Left Ventricular Diastolic Wall Thickness Research Articles

Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

Familial cardiomyopathy in Norwegian Forest cats.

Norwegian Forest cats (NFCs) are often listed as a breed predisposed to cardiomyopathy, but the characteristics of cardiomyopathy in this breed have not been described. The aim of this preliminary study was to report the features of NFC cardiomyopathy based on prospective echocardiographic screening of affected family groups; necropsy findings; and open-source breed screening databases. Prospective examination of 53 NFCs revealed no murmur or left ventricular (LV) outflow tract obstruction in any screened cat, though mild LV hypertrophy (defined as diastolic LV wall thickness ≥5.5mm) was present in 13/53 cats (25%). Gross pathology results and histopathological sections were analysed in eight NFCs, six of which had died of a cardiac cause. Myocyte hypertrophy, myofibre disarray and interstitial fibrosis typical of hypertrophic cardiomyopathy were present in 7/8 cats, but endomyocardial fibrosis suggestive of restrictive cardiomyopathy was also present in the same cats. Pedigree data analysis from 871 NFCs was supportive of a familial cardiomyopathy in this breed.

Assessment of left ventricular global systolic strain in hypertrophic cardiomyopathy by three-dimensional speckle tracking echocardiography

Objective To explore the value of three-dimensional speckle tracking imaging (3D-STI) in evaluating the global systolic strain of left ventricular (LV) in patients with hypertrophic cardiomyopathy (HCM).Methods A total of 90 consecutive patients with HCM were enrolled,in which 58 patients were nonobstructive HCM (HNCM),32 patients were obstructive HCM (HOCM).In addition,72 healthy subjects were recruited as a control group.An ultrasound system iE33 (Philips Medical Systems,Bothell) was used to acquire and analyze two-dimensional images.Full-volume three-dimensional dynamic images were performed using matrix transducer X5-1.LV global longitudinal strain(GLS),global circumferential strain(GCS),global radial longitudinal(GRS),global strain (GS),were analysis using off-line TomTec software,the differences among three groups were compared.Results Compared with the control group,LV end-diastolic,end-systolic volumes and stroke volume significantly decreased,LV mass and LV diastolic wall thickness significanty increased.Howeve,there was no significant difference between LVEF in the HCM and control group (P =0.178).The comparson of the 3D systolic strain in the four groups as followed,compared with the control group,GS was no significant difference,GLS was significantly reduced,however GCS,GRS was significantly increased in HCM groups.When compared with the HNCM,GLS was significant reduced,however GCS,GRS were significant increased in the HOCM group.Bland-Altman analysis showed there were good agreements in both patients with HCM and control subjects.Conclusions 3D-STI can detecte the early impairment of LV global myocardial contractility in HCM,and provides valuable information for clinical in early diagnosis,prevention and treatment. Key words: Echocardiography; Cardiomyopathy, hypertrophic; Ventricular function, left; Three dimensional speckle tracking imaging

Prognostic Indicators in Cats with Hypertrophic Cardiomyopathy

Left atrial (LA) enlargement, congestive heart failure (CHF), and aortic thromboembolism (ATE) are associated with decreased survival in cats with hypertrophic cardiomyopathy (HCM), but the prognostic value of echocardiographic variables has not been well characterized. We hypothesized that LA echocardiographic variables and assessment of left ventricular (LV) diastolic and systolic function would have prognostic value in cats with HCM. Two hundred eighty-two cats diagnosed with HCM. Clinical and echocardiographic records of affected cats seen at the Royal Veterinary College from 2004 to 2009 were retrospectively analyzed. Only cats with echocardiographic confirmation of LV diastolic wall thickness ≥ 6 mm were included. Outcomes were obtained from clinical records or referring veterinarians and owners. Deaths occurred in 164 cats, of which 107 were believed to have been cardiac deaths. Univariable predictors of an increased risk of cardiac death included older age, absence of a murmur, presence of a gallop sound or arrhythmia, presentation with either CHF or ATE, extreme LV hypertrophy (≥ 9.0 mm), LV fractional shortening (FS%) ≤ 30%, regional wall hypokinesis, increased left atrial size, decreased left atrial function, spontaneous echo-contrast/thrombus or both, absence of left ventricular outflow tract obstruction, and a restrictive diastolic filling pattern. Cox's proportional hazard analysis identified LA dysfunction, low LV systolic function, and extreme LV hypertrophy as independent predictors of decreased cardiac survival time. Echocardiographic measurement of LA function, extreme LV hypertrophy, and LV systolic function provides important prognostic information in cats with HCM.

