Intrinsic Cardiac Elastography in Patients with Amyloidosis: Comparison with Chamber Stiffness and Global Longitudinal Strain

The aim of this study was to test the hypothesis that intrinsic cardiac elastography can detect diastolic tissue abnormalities produced by cardiac amyloid infiltration and that measurements may have incremental value beyond traditional echocardiographic measures. The specific aims were (1) to evaluate the relationship between left ventricular myocardial stiffness (by elastography) and measures of diastolic chamber stiffness and systolic strain in patients with amyloidosis and (2) to compare their prognostic potential. We prospectively studied 67 patients with amyloidosis (cardiac amyloidosis, n=48; noncardiac amyloidosis, n=19) and 40 normal subjects. Patients underwent comprehensive echocardiography including measurement of left ventricular global longitudinal strain (GLS) by speckle-tracking. Intrinsic velocity propagation of myocardial stretch (iVP), a direct measure of myocardial elasticity, was quantified using intrinsic cardiac elastography. Chamber stiffness was evaluated from the end-diastolic pressure-volume relationships (P=αVβ). The major end point at follow-up was the composite of death, cardiac hospitalization, worsening heart failure, and stroke. The iVP of myocardial stretch was highest in patients with cardiac amyloidosis compared with those with noncardiac amyloidosis and normal subjects (3.2±1.0, 1.8±0.4, and 1.6±0.2m/sec, respectively; P<.0001) and correlated with chamber stiffness, function, and structure (β coefficient, operating chamber stiffness, GLS, wall thickness; P≤.001 for all). At follow-up (median, 2.6years), measures of left ventricular and myocardial stiffness, GLS, diastolic dysfunction grade, and N-terminal pro-brain natriuretic peptide were associated with excess events. At multivariate analysis, iVP of myocardial stretch remained an independent predictor of adverse events, incremental to GLS and N-terminal pro-brain natriuretic peptide. Measurements by cardiac elastography correlate with functional and structural derangements produced by cardiac amyloid infiltration but provide unique information that is incremental to conventional echocardiography.

Impact of Epicardial Adipose Tissue in Heart Failure with Preserved Ejection Fraction

IntroductionObesity is a strong risk factor for heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF patients with obesity display distinct structural and functional changes in the heart compared to non-obese HFpEF. In addition to generalized obesity, fat distribution may also be important. Prior studies have shown that epicardial adipose tissue (EAT) is associated with inflammation, atrial fibrillation and cardiac fibrosis. Based upon its location, EAT might also influence hemodynamics and ventricular interaction via direct mechanical effects. However, no study has directly evaluated the impact of EAT content in HFpEF.HypothesisWe hypothesized that among patients with obesity and HFpEF, those with excess EAT (EAT+, n=77) would display more deranged hemodynamics compared to obese HFpEF patients without excess EAT (EAT−, n=92).MethodsPatients underwent invasive hemodynamic cardiopulmonary exercise testing and echocardiography. Obesity was defined by BMI≥30 kg/m2 and excess EAT was defined by EAT thickness ≥9mm by echocardiography. Ventricular interaction was assessed by the left ventricular eccentricity index (LVecc), where higher values indicate greater interdependence.ResultsEAT+ and EAT− patients displayed similar cardiac structure and function (Table). However, compared to EAT−, LVecc were elevated in EAT+. Right atrial (RA), pulmonary artery (PA), and pulmonary capillary wedge pressures (PCWP) were higher at rest and during exercise in EAT+ compared to EAT−, despite similar diastolic chamber stiffness (β) among EAT+ and EAT−. Peak VO2 was reduced in both groups, but was significantly lower in EAT+ compared to EAT−.ConclusionAmong patients with the obese phenotype of HFpEF, the presence of increased EAT is associated with more profound hemodynamic derangements at rest and exercise, greater pericardial restraint, and poorer exercise capacity (VO2). Further study is needed to understand the biology and potential treatment of excessive EAT in patients with HFpEF. Obesity is a strong risk factor for heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF patients with obesity display distinct structural and functional changes in the heart compared to non-obese HFpEF. In addition to generalized obesity, fat distribution may also be important. Prior studies have shown that epicardial adipose tissue (EAT) is associated with inflammation, atrial fibrillation and cardiac fibrosis. Based upon its location, EAT might also influence hemodynamics and ventricular interaction via direct mechanical effects. However, no study has directly evaluated the impact of EAT content in HFpEF. We hypothesized that among patients with obesity and HFpEF, those with excess EAT (EAT+, n=77) would display more deranged hemodynamics compared to obese HFpEF patients without excess EAT (EAT−, n=92). Patients underwent invasive hemodynamic cardiopulmonary exercise testing and echocardiography. Obesity was defined by BMI≥30 kg/m2 and excess EAT was defined by EAT thickness ≥9mm by echocardiography. Ventricular interaction was assessed by the left ventricular eccentricity index (LVecc), where higher values indicate greater interdependence. EAT+ and EAT− patients displayed similar cardiac structure and function (Table). However, compared to EAT−, LVecc were elevated in EAT+. Right atrial (RA), pulmonary artery (PA), and pulmonary capillary wedge pressures (PCWP) were higher at rest and during exercise in EAT+ compared to EAT−, despite similar diastolic chamber stiffness (β) among EAT+ and EAT−. Peak VO2 was reduced in both groups, but was significantly lower in EAT+ compared to EAT−. Among patients with the obese phenotype of HFpEF, the presence of increased EAT is associated with more profound hemodynamic derangements at rest and exercise, greater pericardial restraint, and poorer exercise capacity (VO2). Further study is needed to understand the biology and potential treatment of excessive EAT in patients with HFpEF.

