Myocardial Stiffness Constant Research Articles

Low diastolic wall strain is associated with raised post-exercise E/E' ratio in elderly patients without obvious myocardial ischemia.

It has been reported that the diastolic wall strain (DWS) inversely correlates with the myocardial stiffness constant. The ratio of early diastolic transmitral flow velocity to annulus velocity (E/E') correlates with the left ventricular (LV) filling pressure. Increased LV wall stiffness is thought be associated with increased LV filling pressure after exercise. The purpose of this study was to evaluate the correlation between the DWS and post-exercise E/E' in elderly patients without obvious myocardial ischemia. Fifty-eight elderly patients (age=74±6years) who underwent treadmill stress echocardiography were studied. All patients had normal LV wall motion at rest, and patients with exercise-induced wall motion abnormality were excluded. The DWS was calculated as follows: DWS=(PWTs-PWTd)/PWTs, where PWTs is the LV posterior wall thickness at end-systole and PWTd is that at end-diastole. As previously reported, DWS≤0.33 was defined as low DWS and E/E' ≥15.0 was defined as a marker of increased LV filling pressure. Eighteen patients had low DWS. Patients with low DWS had greater post-exercise E/E' (17.9±3.2 vs. 12.8±3.3, p<0.0001). The DWS was inversely and strongly correlated with post-exercise E/E' (r (2)=0.534, p<0.0001). Low DWS predicted the development of raised post-exercise E/E' ≥15.0 with a positive predictive value of 94% and a negative predictive value of 85%. In elderly patients without obvious myocardial ischemia, the DWS correlates strongly and inversely with post-exercise E/E'. Patients with low DWS were likely to develop raised E/E' after exercise.

Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction

BackgroundChronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process.Methods and ResultsAn analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.ConclusionOur data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Abstract 8573: L-carnitine Prevents Heart Failure with Preserved Ejection Fraction in Associated with Attenuation of Cardiac Fibrosis

Backgrounds: Prognosis of heart failure with preserved ejection fraction (HFpEF) has not been improved because of unknown pathophysiology and unestablished therapeutic strategy. Cardiac fibrosis is known to play a crucial role in the development of HFpEF. Methods and Results: The comprehensive and quantitative analysis of metabolites with capillary electrophoresis time-of-flight mass spectrometry was conducted to find a substance which may be related to the development of HFpEF, and revealed decreased plasma free-carnitine levels in Dahl salt-sensitive rats (DSR) fed high-salt diet, a model of hypertensive HFpEF. We confirmed this result with enzymatic cycling method by showing decreased plasma and left ventricular (LV) free-carnitine levels with increased urinary free-carnitine excretion in HFpEF rats compared to control DSR fed normal chow. We also found that blood free-carnitine levels were decreased in HFpEF patients compared to age-matched normal volunteers. Expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was decreased in the LV and kidney of HFpEF rats. L-carnitine administration to HFpEF rats increased plasma and LV levels of free-carnitine, and prevented HFpEF with decreased myocardial stiffness constant and decreased area of LV fibrosis. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced increase in 3 H-proline incorporation. L-carnitine increased prostacyclin production and expression of fatty acid desaturase 1/2, rate-limiting enzymes in forming arachidonic acid, in the LV of DSR and cultured cardiac fibroblasts. LV arachidonic acid levels were increased in HFpEF rats by L-carnitine administration. Conclusions: L-carnitine may be effective in the prevention of HFpEF through enhanced production of prostacyclin and prevention of LV fibrosis and stiffening. L-carnitine supplementation may become a therapeutic option for HFpEF.

Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure

This study was designed to determine the prognostic importance of left ventricular (LV) myocardial stiffness, a hemodynamic index which is closely related to B-type natriuretic peptide (BNP) concentration in patients with congestive heart failure (CHF). While elevated BNP, an abnormality of cardiac neurohormones, is known to be an independent marker of death or re-admission, it remains to be clarified whether there is also a strong predictor directly related to cardiac dysfunction. LV performance variables and stress-strain analyses including diastolic myocardial stiffness constant (K(m)) were obtained from 37 patients with initial CHF by the combined simultaneous measurement of echocardiographic and hemodynamic data. Survivors were monitored for a mean of 23 months, with the main endpoint being combined death or first re-admission for CHF. Ten patients (27%) were primary endpoint cases. Both K(m) and plasma BNP levels were higher in the event than in the event-free group. By Cox proportional hazards analysis, K(m)≥4.0 was identified as the only variable with significant and independently incremental predictive power to affect the primary endpoint (adjusted hazard ratio=7.354, 95% confidence interval 1.379-39.232, p=0.02). In patients with CHF, increased myocardial stiffness may have greater prognostic significance compared to other conventional predictors. Increased myocardial stiffness may be considered to be an important prognostic factor independent of the loading conditions.