An echocardiographic index for decompensation of the chronically volume-overloaded left ventricle in children

The criterions for the timing of surgical intervention in children with rheumatic mitral or aortic valvar regurgitation are not defined. I hypothesized that, in children with chronic mitral or aortic regurgitation, an index for decompensation could be created by using the ratio of the diastolic left ventricular wall thickness to the radius, and that such an index could prove useful in determining the optimal time for surgical intervention. The left ventricular echocardiograms were obtained at the tips of the leaflets of the mitral valve by M-mode echocardiography. The diastolic septal wall thickness was measured between the right and left ventricular endocardial layers, and the posterior wall thickness between the endocardium and the interphase between the epicardium and the myocardium. The left ventricular diastolic dimension was then measured, between the posterior and septal wall endocardial layers, and systolic dimension as the smallest distance detected between these layers. All diastolic measurements were made at the time of the R wave of electrocardiogram, using the leading edge technique. The ratio of wall thickness was measured using the mean of septal and posterior wall thicknesses divided by half the diastolic dimensions, the normalized thickness of the wall previously referred to as the h/r ratio and relative mural thickness. The ratio of wall thickness to left ventricular radius, and its relation to systolic left ventricular pressure or systolic blood pressure, was found to be linear in 89 normal school children, and 39 children with aortic stenosis. For future predictions, I calculated the 95th percentile limits and the 95th percentile confidence bands for this relation. Using the same data, it proved possible to calculate ratios of wall thickness for various ranges of either systolic blood pressure or left ventricular peak pressure. By using the normal limits of 0.356 plus or minus 0.0316 of the ratio, appropriate for the systolic blood pressure of children with mitral regurgitation, I determined the adequacy of the ratio of wall thickness. Of the children, 51 were in ventricular failure, and these had an inadequate ratio, below two standard deviation. Of the others, 21 had an inadequate ratio to within minus one to minus two standard deviations, and 12 of these were asymptomatic, 8 were symptomatic, but only one was in ventricular failure. For 18 children with aortic regurgitation, using the same limits, one child was within 1 standard deviation and was asymptomatic, 8 fell within minus 1 to minus 2 standard deviations and 2 of these were symptomatic, 5 were in ventricular failure, and 1 was asymptomatic, while the other 9 had ratios falling less than minus 2 standard deviations, and all were in ventricular failure. I conclude that the index of normalized wall thickness defined as the ratio of the left ventricular wall thickness to its radius is adequate, and within normal limits, when there is compensated volume overload, but is inadequate and below normal limits when the volume overloaded left ventricle becomes decompensated. My data suggests that the persistently decreasing ratio of wall thickness below the limits of normality serves as an indicator of ventricular decompensation, and thus can be used as a new criterion for determining the optimal time for surgical intervention.

Sequential monitoring of intragraft cytokine mRNA expression in relation to diastolic left ventricular wall thickness and function early after heart transplantation.

Because production of immune regulatory proteins may play a role in early graft dysfunction after heart transplantation, we analyzed whether intragraft cytokine messenger RNA (mRNA) expression levels are associated with diastolic left ventricular function in cardiac allografts. We intensively monitored 16 cardiac allograft recipients during the first 3 months after transplantation. The mRNA expression levels of tumor necrosis factor (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF-beta), platelet derived growth factor (PDGF-A), and basic fibroblast growth factor (bFGF) were measured in endomyocardial biopsies (n = 123) by quantitative RT-PCR. To determine diastolic allograft function, concurrent M-mode and two-dimensional Doppler echocardiograms were analyzed for the following parameters: left ventricular total wall thickness, maximal early and atrial mitral flow velocity, deceleration time of maximal early mitral flow velocity, and isovolumetric relaxation period. During the first 3 months post-transplant an overall decrease in mRNA expression levels of almost all measured cytokines was observed, which paralleled an improvement in diastolic left ventricular wall thickness and function. However, no straightforward relationship could be found between a specific cytokine mRNA expression pattern and the studied echocardiographic parameters. Our data suggest that the improvement in diastolic left ventricular function is associated with a general reduction of inflammation within the allograft, rather than related to a specific cytokine expression pattern.