Heat Acclimatization Protects the Left Ventricle from Increased Diastolic Chamber Stiffness Immediately after Coronary Artery Bypass Surgery: A Lesson from 30 Years of Studies on Heat Acclimation Mediated Cross Tolerance.

During the period of 1986–1997 the first 4 publications on the mechanical and metabolic properties of heat acclimated rat's heart were published. The outcome of these studies implied that heat acclimation, sedentary as well as combined with exercise training, confers long lasting protection against ischemic/reperfusion insult. These results promoted a clinical study on patients with coronary artery disease scheduled for elective coronary artery bypass operations aiming to elucidate whether exploitation of environmental stress can be translated into human benefits by improving physiological recovery. During the 1998 study, immediate-post operative chamber stiffness was assessed in patients acclimatized to heat and low intensity training in the desert (spring in the Dead Sea, 17–33°C) vs. patients in colder weather (spring in non-desert areas, 6–19°C) via echocardiogram acquisition simultaneous with left atrial pressure measurement during fast intravascular fluid bolus administration. We showed that patients undergoing “heat acclimatization combined with exercise training” were less susceptible to ischemic injury, therefore expressing less diastolic dysfunction after cardiopulmonary bypass compared to non-acclimatized patients. This was the first clinical translational study on cardiac patients, while exploiting environmental harsh conditions for human benefits. The original experimental data are described and discussed in view of the past as well as the present knowledge of the protective mechanisms induced by Heat Acclimation Mediated Cross-tolerance.

Left Atrial Remodeling and Atrioventricular Coupling in a Canine Model of Early Heart Failure With Preserved Ejection Fraction

Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13-24]% versus 12 [10-14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9-3.2]mm Hg/mL HFpEF versus 1.5 [1.2-2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [βLA] 0.16 [0.11-0.18]mm Hg/mL versus 0.06 [0.04-0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with βLA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with βLA. In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

Abstract 16054: Ventricular-Arterial Coupling Biphasically Correlates to Ventricular Diastolic Chamber Stiffness in Children–Association With Aldosterone Activation

Introduction: Left ventricular–arterial coupling (LVAC), the ratio of end–systolic to effective arterial elastance (Ees/Ea), determines end–systolic pressure and stroke volume in a given preload. LV diastolic chamber stiffness (LV–K) is an important diastolic property to affect LV filling. However, the relationship between Ees/Ea and LV–K in children remains unestablished. Aldosterone (ALD) accelerates LV and arterial stiffening. Hypothesis: This study was undertaken to test the hypothesis that Ees/Ea may affect LV–K through ALD regulation in children. Methods: During catheterizations for children with biventricular circulation (N=75, median 2.5 years), blood samples for ALD were collected, and LV pressure and area relationships (PAR) were recorded using high-fidelity pressure–guidewire and echocardiographic AQ method during steady state and transient IVC occlusion. LV–K was obtained by dividing the pressure difference between LV minimal and end-diastolic pressure (EDP) by stroke volume. ALD levels were transformed into common logarithm. Results: Ees/Ea biphasically correlated to LV–K, which was approximated by downward convex parabola with a minimum at 0.9 of Ees/Ea (R=0.61, P&lt;0.0001). Ees/Ea also bipahsically correlated to log ALD, which was approximated by downward convex parabola with a minimum at 0.8 of Ees/Ea (R=0.45, P&lt;0.005). Moreover, LV–K linearly correlated to log ALD (R=0.38, P&lt;0.005). There was no significant relationship between LV–K and relative wall thickness. Conclusions: To our knowledge, this is the first study to demonstrate that Ees/Ea bipahsically correlated to LV–K and ALD. Dilated LV with low Ees/Ea accompanies elevated filling pressure and shows restrictive physiology with higher LV–K. On the other hand, when Ees/Ea is higher than normal range, this study indicates that there should be an increased LV diastolic stiffness which is not always associated with wall hypertrophy. Because LVAC abnormality may induce LV stiffening associated with ALD activation, chronic inhibition therapy of renin–angiotensin system to keep Ees/Ea within appropriate range may inhibit LV stiffening directly and through LVAC &amp; LV–K interaction.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism But Has a Beneficial Effect on Diastole

Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography. Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(ΔRRM)mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20(ΔRRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(ΔRRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(ΔRRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice. Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.

Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism but has a Beneficial Effect on Diastole

Background. Experimentally upregulating compliant titins has been suggested as a possible therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study.Here we investigate the effect of upregulating compliant titins on diastolic and systolic function in a novel mouse model that we made with a genetically altered titin splicing factor. We employed integrative approaches from intact cardiomyocytes studied with a carbon-fiber force-measuring system to the left ventricular (LV) chamber studied with pressure(P)-volume(V) analysis and Doppler echocardiography. Methods and Results. Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20(Rbm20ΔRRMmice). At both cardiomyocyte and LV chamber levels diastolic stiffness was reduced in heterozygous (+/-) Rbm20ΔRRMmice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20ΔRRM hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20ΔRRM mice, at both the cardiomyocyte and LV chamber levels.Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions. Results support that titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titin isoforms reduces diastolic chamber stiffness due to increased compliance of myocytes but depresses systolic cardiac reserve; under conditions of exercise-induced cardiac stress the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system and careful dosing might be able to avoid effects on fibrosis and systolic function while improving diastolic function of heart failure patients.

Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction

BackgroundRecent studies have examined haemodynamic changes with stressors such as isometric handgrip and rapid atrial pacing in heart failure with preserved ejection fraction (HFpEF), but little is known regarding left...

Cardiac Titin

Titin constitutes the third myofilament of cardiac muscle, with a single giant polypeptide spanning from Z-disk to the M-band region of the sarcomere1 (Fig. 1). The ∼1.0 MDa region in the I-band is extensible and consists of tandemly arranged immunoglobulin (Ig)-like domains that make up proximal (near Z-disk) and distal (near A-I junction) segments, interspersed by the PEVK sequence (rich in proline, glutamate, valine, and lysine residues) and the N2B element2. Each functions as a distinct spring element3. The C-terminal ∼2 MDa of titin is located in the A-band and is inextensible. It is composed of regular arrays of Ig and fibronectin type 3 (Fn3) modules forming so-called super-repeats2. A-band titin may function as a molecular ruler, regulating assembly of the thick filament2,4,5. Titin's ∼250-kDa COOH-terminal region is an integral part of the M-band and contains a kinase domain6,7. As in the Z-disk, where titin filaments from opposite sarcomeres overlap, titin filaments from opposite half-sarcomeres overlap within the M-band, where they are interconnected by M-band proteins8. Thus, titin filaments with opposite polarity overlap in both Z-disk and M-band, forming a contiguous filament along the myofibril. In this review, we discuss titin's functions in the heart, with an emphasis on its role in diastolic function and the various mechanisms whereby passive stiffness can be tuned. Due to space constraints, it has not been possible to provide inclusive references to all original articles in the field. Figure 1 Schematic of titin in sarcomere. Differential splicing Titin is encoded by a single gene containing 368 exons. Multiple splice pathways in the I-band encoding region (∼230 exons) give rise to isoforms with different spring composition9. The three cardiac isoform classes are shown in Fig. 1. The relatively small ∼3.0 MDa isoform is known as N2B titin (it contains the N2B element)9. A second class also contains the N2A element, and is termed N2BA titin. N2BA titins have a longer PEVK segment and a variable number of additional Ig domains resulting in a ∼3.3-3.5 MDa size9. The third class includes isoforms that predominate in fetal-neonatal life which contain additional spring elements in both tandem Ig and PEVK regions, resulting in a ∼3.6-3.8 MDa size protein10-12. These isoforms gradually disappear during postnatal development. Regulation of the spring composition of titin in fetal-neonatal myocardium allows adjustment of diastolic filling properties during development.