Persistent Diastolic Dysfunction Late After Valve Replacement in Severe Aortic Regurgitation

Regression of left ventricular (LV) hypertrophy with normalization of diastolic function has been reported in patients with aortic stenosis late after aortic valve replacement (AVR). The purpose of the present study was to evaluate the effect of AVR on LV function and structure in chronic aortic regurgitation early and late after AVR. Twenty-six patients were included in the present analysis. Eleven patients with severe aortic regurgitation were studied before, early (21 months) and late (89 months) after AVR through the use of LV biplane angiograms, high-fidelity pressure measurements, and LV endomyocardial biopsies. Fifteen healthy subjects were used as controls. LV systolic function was determined from biplane ejection fraction and midwall fractional shortening. LV diastolic function was calculated from the time constant of LV relaxation, peak filling rates, and myocardial stiffness constant. LV structure was assessed from muscle fiber diameter, interstitial fibrosis, and fibrous content. LV muscle mass decreased significantly by 38% early and 55% late after surgery. Ejection fraction was significantly reduced preoperatively and did not change after AVR (P=NS). LV relaxation was significantly prolonged before surgery (89+/-28 ms) but was normalized late after AVR (42+/-14 ms). Early and late peak filling rates were increased preoperatively but normalized postoperatively. Diastolic stiffness constant was increased before surgery (22+/-6 versus 9+/-3 in control subjects; P=0.0003) and remained elevated early and late after AVR (23+/-4; P=0.002). Muscle fiber diameter decreased significantly after AVR but remained increased at late follow-up. Interstitial fibrosis was increased preoperatively and increased even further early but decreased late after AVR. Fibrosis was positively linearly correlated to myocardial stiffness and inversely correlated to LV ejection fraction. Patients with aortic regurgitation show normalization of macroscopic LV hypertrophy late after AVR, although fiber hypertrophy persists. These changes in LV myocardial structure late after AVR are accompanied by a change in passive elastic properties with persistent diastolic dysfunction.

Noninvasive Assessment of Wall Distensibility With the Evaluation of Diastolic Epicardial Movement

Background Left ventricular (LV) wall stiffening plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Based on the linear elastic theory, we hypothesized that the evaluation of epicardial movement during diastole is helpful for the noninvasive assessment of LV wall distensibility. Methods and Results Based on the linear elastic theory, the epicardial movement index (EMI) was calculated on the echocardiogram as: endocardial movement during diastole − epicardial movement during diastole wall thickness at the beginning of diastole * epicardial movement during diastole We calculated diastolic wall strain (DWS) as follows to examine whether DWS substitutes for EMI: LV posterior wall thickness at end-systole − LV posterior wall thickness at end-diastole LV posterior wall thickness at end-systole The animal study using hypertensive Dahl salt-sensitive rats, HFpEF model, and normotensive Dahl rats showed the significant and inverse correlation of EMI or DWS with myocardial stiffness constant. Preload alteration did not affect EMI or DWS. In the clinical study, the HFpEF patients had lower EMI and DWS than the normal volunteers and the asymptomatic patients with LV hypertrophy. Conclusions The evaluation of epicardial movement may be useful in noninvasively assessing wall distensibility in the absence of LV systolic dysfunction.

