Chamber Stiffness Research Articles

The Diastolic Function to Cyclic Variation of Myocardial Ultrasonic Backscatter Relation: The Influence of Parametrized Diastolic Filling (PDF) Formalism Determined Chamber Properties

Myocardial tissue characterization represents an extension of currently available echocardiographic imaging. The systematic variation of backscattered energy during the cardiac cycle (the “cyclic variation” of backscatter) has been employed to characterize cardiac function in a wide range of investigations. However, the mechanisms responsible for observed cyclic variation remain incompletely understood. As a step toward determining the features of cardiac structure and function that are responsible for the observed cyclic variation, the present study makes use of a kinematic approach of diastolic function quantitation to identify diastolic function determinants that influence the magnitude and timing of cyclic variation. Echocardiographic measurements of 32 subjects provided data for determination of the cyclic variation of backscatter to diastolic function relation characterized in terms of E-wave determined, kinematic model-based parameters of chamber stiffness, viscosity/relaxation and load. The normalized time delay of cyclic variation appears to be related to the relative viscoelasticity of the chamber and predictive of the kinematic filling dynamics as determined using the parametrized diastolic filling formalism (with r-values ranging from .44 to .59). The magnitude of cyclic variation does not appear to be strongly related to the kinematic parameters.

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...

The thermodynamics of diastole: kinematic modeling-based derivation of the P-V loop to transmitral flow energy relation with in vivo validation

Pressure-volume (P-V) loop-based analysis facilitates thermodynamic assessment of left ventricular function in terms of work and energy. Typically these quantities are calculated for a cardiac cycle using the entire P-V loop, although thermodynamic analysis may be applied to a selected phase of the cardiac cycle, specifically, diastole. Diastolic function is routinely quantified by analysis of transmitral Doppler E-wave contours. The first law of thermodynamics requires that energy (ε) computed from the Doppler E-wave (εE-wave) and the same portion of the P-V loop (εP-V E-wave) be equivalent. These energies have not been previously derived nor have their predicted equivalence been experimentally validated. To test the hypothesis that εP-V E-wave and εE-wave are equivalent, we used a validated kinematic model of filling to derive εE-wave in terms of chamber stiffness, relaxation/viscoelasticity, and load. For validation, simultaneous (conductance catheter) P-V and echocadiographic data from 12 subjects (205 total cardiac cycles) having a range of diastolic function were analyzed. For each E-wave, εE-wave was compared with εP-V E-wave calculated from simultaneous P-V data. Linear regression yielded the following: εP-V E-wave=αεE-wave+b (R2=0.67), where α=0.95 and b=6e(-5). We conclude that E-wave-derived energy for suction-initiated early rapid filling εE-wave, quantitated via kinematic modeling, is equivalent to invasive P-V-defined filling energy. Hence, the thermodynamics of diastole via εE-wave generate a novel mechanism-based index of diastolic function suitable for in vivo phenotypic characterization.

Assessment of the Left Ventricular Chamber Stiffness in Athletes

Since diastolic dysfunction is an early sign of the heart disease, detecting diastolic disturbances is predicted to be the way for early recognizing underlying heart disease in athletes. So-called chamber stiffness index (E/e')/LVDd was predicted to be useful in distinguishing physiological from pathological left ventricular hypertrophy, because it was shown to be reduced in athletes. It remains unknown whether it is reduced in all athletic population. Standard and tissue Doppler were used to assess cardiac parameters at rest in 16 elite male wrestlers, 21 water polo player, and 20 sedentary subjects of similar age. In addition to (E/e')/LVDd index, a novel (E/e')/LVV, (E/e')/RVe'lat indices were determined. Progressive continuous maximal test on treadmill was used to assess the functional capacity. VO(2) max was the highest in water polo players, and higher in wrestlers than in controls. LVDd, LVV, LVM/BH(2.7) were higher in athletes. Left ventricular early diastolic filling velocity, deceleration and isovolumetric relaxation time did not differ. End-systolic wall stress was significantly higher in water polo players. RV e' was lower in water polo athletes. Right atrial pressure (RVE/e') was the highest in water polo athletes. (E/e'lat)/LVDd was not reduced in athletes comparing to controls (water polo players 0.83 ± 0.39, wrestlers 0.73 ± 0.29, controls 0.70 ± 0.28; P = 0.52), but (E/e's)/RVe'lat better distinguished examined groups (water polo players 0.48 ± 0.37, wrestlers 0.28 ± 0.15, controls 0.25 ± 0.16, P = 0.015) and it was the only index which predicted VO(2) max. In conclusion, intensive training does not necessarily reduce (E/e'lat)/LVDd index. A novel index (E/e's)/RVe'lat should be investigated furthermore in detecting diastolic adaptive changes.