Different left ventricular remodelling and function in two models of pressure overload as assessed in vivo by magnetic resonance imaging.

To follow the development of left ventricular structure and function in vivo in two different models of pressure-overload hypertrophy. From age 6 weeks, left ventricular structure and function changes in spontaneously hypertensive (SHR) and renal hypertensive (RHR) rats were followed in vivo by magnetic resonance imaging over 7 months. Wistar-Kyoto rats served as controls. Systolic blood pressure (SBP) was measured once a week by the tail-cuff method. Transverse left ventricular sections were obtained at end-diastole and end-systole by electrocardiogram-gated magnetic resonance imaging, allowing the determination of left ventricular mass, wall thickness and volume. Angiotensin II (Ang II) plasma levels were determined at 2 and 4 weeks into the study. At the end of the study functional parameters were obtained by left ventricular catheterization. After 4 weeks both SHR and RHR showed a similar degree of hypertension. At 4 weeks Ang II levels were significantly elevated in RHR and suppressed in SHR relative to controls. The extent of left ventricular hypertrophy was essentially the same in SHR and RHR, but the diastolic left ventricular wall thickness: volume ratio was substantially increased in RHR only. During the first 11 weeks of the study, a small end-systolic volume and an increased end-systolic wall thickness allowed the systolic wall stress in RHR to be maintained near control values. Thereafter a discrete deterioration of left ventricular function was observed, as demonstrated by the steady increase in end-systolic volume. In contrast, SHR did not show an increase in end-systolic wall thickness at any time, resulting in an elevated systolic wall stress. However, left ventricular function was stable during the observed period. Despite similar SBP and left ventricular mass, left ventricular remodelling and function were different in RHR and SHR. SHR appeared to be stable during the 30-week observation period, whereas RHR exhibited a progressive functional impairment after week 11. The distinct involvement of the renin-angiotensin system in the pathogenesis of hypertension in these models may account for these differences.

974-40 Ventricular and Myocardial Function Following Regression of Hypertensive Left Ventricular Hypertrophy

It has been hypothesized that left ventricular(LV)function may deteriorate follOWing reduction in LV mass in treated hypertensives. We therefore assessed ventricular and myocardial function follOWing a substantial regression of LV mass (≥80 g) after 1 year of antihypertensive treatment in 17 patients. These pts were part of a cohort of 239 undergoing echocardiography at baseline and 1 year who took part in a multicenter VA cooperative study of monotherapy in hypertension. We hypothesized that an 80 g reduction represents true LV mass regression, since it exceedS 2 standard deviations of test-retest reliability of M-mode echocardiography; such a large reduction in LV mass should allow the detection of functional changes that accompany hypertrophy regression. Circumferential stress (σc, g/cm2) vs endocardial fractional shortening (FSendo, %) relations were used to characterize LV function; ac vs midwall fractional shortening (FSmw, %) was used to define myocardial function. FSmw was derived from a two-shell model that accounts for nonuniform wall thickening, is independent of relative wall thickness (RWT) and is anatomically appropriate, since midwall fibers are oriented circumferentially. Thd and Dd are LV diastolic wall thickness and diastolic dimension (mm); SBP = systolic pressure; Data are mean ± SEEmpty CellSBPTh dDdRWTLVMassFSendoFSmwσcbaseline153 ± 414 ± 156 ± 10.50 ± 0.03438 ± 2639 ± 220 ± 195 ± 101 year139 ± 4*11 ± 1*52 ± 2*0.46 ± 0.03326 ± 24*36 ± 220 ± 1106 ± 12**P < 005 vs baseline P < 005 vs baseline A significant decrease in SSP was accompanied by a substantial reduction in LV mass and a significant, albeit small, increment in aC. The increase in ac was associated with a small (p = NS) decrease in FSendo and no change in FSmw. Thus major changes in mass associated with anti-hypertensive therapy are not accompanied by a decrement in LV or myocardial function. Indeed the unchanged FSmw in the presence of increased ac suggests improved myocardial contractile function

Changes in left ventricular diastolic wall thickness induced by chronic asynchronous electrical activation

Changes in left ventricular diastolic wall thickness induced by chronic asynchronous electrical activation