Abstract 4203: Diastolic Wall Strain Can Noninvasively Predict Hemodynamic Deterioration Unassociated with Systolic Dysfunction in Hypertensive Hearts

This study examined whether LV diastolic wall strain (DWS) could noninvasively predict the transition to decompensated diastolic heart failure (DHF) in hypertensive hearts. Dahl salt-sensitive rats fed 0.3 % NaCl diet served as control group (group N: n=8) and those fed 8 % NaCl diet as hypertensive group (group HT: n=15). Serial Doppler echocardiographic studies were performed at age 13, 17 and 19 weeks. At 19 weeks, LV pressure was measured following the echocardiographic study. DWS was calculated as [(end-systolic thickness of LV posterior wall) - (end-diastolic thickness of LV posterior wall)]/(end-systolic thickness of LV posterior wall). Mid-wall fractional shortening (MFS) was not different between two groups at any stage. At 13 weeks (compensatory hypertrophic stage), the transmitral flow velocity curves (TMFV) represented the abnormal relaxation pattern with low E/A ratio in group HT. At 19 weeks (heart failure stage), E/A increased with the elevation of LV end-diastolic pressure and lung weight in group HT. DWS was not different between two groups at 13 weeks, however, its decrease preceded the pseudonormalization of TMFV at 17 weeks in group HT and continued until 19 weeks. The difference between the endocardial and epicardial movements is equal to that between the wall thickness at end-systole and end-diastole (a numerator of DWS). Therefore, based on the linear elastic theory, DWS is considered to decrease with increase of LV wall stiffness. We previously demonstrated that myocardial stiffness constant was elevated at age 17 weeks but not at age 13 weeks in Dahl salt-sensitive rats fed high-salt diet. The current results indicate that DWS is helpful in noninvasively predicting hemodynamic deterioration without the changes in systolic function, which is explained partly by the theory that DWS reflects LV wall stiffness. Echocardiographic Parameters and Hemodynamic Data in Control Group and Hypertensive Group

Abstract 2654: Persistent Diastolic Dysfunction Late After Valve Replacement In Severe Aortic Regurgitation

Introduction: Regression of left ventricular (LV) hypertrophy with normalization of diastolic function has been reported in patients with aortic stenosis. The purpose of the present study was to evaluate the effect of aortic valve replacement (AVR) on LV systolic and diastolic function an LV structure in chronic aortic regurgitation (AR) early and late after AVR. Methods: 25 patients were included in the present analysis. Ten patients with severe AR were studied before, early (21 months) and late (89 months) after AVR using LV biplane angiograms, high-fidelity pressure measurements, and endomyocardial biopsies. Fifteen healthy subjects were used as controls. LV systolic function was determined from biplane ejection fraction (EF) and midwall fractional shortening, LV diastolic function from the time constant of LV relaxation, peak filling rates, and myocardial stiffness constant. LV structure was assessed from muscle fiber diameter, interstitial fibrosis and volume fraction of myofibrils. Results : LV muscle mass was significantly increased preoperatively but decreased by 38% early and 55% late after surgery, but remained (ns) elevated compared to controls. LV EF and midwall fractional shortening did not change after AVR. LV relaxation was significantly prolonged before (89±28 ms vs. controls 47±11 ms, p&lt;0.001) and early (67±19 ms) but normal late after AVR (42±14 ms). Early and late peak filling rates were increased preoperatively and were normalized early after surgery. Myocardial stiffness constant was increased in AR patients before surgery (22±6 vs. controls 9±3, p&lt;0.001) but decreased significantly after AVR. However, it remained increased at late follow-up (15±4, p&lt;0.05). Muscle fiber diameter decreased significantly early and late after AVR, but remained hypertrophied at late follow-up. Interstitial fibrosis was increased preoperatively and increased even further early but decreased only late after AVR. Conclusions : Patients with AR show normalization of macroscopic LV hypertrophy late after AVR, altough fiber hypertrophy persists. These changes in LV myocardial structure late after AVR are accompanied by a change in passive elastic properties with persistent diastolic dysfunction due to the increased interstitial fibrosis.