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

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

Echocardiographic Evaluation of Diastolic Function Can Be Used to Guide Clinical Care

For normal cardiac performance, the left ventricle (LV) must be able to eject an adequate stroke volume at arterial pressure (systolic function) and fill without requiring an elevated left atrial (LA) pressure (diastolic function). These systolic and diastolic functions must be adequate to meet the needs of the body both at rest and during stress. Response by Tschope and Paulus on p 809 Systolic function is conveniently (although not always accurately) measured as the ejection fraction (EF), calculated as stroke volume divided by end-diastolic volume.1 The LV EF is easily interpreted. The lower limit of normal is ≈50%. The lower the EF is, the greater the reduction in systolic function. Diastolic function has been more difficult to evaluate.2 Traditionally, invasive measures of LV diastolic pressure-volume relations and the rate of LV pressure fall during isovolumetric relaxation have been used. However, these methods are not practical for routine clinical use and do not adequately evaluate all aspects of diastolic filling.3 Comprehensive echocardiographic evaluation of the dynamics of LV filling using blood pool and tissue Doppler has now progressed so that it provides clinically important information that can be used to direct patient care. We present data that support the use of echocardiographic evaluation of diastolic function to recognize cardiac dysfunction in patients with heart failure, especially those with preserved EF; to guide the management of patients by identifying those with and without elevated left filling pressures regardless of underlying EF; and to determine prognosis in a wide variety of patient populations. Although the LV end-diastolic pressure-volume relation describes the passive properties of the LV, LV filling is not a passive or slow process.3 In fact, the peak flow rate across the mitral valve is equal to or greater than the peak flow rate across the aortic valve. …

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.

Left Ventricular Untwisting Is an Important Determinant of Early Diastolic Function

We sought to establish the relationship between invasive measures of diastolic function and untwisting parameters measured with speckle tracking imaging. Left ventricular (LV) diastolic function is determined by early diastolic relaxation (which creates suction gradients for LV filling) and myocardial stiffness. Assessment of LV torsion has shown that untwisting begins before aortic valve closure and, in animals, might be an important component of normal diastolic filling. Studies in human subjects using indirect indexes derived from right heart catheterization have suggested a relationship between tau and measures of untwisting, but the relationship between directly measured diastolic function indexes with micromanometer catheters and untwisting parameters has not been established in human subjects. Simultaneous Millar micromanometer LV pressure and echocardiographic assessment was performed on 18 patients (10 male, mean age 66 years) with normal systolic function and a spectrum of diastolic function. Invasive rate of the rise of LV pressure, dp/dt minimum and tau were recorded as measures of active relaxation, and the LV minimum diastolic pressure was recorded as an index of diastolic suction. The LV stiffness constant and functional chamber stiffness were estimated from hybrid pressure-volume loops. Echocardiographic speckle tracking imaging was used to quantify torsion. As relaxation was impaired, (prolonged tau) untwisting was delayed (r = 0.35, p < 0.01). There were nonsignificant associations between reduced untwisting and longer values of tau and lower dp/dt minimum. Reduction in the extent of untwisting before mitral valve opening was associated with increased LV minimum diastolic pressure (r = -0.30, p < 0.034). No relation was observed between the LV stiffness constant (beta: r = 0.11, p = NS) or the functional LV chamber stiffness (b: r = 0.11, p = NS) and untwisting. Untwisting parameters are related to invasive indexes of LV relaxation and suction but not to LV stiffness. These data suggest that untwisting is an important component of early diastolic LV filling but not later diastolic events.