Effect of Adjustable Passive Constraint on the Failing Left Ventricle: A Finite-Element Model Study

Passive constraint is used to prevent left ventricular dilation and subsequent remodeling. However, there has been concern about the effect of passive constraint on diastolic left ventricular chamber stiffness and pump function. This study determined the relationship between constraint, diastolic wall stress, chamber stiffness, and pump function. We tested the hypothesis that passive constraint at 3 mm Hg reduces wall stress with minimal change in pump function. A three-dimensional finite-element model of the globally dilated left ventricle based on left ventricular dimensions obtained in dogs that had undergone serial intracoronary microsphere injection was created. The model was adjusted to match experimentally observed end-diastolic left ventricular volume and midventricular wall thickness. The experimental results used to create the model were previously reported. A pressure of 3, 5, 7, and 9 mm Hg was applied to the epicardium. Fiber stress, end-diastolic pressure-volume relationship, end-systolic pressure-volume relationship, and the stroke volume-end-diastolic pressure (Starling) relationship were calculated. As epicardial constraint pressure increased, fiber stress decreased, the end-diastolic pressure-volume relationship shifted to the left, and the Starling relationship shifted down and to the right. The end-systolic pressure-volume relationship did not change. A constraining pressure of 2.3 mm Hg was associated with a 10% reduction in stroke volume, and mean end-diastolic fiber stress was reduced by 18.3% (inner wall), 15.3% (mid wall), and 14.2% (outer wall). Both stress and cardiac output decrease in a linear fashion as the amount of passive constraint is increased. If the reduction in cardiac output is to be less than 10%, passive constraint should not exceed 2.3 mm Hg. On the other hand, this amount of constraint may be sufficient to reverse eccentric hypertrophy after myocardial infarction.

Invited Commentary

Invited Commentary

Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice

Activation of the receptor for advanced glycation end products (RAGE) is associated with long-term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction. Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age-dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 +/- 13.8 vs. 94.5 +/- 14.9 mmHg/microL, P = 0.04) and development of increased LV diastolic chamber stiffness (0.18 +/- 0.05 vs. 0.27 +/- 0.07 mmHg, P = 0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCbeta) to the adult isoform (MHCalpha). Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

The mechanisms that are responsible for the development of myocardial fibrosis in inflammatory cardiomyopathy are unknown. We have previously generated lines of transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increased levels transforming growth factor-beta (TGF-beta)(mRNA and protein. In order to determine whether TGF-beta-mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-beta receptor antagonist (NP-40208). At the time of terminal study, myocardial collagen content was determined using the picrosirius red technique, and left ventricular (LV) systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant (P < 0.05) 65% decrease in nuclear translocation of Smad 2/3, a significant (P < 0.05), decrease in the heart-weight to body-weight ratio from 6.5 to 5.7, a approximately 37% decrease in fibrillar collagen content (P < 0.01) and a significant (P < 0.05) decrease in the LV chamber stiffness by approximately 25% in the MHCsTNF mice when compared to diluent-treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on cardiac myocyte size or fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-beta-mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

Relative systolic dysfunction in female spontaneously hypertensive rat myocardium

Hypertension and exercise independently induce left ventricular (LV) remodeling and alter LV function. The purpose of this study was to determine systolic and diastolic LV pressure-volume relationships (LV-PV) in spontaneously hypertensive rats (SHR) with and without LV hypertrophy, and to determine whether 6 mo of exercise training modified the LV-PV in SHR. Four-month-old female SHR (n = 20), were assigned to a sedentary (SHR-SED) or treadmill-trained (SHR-TRD) group (approximately 60% peak O2 consumption, 5 days/wk, 6 mo), while age-matched female Wistar-Kyoto rats (WKY; n = 13) served as normotensive controls. The LV-PV was determined using a Langendorff isolated heart preparation at 4 (no hypertrophy: WKY, n = 5; SHR, n = 5) and 10 mo of age (hypertrophy: WKY, n = 8; SHR-SED, n = 8; SHR-TRD, n = 7). At 4 mo, the LV-PV in SHR was similar to that observed in WKY controls. However, at 10 mo of age, a rightward shift in the LV-PV occurred in SHR. Exercise training did not alter the extent of the shift in the LV-PV relative to SHR-SED. Relative systolic function, i.e., relative systolic elastance, was approximately 50% lower in SHR than WKY at 10 mo of age (P < 0.05). Doppler-derived LV filling parameters [early wave (E), atrial wave (A), and the E/A ratio] were similar between groups. LV capacitance was increased in SHR at 10 mo (P < 0.05), whereas LV diastolic chamber stiffness was similar between groups at 10 mo. Hypertrophic remodeling at 10 mo of age in female SHR is manifest with relative systolic decompensation and normal LV diastolic function. Exercise training did not alter the LV-PV in SHR.