The Impact of Angiotensin-Converting Enzyme Inhibitor Therapy on the Extracellular Collagen Matrix During Left Ventricular Assist Device Support in Patients With End-Stage Heart Failure

We hypothesized that angiotensin-converting enzyme inhibition (ACE-I) during left ventricular assist device (LVAD) support in patients with end-stage heart failure prevents potentially deleterious effects on the extracellular matrix. Left ventricular assist device-induced mechanical unloading increases myocardial collagen and stiffness and may contribute to the low rate of recovery. Heart samples obtained before and after LVAD implantation were divided into groups depending on whether the patients received (n = 7) or did not receive (control; n = 15) ACE-I. At transplant, ex vivo pressure-volume relationships were measured and chamber and myocardial stiffness constants determined. Myocardial tissue content of angiotensin (Ang) I and II, matrix metalloproteinase (MMP)-1, tissue inhibitor of MMPs (TIMP)-1, and total and cross-linked collagen was measured. Duration of support was comparable between ACE-I and control subjects (96 +/- 65 days vs. 109 +/- 22 days). Pre-LVAD Ang I and II and total and cross-linked collagen were similar between groups. Post-LVAD, Ang II was reduced in the ACE-I group but increased in control subjects (181 +/- 7 fmol/g vs. 262 +/- 41 fmol/g; p < 0.05). Similarly, cross-linked collagen decreased during LVAD support in the ACE-I group. Left ventricular (LV) mass and myocardial stiffness were lower in the ACE-I group. ACE-I normalized the LV and right ventricular (RV) MMP-1/TIMP-1 ratio. Collagen content and characteristics of the RV were not affected by ACE-I. ACE-I therapy was associated with decreased Ang II, myocardial collagen content, and myocardial stiffness during LVAD support. This is the first demonstration of a pharmacologic therapy that can impact myocardial properties during mechanical unloading, and it could foster new lines of investigation in strategies of enhancing myocardial recovery during LVAD support.

Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145+/-33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (P<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.

Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties.

Chronic beta-adrenoreceptor (beta-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern beta-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg.kg(-1).day(-1) from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that beta-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.

Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction.

Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident. Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks. Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings' upregulation. This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.

Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart.

Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart. Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks (n=7), rats treated with calcineurin inhibitor from 8 weeks (n=6), and untreated rats (n=7). Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed. Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.

Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy.

Pressure overload cardiac hypertrophy may be a compensatory mechanism to normalize systolic wall stress and preserve left ventricular (LV) function. To test this concept, we developed a novel in vivo method to measure myocardial stress (sigma)-strain (epsilon) relations in normal and hypertrophied mice. LV volume was measured using two pairs of miniature omnidirectional piezoelectric crystals implanted orthogonally in the endocardium and one crystal placed on the anterior free wall to measure instantaneous wall thickness. Highly linear sigma-epsilon relations were obtained in control (n = 7) and hypertrophied mice produced by 7 days of transverse aortic constriction (TAC; n = 13). Administration of dobutamine in control mice significantly increased the load-independent measure of LV contractility, systolic myocardial stiffness. In TAC mice, systolic myocardial stiffness was significantly greater than in control mice (3,156 +/- 1,433 vs. 1,435 +/- 467 g/cm(2), P < 0.01), indicating enhanced myocardial contractility with pressure overload. However, despite the increased systolic performance, both active (time constant of LV pressure decay) and passive (diastolic myocardial stiffness constant) diastolic properties were markedly abnormal in TAC mice compared with control mice. These data suggest that the development of cardiac hypertrophy is associated with a heightened contractile state, perhaps as an early compensatory response to pressure overload.

Ventricular remodeling and diastolic myocardial dysfunction in rats submitted to protein-calorie malnutrition.

The effects of protein-calorie malnutrition (PCM) on heart structure and function are not completely understood. We studied heart morphometric, functional, and biochemical characteristics in undernourished young Wistar rats. They were submitted to PCM from birth (undernourished group, UG). After 10 wk, left ventricle function was studied using a Langendorff preparation. The results were compared with age-matched rats fed ad libitum (control group, CG). The UG rats achieved 47% of the body weight and 44% of the left ventricular weight (LVW) of the CG. LVW-to-ventricular volume ratio was smaller and myocardial hydroxyproline concentration was higher in the UG. Left ventricular systolic function was not affected by the PCM protocol. The myocardial stiffness constant was greater in the UG, whereas the end-diastolic pressure-volume relationship was not altered. In conclusion, the heart is not spared from the adverse effects of PCM. There is a geometric alteration in the left ventricle with preserved ventricular compliance despite the increased passive myocardial stiffness. The systolic function is preserved.