Impact of Treatment on Myocardial Lysyl Oxidase Expression and Collagen Cross-Linking in Patients With Heart Failure

The aim of this study was to investigate whether torasemide modifies collagen cross-linking in the failing human heart. We analyzed the degree of cross-linking and the expression of the enzyme lysyl oxidase, which regulates cross-linking, in the myocardium of patients with chronic heart failure at baseline and after 8 months of treatment with either torasemide or furosemide in addition to their standard heart failure therapy. Whereas lysyl oxidase protein expression was very scarce in normal hearts, it was highly expressed in failing hearts. Cross-linking was increased (P<0.001) in heart failure patients compared with normal hearts. These 2 parameters decreased (P=0.021 and P=0.034) in torasemide-treated patients and remained unchanged in furosemide-treated patients. In addition, more (P=0.009) patients showed normalization of left ventricular chamber stiffness in the torasemide subgroup than in the furosemide subgroup after treatment. Lysyl oxidase expression correlated with cross-linking (r=0.661; P<0.001), and cross-linking correlated with left ventricular chamber stiffness (r=0.452; P=0.002) in all patients. These findings show for the first time that lysyl oxidase overexpression is associated with enhanced collagen cross-linking in the failing human heart. In addition, we report that the ability of torasemide to correct both lysyl oxidase overexpression and enhanced collagen cross-linking results in normalization of left ventricular chamber stiffness in patients with heart failure. Lysyl oxidase may thus represent a target for reduction of stiff collagen and improvement of left ventricular mechanical properties in heart failure patients.

Abstract 4206: Microvascular Dysfunction and Left Ventricular Chamber Stiffness after Successful Percutaneous Coronary Intervention Critically Determine Left Ventricular Remodeling in Patients with Acute Myocardial Infarction

In patients with acute myocardial infarction (AMI), the short deceleration time of left ventricular (LV) early filling by Doppler is a powerful independent predictor of LV remodeling. On the other hand, recent studies have shown that microvascular dysfunction in recanalized infarct-related coronary arteries may predict progressive LV dilation. The purpose of this study was to examine the effects of both microvascular dysfunction and LV chamber stiffness on LV remodeling after successful percutaneous coronary intervention (PCI) in AMI patients. Two hundred and one consecutive patients with first anterior AMI were studied following successful PCI. Microvascular injury was evaluated on the basis of coronary flow velocity patterns immediately after successful PCI using Doppler guidewires. We defined the presence of microvascular dysfunction as diastolic deceleration time ≤600 ms and the presence of systolic flow reversal. LV filling patterns were determined by mitral inflow pulsed-wave Doppler examination on day 3 after AMI. Deceleration time ≤130 ms was defined as restrictive. We classified the patients into three categories: without restrictive and microvascular dysfunction (group 1, n=116), with restrictive or microvascular dysfunction (group 2, n= 38), and with restrictive and microvascular dysfunction (group 3, n=47). Left ventriculograms were obtained immediately and 6 months after PCI. LV remodeling was defined as an increase in end-diastolic volume index ≥20%. Group 3 was at the highest risk of LV remodeling, while group 1 was at the lowest (Table ). Assessment of both microvascular dysfunction and LV chamber stiffness enable accurate prediction of LV remodeling in AMI patients after successful PCI. LV remodeling in each group

Direct Renin Inhibition

The process of cardiac healing and recovery after an acute myocardial infarction encompasses profound changes in the necrotic area (“infarct zone”), in the neighboring ischemic zone (“area at risk”), and in the nonischemic myocardium (“nonischemic region”). Patient’s prognosis ultimately depends on the functional, biochemical, electric, and structural changes taking place in these 3 different areas as a consequence of the acute ischemic event. These extracellular, cellular, and subcellular events are globally referred to as “postinfarction remodeling,” and therapeutic interventions able to slow or reverse its progression have a favorable impact on patient prognosis.1 A pivotal role in these processes is played by the renin-angiotensin-aldosterone system (RAAS) that is undoubtedly hyperactivated after myocardial infarction, together with other neural and endocrine systems. Locally synthesized angiotensin II has been suggested to act as an autocrine, paracrine, and intracrine modulator of cardiac function.2 Notably, the major components of the RAAS components have been shown in cardiac tissue, and extracardiac renin uptake is associated with local release by myocardial mast cells.3 Angiotensin II intracellular signal transduction involves the phosphorylation of several proteins, such as membrane transporters and selective ion channels, structural and contractile proteins, and enzymes that regulate metabolism, protein synthesis, and gene expression. These multiple actions are mediated via complex intracellular signaling pathways, including stimulation of the phospholipase C-inositol 1,4,5-trisphosphate-1,2-diacylglycerol cascade, mitogen-activated protein kinases, tyrosine kinases, RhoA/Rho kinase, and reactive oxygen species generation through vascular NADPH oxidase activation. Beyond directly affecting vasomotor tone, angiotensin II potentiates the effects of several vasoconstrictor hormones, facilitates the central and …

Quest for Diastolic Prognostic Indicators of Clinical Outcome After Acute Myocardial Infarction