Assessment of myocardial systolic wall thickening using nuclear magnetic resonance imaging

A quantitative nuclear magnetic resonance (NMR) imaging method of evaluating regional left ventricular function was compared with histochemical evidence of infarction in dogs and functional measurements in patients. Short-axis images of the heart were obtained at end-diastole and at 100 ms intervals thereafter. Regional diastolic left ventricular wall thickness and maximal percent systolic wall thickening were measured at the level of the papillary muscles in each of six segments. In six normal dogs, the mean end-diastolic wall thickness was 9 ± 1.6 mm, and the mean maximal percent thickening was 61 ± 11%. In eight dogs with a 4 day old infarct, maximal percent thickening was 5 ± 8% (p < 0.001) in the infarcted segments.In 10 normal human volunteers, the mean end-diastolic wall thickness was 10.1 ± I mm, and the mean maximal percent systolic wall thickening was 60 ± 18%. Reduced maximal percent systolic wall thickening was defined as a value ≥2 SD below the mean value obtained in normal volunteers. Seven patients with regional wall motion abnormalities were independently assessed by NMR imaging and biplane ventriculography. With a sensitivity of 94% and a specificity of 80%, NMR imaging demonstrated reduced maximal percent systolic wall thickening in the same segments identified as akinetic or dyskinetic by biplane ventriculography. Thus, abnormalities of regional systolic wall thickening are accurately identified with this quantitative imaging technique.

Is parathormone a cardiac toxin in uremia?

In uremia, parathormone (PTH) has been associated with inadequate left ventricular hypertrophy, cardiomyopathy, and mitral anular calcification (MAC). We related levels of serum PTH, calcium, phosphate, magnesium, calcium-phosphate product, and systolic blood pressure to average left ventricular wall thickness, left ventricular mass index, ejection fraction, and presence and extent of MAC by echocardiography in 44 patients before and after renal transplantation. Pre-transplant, 18 patients (41%) had MAC; these and the 26 others had similar values for serum PTH, calcium-phosphate product, systolic blood pressure, age, and years of hemodialysis. The patients with PTH levels greater than 1000 mcl eq/ml had higher systolic blood pressures pre-transplant (157 +/- 21 vs 147 +/- 17 mm Hg, p less than 0.05), but not post-transplant as PTH levels normalized. Post-transplant, there were significant decreases in left ventricular mass index (140 +/- 35 to 103 +/- 25 g/m2) and average diastolic left ventricular wall thickness (1.4 +/- 0.2 to 1.2 +/- 0.2 cm, both p less than 0.05); however, ejection fraction and extent of MAC did not change. Left ventricular mass index, average diastolic left ventricular wall thickness, and ejection fraction did not correlate with serum PTH or electrolyte levels before or after renal transplantation. MAC is present in more than one third of uremic pts and does not resolve after renal transplantation. Although PTH does not correlate with left ventricular hypertrophy, cardiac function, or MAC before or after transplantation, elevated levels pre-transplant are associated with a slightly greater degree of hypertension. Thus PTH may be a mild vasoactive pressor in some patients with end-stage renal failure.

Transposition of the great arteries with intact ventricular septum: Arterial switch in the first month of life

Twenty-three infants with simple transposition of the great arteries and intact ventricular septum were operated on from October 1983 to October 1986. The age at operation in 22 infants ranged from 2 to 21 days and in one was 35 days (mean 9.82 +/- 6.86 days). The infants were evaluated with cardiac catheterization at 1 to 27 days of age. Twenty-two infants had balloon atrial septostomy, and 22 received prostaglandin E1 infusion. The left ventricular diastolic wall thickness, assessed by M-mode echocardiograms, varied between 2.8 and 4 mm. There were two hospital deaths in this group of 23 infants (mortality 8.6%), and there were no late deaths. All surviving patients are doing well clinically. One patient had asymptomatic nonsustained ventricular tachycardia necessitating phenytoin. Postoperative echocardiographic assessment performed on 15 patients at 0.93 +/- 0.61 years of age and cardiac catheterization and angiographic studies on seven patients at 1.07 +/- 0.13 years after operation revealed excellent ventricular performance, good semilunar valve function, and mild gradient at the right ventricular outflow with a mean right ventricular pressure of 37.4 +/- 4.1 torr.