Heart failure in pressure overload hypertrophy: The relative roles of ventricularremodeling and myocardial dysfunction

ObjectivesWe sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BackgroundThe mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. MethodsTwenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. ResultsThe LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure–diameter relationship and ex vivo from the pressure–volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress–midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress–strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. ConclusionsThe two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.

Prognostische Relevanz linksventrikulärer diastolischer Funktionsparameter bei dilatativer Kardiomyopathie

Patients with dilated cardiomyopathy (DCM) generally have an impaired functional capacity and poor long-term out-comes. A mortality of 5-15% per year has been described actually. Aim of this study was to verify the prognostic relevance of invasive and non-invasive parameters of diastolic function in patients with DCM. In 33 patients with DCM, cardiac catheterization was performed and left ventricular systolic (ejection fraction (EF; %)); left ventricular enddiastolic pressure (LVEDP; mmHg) and diastolic function (time constant of relaxation (T, ms); the constant of myocardial stiffness (b) were derived from biplane laevocardiography and simultaneous micromanometric registration of pressure-volume curves. For evaluation of clinical out-come, the follow-up period was defined as beginning on the day after cardiac catheterization and ending on the most recent date or with a cardiac event (death or cardiac transplantation). All patients were reevaluated for NYHA functional class and completed a standard questionnaire. The following hemodynamic parameters were evaluated: invasive parameters of left ventricular diastolic function (constant of relaxation: tau (ms), constant of myocardial stiffness: b)), as well as parameters of systolic function (ejection fraction (EF; %)), left ventricular pressure (LVEDP; mmHg), left ventricular muscle mass index (LVMMI; g/m2), left ventricular enddiastolic volume index (LVEDVI; ml/m2) and non-invasive parameters of morphological data, left ventricular systolic (fractional shortening (FS, %) and ejection fraction) and diastolic parameters with echocardiography. During the follow-up period of 36 months, 11 of 33 patients experienced a major cardiac event (cardiac death n = 8, heart transplantation n = 3). The major cause of death was progressive pump failure. The remaining 22 patients were further classified with respect to changes in functional status. While clinical symptoms could be improved medically in patients with moderate increase of myocardial stiffness, patients with severe increase of myocardial stiffness (b: 76.1 +/- 12.1 vs 17.9 +/- +8.1, p < 0.001) could not be improved and suffered more cardiac events. Doppler echocardiographic measurements in these patients showed a restrictive filling pattern (VE 0.91 +/- 0.21 vs 0.64 +/- 0.18 m/s; p < 0.01; VA 0.52 +/- 0.23 vs 0.57 +/- 0.24 m/s; p < 0.01, deceleration time 129 +/- 17 vs 211 +/- 14 ms; p < 0.01). The medical heart failure therapy was comparable in both groups. In patients with cardiac events, the diastolic left ventricular variables did not significantly differ between patients who underwent heart transplantation and those who died. Patients who demonstrated a sole impairment of relaxation (tau: > 50 ms) suffered no cardiac events. Impaired diastolic function contributes to the clinical picture of congestive heart failure. Parameters of left ventricular diastolic function are powerful and important predictors of major cardiac events in patients with DCM, like heart transplantation and non-sudden death, and may indicate future clinical success of medical treatment. Invasive and non-invasive parameters of diastolic function reveal comparable information for the estimation of prognosis of patients with DCM in order to initiate early therapy.

Diastolic heart failure.