Immediately after acute infarction, the region of the myocardium ceases to contract, and over the next 72 hours, the infarct zone stretches and thins, a process known as infarct expansion. This regional left ventricular wall thinning and failure to contract perturb the normally uniform distribution of the stress/strain relationship that preserves cardiac architecture and function. Simultaneous with these early biomechanical changes, myocyte necrosis releases a number of cytokines that, together with the local increase in the regional myocardial deformation, cause stretch activation of a portfolio of matrix metalloproteinases that initiate myocardial repair. Article p 2591 The stability of myocardial repair after acute myocardial infarction is determined by the balance between the distending forces from ventricular dilatation resulting from infarct expansion and the restraining forces from deposition of a viscoelastic collagen scaffold by the extracellular matrix that increases the tensile strength of the scar. The dynamic equilibrium between collagen degradation and collagen deposition is modulated by a number of activated cytokines and neurohormones that normally result in buttressing the infarct and adjacent border zones, preventing progressive remodeling to heart failure. Changes in the composition of the myocardium in terms of increased collagen content during and after repair of the infarct zone in forming a fibrous tissue scar alter the material properties of the myocardium after myocardial infarction and confer on the heart increased myocardial and chamber stiffness. These alterations in left ventricular composition, architecture, and chamber/myocardial stiffness affect left ventricular filling dynamics, the rate of detachment of cross-linking, and sequestration of cytosolic calcium by the sarcoplasmic reticulum, all of which affect diastolic function as much as systolic function. However, most studies of the predictors of clinical outcome after myocardial infarction have focused almost exclusively on ejection-phase indexes of systolic contraction. Factors shown to be powerful predictors of clinical outcome after myocardial …

The diastatic pressure-volume relationship is not the same as the end-diastolic pressure-volume relationship

The end-diastolic pressure-volume (P-V) relationship (EDPVR) is routinely used to determine the passive left ventricular (LV) stiffness, although the diastatic P-V relationship (D-PVR) has also been measured. Based on the physiological difference between diastasis (the LV and atrium are relaxed and static) and end diastole (LV volume increased by atrial systole and the atrium is contracted), we hypothesized that, although both D-PVR and EDPVR include LV chamber stiffness information, they are two different, distinguishable P-V relations. Cardiac catheterization determined LV pressures, and conductance volumes in 31 subjects were analyzed. Physiological, beat-to-beat variation of the diastatic and end-diastolic P-V points were fit by linear and exponential functions to generate the D-PVR and EDPVR. The extrapolated exponential D-PVR underestimated LVEDP in 82% of the heart beats (P < 0.001). The extrapolated EDPVR overestimated pressure at diastasis in 84% of the heart beats (P < 0.001). If each subject's diastatic and end-diastolic P-V data were combined to form a continuous data set to be fit by one exponential relation, the goodness of fit was always worse than if the diastatic and end-diastolic data were grouped separately and fit by two distinct exponential relations. Diastatic chamber stiffness was less than EDPVR stiffness (defined by the slope of P-V relation) for all 31 subjects (0.16 +/- 0.11 vs. 0.24 +/- 0.15 mmHg/ml, P < 0.001). We conclude that the D-PVR and EDPVR are distinguishable. Because it is not coupled to a contracted atrium, the D-PVR conveys passive LV stiffness better than the EDPVR. Additional studies that fully elucidate the physiology and biology of diastasis in health and disease are in progress.

Restrictive Left Ventricular Filling Pattern Does Not Result From Increased Left Atrial Pressure Alone

The restrictive filling pattern seen with severe heart failure (HF) may be due to diastolic dysfunction with elevated left ventricular (LV) diastolic pressure or may be merely a manifestation of an overfilled LV as a result of increased left atrial (LA) pressure. We investigated whether the LV restrictive filling pattern is due to elevated LA pressure alone. We studied conscious dogs instrumented to measure LA pressure, LV pressure, and 3 LV diameters. LV filling dynamics were evaluated in 2 situations with similar elevations of LA pressure: in normal animals after rapid volume loading with dextran 500 mL and in animals with pacing-induced HF with restrictive filling. With HF, there was increased LV chamber stiffness and slow relaxation. Volume loading and HF had similar heart rates (129+/-19 versus 131+/-15 bpm) and LA pressure (22.1+/-5.8 versus 22.6+/-3.3 mm Hg). The peak early filling rate (E) was increased with both HF and volume loading. However, in HF, the peak mitral annular velocity (E') was decreased and delayed, and the E deceleration time was shorter. In contrast, with volume loading, E' was increased and not delayed. The restrictive filling pattern is distinguished from overfilling of a normal ventricle by a reduced and delayed E' and a shortened E deceleration time that reflect slow relaxation and increased LV stiffness.