Surgical ventricular restoration in patients with ischemic dilated cardiomyopathy: Evaluation of systolic and diastolic ventricular function, wall stress, dyssynchrony, and mechanical efficiency by pressure-volume loops

Surgical ventricular restoration aims at improving cardiac function by normalization of left ventricular shape and size. Recent studies indicate that surgical ventricular restoration is highly effective with an excellent 5-year outcome in patients with ischemic dilated cardiomyopathy. We used pressure-volume analysis to investigate acute changes in systolic and diastolic left ventricular function, mechanical dyssynchrony and efficiency, and wall stress. In 3 patient groups (total, n = 33), pressure-volume loops were measured by conductance catheter before and after surgery. The main study group consisted of 10 patients with ischemic dilated cardiomyopathy (New York Heart Association class III/IV, left ventricular ejection fraction <30%) who had surgical ventricular restoration and coronary artery bypass grafting. In this group, 7 patients had additional restrictive mitral annuloplasty. To assess potential confounding effects of restrictive mitral annuloplasty and cardiopulmonary bypass, we included a group of 10 patients (New York Heart Association class III/IV, left ventricular ejection fraction <30%) who had isolated restrictive mitral annuloplasty and a group of 13 patients with preserved left ventricular function who had isolated coronary artery bypass grafting. After surgical ventricular restoration, end-diastolic and end-systolic volumes were reduced from 211 +/- 54 to 169 +/- 34 mL (P = .03) and from 147 +/- 41 to 110 +/- 59 mL (P = .04), respectively. Left ventricular ejection fraction (from 27% +/- 7% to 37% +/- 13%, P = .04) and end-systolic elastance (from 1.12 +/- 0.71 to 1.57 +/- 0.63 mm Hg/mL, P = .03) improved. Peak wall stress (from 358 +/- 108 to 244 +/- 79 mm Hg, P < .01) and mechanical dyssynchrony (from 26% +/- 4% to 19% +/- 6%, P < .01) were reduced, whereas mechanical efficiency improved (from 0.34 +/- 13 to 0.49 +/- 0.14, P = .03). End-diastolic pressure increased (from 13 +/- 6 to 20 +/- 5 mm Hg, P < .01), whereas the diastolic chamber stiffness constant tended to be increased (from 0.021 +/- 0.009 to 0.037 +/- 0.021 mL(-1), NS). Surgical ventricular restoration achieves normalization of left ventricular volumes and improves systolic function and mechanical efficiency by reducing left ventricular wall stress and mechanical dyssynchrony.

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.

Effects of Preemptive Enoximone on Left Ventricular Diastolic Function After Valve Replacement for Aortic Stenosis

Left ventricular (LV) hypertrophy is associated with increased diastolic chamber stiffness early after aortic valve replacement for valve stenosis. Enoximone, a phosphodiesterase III inhibitor, has been shown to improve myocardial contractility and relaxation when administered as a single dose after cardiac surgery. The present study investigated, by analysis of transmitral flow velocity patterns and end-diastolic pressure-area relations, whether enoximone administered before aortic valve surgery has an effect on LV diastolic properties. Prospective, randomized study. Referral center for cardiothoracic surgery at a university hospital. Thirty-four patients undergoing aortic valve replacement for aortic stenosis. Patients in the enoximone group (n = 17) received a bolus dose of 0.35 mg/kg (0.15 mg/kg before aortic cross-clamping and 0.2 mg/kg added to the cardioplegic solution). Individual pressure-area relations (pulmonary capillary wedge pressure v left ventricular end-diastolic area) were obtained by using volume loading by leg elevation before and after surgery with closed chest. The pressure-area relation on the pressure-area plot was shifted to the left after surgery, indicating decreased LV diastolic distensibility in the enoximone and control groups and providing evidence of decreased LV diastolic function. Indices of LV diastolic chamber stiffness, LV operating stiffness (K(LV)) derived from the deceleration time of early ventricular filling, and the constant of chamber stiffness (beta) derived from pressure-area relations were not different after enoximone treatment. Systolic LV function was unaltered after cardiac surgery in both groups. Analysis of changes in transmitral flow patterns identified an increased atrial filling fraction in enoximone-treated patients, suggesting increased atrial systolic function. The unaltered systolic pulmonary venous flow velocity compared with the decrease in the control group after volume loading further supports preservation of left atrial reservoir function with enoximone in the absence of evidence for decreased LV stiffness. Preemptive enoximone did not change LV diastolic function based on diastolic filling patterns or LV stiffness indices (K(LV) and beta) derived from Doppler early filling deceleration time and pressure-area relations. Doppler data suggested improvement of left atrial systolic function and preservation of left atrial reservoir function with enoximone.