Primary diastolic failure is typically seen in patients with hypertensive or valvular heart disease as well as in hypertrophic or restrictive cardiomyopathy but can also occur in a variety of clinical disorders, especially tachycardia and ischemia. Diastolic dysfunction has a particularly high prevalence in elderly patients and is generally associated, with low mortality but high morbidity. The pathophysiology of diastolic dysfunction includes delayed relaxation, impaired LV filling and/or increased stiffness. These conditions result typically in an upward displacement of the diastolic pressure-volume relationship with increased end-diastolic, left atrial and pulmo-capillary wedge pressure leading to symptoms of pulmonary congestion. Diagnosis of diastolic heart failure requires three conditions: (1) presence of signs or symptoms of heart failure; (2) presence of normal or slightly reduced LV ejection fraction (EF > 50%) and (3) presence of increased diastolic filling pressure. Assessment of diastolic function can be performed with several non-invasive (2D- and Doppler-echocardiography, color Doppler M-mode, Doppler tissue imaging, MR-myocardial tagging, radionuclide ventriculography) and invasive techniques (micromanometry, angiography, conductance method). Doppler-echocardiography is the most useful tool to routinely measure diastolic function. Different techniques can be used alone or in combination to assess LV diastolic function, but most of them are dependent on heart rate, pre- and afterload. The transmitral flow pattern remains the starting point, since it is easy to acquire and rapidly categorizes patients into normal (E > A), delayed relaxation (E < A), and restrictive (E >> A) filling patterns. Invasive assessment of diastolic function allows determination of the time constant of relaxation from the exponential pressure decay during isovolumic relaxation, and the evaluation of the passive elastic properties from the slope of the diastolic pressure-volume (= constant of chamber stiffness) and stress-strain relationship (= constant of myocardial stiffness). The prognosis of diastolic heart failure is usually better than for systolic dysfunction. Diastolic heart failure is associated with a lower annual mortality rate of approximately 8% as compared to annual mortality of 19% in heart failure with systolic dysfunction, however, morbidity rate can be substantial. Thus, diastolic heart failure is an important clinical disorder mainly seen in the elderly patients with hypertensive heart disease. Early recognition and appropriate therapy of diastolic dysfunction is advisable to prevent further progression to diastolic heart failure and death. There is no specific therapy to improve LV diastolic function directly. Medical therapy of diastolic dysfunction is often empirical and lacks clear-cut pathophysiologic concepts. Nevertheless, there is growing evidence that calcium channel blockers, beta-blockers, ACE-inhibitors and AT2-blockers as well as nitric oxide donors can be beneficial. Treatment of the underlying disease is currently the most important therapeutic approach.

Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis

OBJECTIVESThe study evaluates the clinical course and the development of systolic and diastolic left ventricular function in patients with chronic myocarditis with or without autoantibodies against cardiac myosin.BACKGROUNDPatients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available.METHODSThirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation “tau” and the constant of myocardial stiffness “b” were determined at baseline and at follow-up.RESULTSIn 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 ± 10.1%) compared with antibody-positive patients (−0.1 ± 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 ± 31 ml; SVI: +10 ± 17 ml) compared with antibody-positive patients (SV: −14 ± 43 ml; SVI: −8 ± 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation “tau” did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness “b” improved significantly in antibody-negative patients (−6.1 ± 10.8) compared with antibody-positive patients (+7.3 ± 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results.CONCLUSIONSAntimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.

Effects of beta-adrenergic blocking therapy on left ventricular diastolic relaxation properties in patients with dilated cardiomyopathy.

The hemodynamic mechanism for the improvement in left ventricle (LV) end-diastolic pressure in cardiomyopathy patients treated with beta-adrenergic blocking agents is controversial. We hypothesized that the salutary effect of this kind of therapy on LV end-diastolic pressure would be indicative of an improvement in late, passive diastolic relaxation properties. We studied 14 cardiomyopathy patients in normal sinus rhythm with no arteriographic evidence of coronary artery disease and an LV ejection fraction of </=40% by radionuclide angiography both before and after 6 months of metoprolol therapy with simultaneous micromanometry and biplane cineventriculography. Four comparable patients who were not treated with metoprolol were studied in a similar fashion and served as control subjects. In those receiving metoprolol, LV end-diastolic pressure decreased (P=0.001). The isovolumic relaxation index, tau(ln), shortened (P=0.03). In a similar fashion, the LV chamber stiffness constant, kappa, decreased (P=0.02), LV volume elastance improved (P=0.04), and the myocardial stiffness constant, kappa(e), decreased (P=0.02). A multiple regression analysis revealed that the decrease in LV end-diastolic pressure was indicative of significant improvements in tau(ln) and kappa(e) with the relationship: LV end-diastolic pressure=-4.73+0.27 tau(ln)+0.54 kappa(e) (r=0.81, P<0.0001). These LV diastolic relaxation properties did not change or worsened in the control cardiomyopathy patients. We conclude that the decrease in LV end-diastolic pressure in cardiomyopathy patients treated with metoprolol is an indicator of improvement in LV diastolic properties resulting from more complete myocardial relaxation.