Patients with a Hypertensive Response to Exercise Have Impaired Left Ventricular Diastolic Function

An exaggerated increase in systolic blood pressure prolongs myocardial relaxation and increases left ventricular (LV) chamber stiffness, resulting in an increase in LV filling pressure. We hypothesize that patients with a marked hypertensive response to exercise (HRE) have LV diastolic dysfunction leading to exercise intolerance, even in the absence of resting hypertension. We recruited 129 subjects (age 63+/-9 years, 64% male) with a preserved ejection fraction and a negative stress test. HRE was evaluated at the end of a 6-min exercise test using the modified Bruce protocol. Patients were categorized into three groups: a group without HRE and without resting hypertension (control group; n=30), a group with HRE but without resting hypertension (HRE group; n=25), and a group with both HRE and resting hypertension (HTN group; n=74). Conventional Doppler and tissue Doppler imaging were performed at rest. After 6-min exercise tests, systolic blood pressure increased in the HRE and HTN groups, compared with the control group (226+/-17 mmHg, 226+/-17 mmHg, and 180+/-15 mmHg, respectively, p<0.001). There were no significant differences in LV ejection fraction, LV end-diastolic diameter, and early mitral inflow velocity among the three groups. However, early diastolic mitral annular velocity (E') was significantly lower and the ratio of early diastolic mitral inflow velocity (E) to E' (E/E') was significantly higher in patients of the HRE and HTN groups compared to controls (E': 5.9+/-1.6 cm/s, 5.9+/-1.7 cm/s, 8.0+/-1.9 cm/s, respectively, p<0.05). In conclusion, irrespective of the presence of resting hypertension, patients with hypertensive response to exercise had impaired LV longitudinal diastolic function and exercise intolerance.

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.

Abstract 2281: Mitral E Wave Deceleration Time to Peak E Velocity Ratio And Cardiovascular Outcome in Hypertensive Patients During Anti-Hypertensive Treatment: the LIFE Echo-Substudy.

Background: Early mitral flow deceleration time (DTE) is a prognostically validated marker of LV chamber stiffness. However, for any given LV stiffness, a higher E peak velocity (E) is associated with longer DTE, suggesting that the prognostic relevance of DTE might be influenced by variations in cardiac preload (e.g. during anti-hypertensive treatment). It is not known whether normalization of deceleration time for E-velocity (DTE/E) might be a more stable diastolic index for prediction of incident cardiovascular (CV) events in hypertensive patients during treatment, as compared to DTE. Methods: We evaluated 770 hypertensive patients (66±7 years; 42% women) with ECG-LV hypertrophy enrolled in the LIFE echo-substudy. Echocardiographic exams were performed annually for 5 years during anti-hypertensive treatment. Prognostic value of basal DTE/E was preliminary evaluated. Variation over time of both DTE/E and DTE were therefore analyzed in relation to incident combined fatal and non-fatal CV events. Results: During follow-up, 69 CV events occurred (9% of study population). Mean basal DTE/pE was 3.55±1.55 sec 2 /cm*10 −3. In univariate analysis baseline DTE/E was associated positively with age (r=0.10; p&lt;0.01), relative wall thickness (r=0.13; p&lt;0.01) and isovolumic relaxation time (r=0.26; p&lt;0.001) and negatively with heart rate (r=−0.20; p&lt;0.001); no association was found with systolic blood pressure, diastolic blood pressure, LV mass or ejection fraction. Unadjusted Cox regression showed a positive association between baseline DTE/E and CV events [(HR=1.21 (95%CI= 1.07–1.37); p=0.002]. In time-varying Cox model, independently of age, gender, type of anti-hypertensive treatment and in-treatment heart rate, higher in-treatment DTE/E was associated with higher rate of CV events [(HR=1.26 (95%CI= 1.04 –1.80); p&lt;0.026], whereas no association was found for in-treatment DTE (p=NS). Conclusions: In a population of treated hypertensive patients with ECG-LV hypertrophy, the ratio of in-treatment DTE/E, but not DTE alone, independently predicts incident CV events. In high-risk hypertensive patients, normalization of DTE for E peak velocity might be preferred to DTE in evaluating diastolic function during anti-hypertensive treatment.