Decrease In Diastolic Function Research Articles

Temporal Responses of a Low-Energy Meal Replacement Plan or Exercise Training on Cardiovascular Function and Fibro-Inflammatory Markers in People with Type 2 Diabetes—A Secondary Analysis of the “Diabetes Interventional Assessment of Slimming or Training to Lessen Inconspicuous Cardiovascular Dysfunction” Study

Background: This study assesses the temporal responses of cardiovascular function, fibro-inflammation, and glucometabolic profiles in asymptomatic adults with type 2 diabetes, following a low-energy meal replacement plan (MRP) or exercise training. Methods: Secondary analysis of DIASTOLIC: a randomised, open-label, blinded-endpoint trial of 12 weeks MRP (~810 kcal/day) or exercise training. Cardiac magnetic resonance, plasma fibroinflammatory, and metabolic markers were undertaken at baseline, 4, and 12 weeks. Results: Out of 24 participants in the MRP group and 22 in exercise training, 18 and 11 completed all three visits. MRP resulted in early (0–4 weeks) improvement in insulin resistance (HOMA-IR: 10.82 to 4.32), decrease in FABP-4 (4.87 ± 0.19 to 5.15 ± 0.32 mg/L), and improvement in left ventricular remodelling LV mass: volume (0.86 ± 0.14 to 0.78 ± 0.11), all with large effect sizes. MMP8 levels increased moderately at 4–12 weeks. Peak early diastolic strain rate (cPEDSR) initially decreased, then improved. Exercise training led to minor improvements in insulin resistance and MMP-8 levels, with no significant changes in cPEDSR or LV remodelling. Conclusions: MRP resulted in early improvements in insulin resistance, cardiac remodelling, and inflammation, but with an initial decrease in diastolic function, improving by 12 weeks. Exercise training showed minor early benefits in insulin resistance and inflammation, but no significant cardiac changes.

Correlation Between 25-Hydroxyvitamin D Level and Cardiac Diastolic Dysfunction in Chinese Adults with Early-Onset Type 2 Diabetes Mellitus: A Cross-Sectional Study.

PurposeChinese adults with early-onset type 2 diabetes mellitus have impaired diastolic function. This study aims to analyse the association between serum vitamin D levels and cardiac diastolic dysfunction in Chinese adults with early-onset type 2 diabetes mellitus.Patients and MethodsWe enrolled Chinese adults with early-onset type 2 diabetes mellitus in this study. These patients were divided into two groups: those with diastolic dysfunction and those without diastolic dysfunction. We then compared the levels of serum 25-hydroxyvitamin D [25-(OH)D] between the two groups. The correlation between diastolic function and 25-(OH)D was evaluated by Pearson correlation analysis. Finally, binary logistic regression was used to analyse the relationship between the decrease in diastolic function and 25-(OH)D and other indexes in Chinese adults with early-onset type 2 diabetes mellitus.ResultsThe level of 25-(OH)D in patients with early-onset type 2 diabetes mellitus complicated with cardiac diastolic dysfunction was significantly lower than that in patients without cardiac diastolic dysfunction (P<0.01). The degree of liver fibrosis in adult patients with early-onset type 2 diabetes mellitus complicated with diastolic dysfunction was significantly higher than that in adult patients without diastolic dysfunction (P<0.01). Moreover, decreased 25-(OH)D levels were associated with decreased diastolic function in adults with early-onset type 2 diabetes.Conclusion25-(OH)-D was identified as an independent predictor of decreased diastolic function in adults with early-onset type 2 diabetes. The serum 25-(OH)D level in adults with early-onset type 2 diabetes was significantly reduced. 25-(OH)D influences the reduction in diastolic function in adults with early-onset type 2 diabetes and can be used as a predictor of decreased diastolic function in such patients.

Left and Right Ventricular Impairment Shortly After Correction of Tetralogy of Fallot

Surgical repair of Tetralogy of Fallot (ToF) is usually performed in the first months of life with low early postoperative mortality. During long-term follow-up, however, both right (RV) and left ventricular (LV) performances may deteriorate. Tissue Doppler imaging (TDI) and speckle tracking echocardiography (ST) can unmask a diminished RV and LV performance. The objective of the current study was to assess the cardiac performance before and shortly after corrective surgery in ToF patients using conventional, TDI and ST echocardiographic techniques. Thirty-six ToF patients after surgery were included. Transthoracic echocardiography including TDI and ST techniques was performed preoperatively and at hospital discharge after surgery (10 days to 4 weeks after surgery). Median age at surgery was 7.5 months [5.5–10.9]. Regarding the LV systolic function there was a significant decrease in interventricular septum (IVS) S′ at discharge as compared to preoperatively (pre IVS S′ = 5.4 ± 1.4; post IVS S′ = 3.9 ± 1.2; p < 0.001) and in global longitudinal peak strain (GLS) (pre = − 18.3 ± 3.4; post = − 14.2 ± 4.1; p = 0.003); but not in the fractional shortening (FS). Both conventional and TDI parameters showed a decrease in diastolic function at discharge. Tricuspid Annular Plane Systolic Excursion and RV S′ were significantly lower before discharge. When assessing the RV diastolic performance, only the TDI demonstrated a RV impairment. There was a negative correlation between age at surgery and postoperative LV GLS (R = − 0.41, p = 0.031). There seems to be an impairment in left and right ventricle performance at discharge after ToF corrective surgery compared to preoperatively. This is better determined with TDI and ST strain imaging than with conventional echocardiography.

Age-related longitudinal change in cardiac structure and function in adults at increased cardiovascular risk.

AimHeart failure (HF) incidence increases markedly with age. We examined age‐associated longitudinal change in cardiac structure and function, and their prediction by age and cardiovascular disease (CVD) risk factors, in a community‐based cohort aged ≥60 years at increased CVD risk but without HF.Methods and resultsCVD risk factors were recorded in 3065 participants who underwent a baseline echocardiographic examination, of whom 2358 attended a follow‐up examination 3.8 [median, inter‐quartile range (IQR) 3.5, 4.2] years later. Median age was 71 (IQR 67, 76) years and 55% of participants were male. Age was associated with longitudinal increase in left ventricular (LV) mass index (LVMI); decrease in LV volumes; increase in LV ejection fraction; decrease in mitral annular systolic velocity; decrease in diastolic function (decreased mitral early diastolic annular velocity (e′); and increase in left atrial volume index, mitral peak early diastolic flow velocity (E)/e′ ratio, and tricuspid regurgitant velocity (TRVmax) in men and women, except for TRVmax in men). In multivariable analysis, longitudinal increase in LVMI was explained by CVD risk factors alone, whereas age, together with CVD risk factors, independently predicted longitudinal change in all other echocardiographic parameters. CVD risk factors were differentially associated with longitudinal change in different echocardiographic parameters.ConclusionsWhereas the increase in LVMI with age was explained by CVD risk factors alone, age, together with risk factors, independently predicted longitudinal change in all other echocardiographic parameters, providing evidence for age‐specific mechanisms of change in cardiac structure and function as people age. Age‐associated change in LVMI, LV volumes, and diastolic function resembled what might be expected for the evolution of HF with preserved ejection fraction. Given the differential association of different CVD risk factors with longitudinal change in different echocardiographic parameters, therapies aimed at attenuation of age‐associated change in cardiac structure and function, and HF evolution, will likely need to address multiple CVD risk factors.

P899Long-term evolution of Fabry cardiomyopathy under enzyme replacement therapy in the Swiss Fabry cohort. An echocardiographic study

Abstract Introduction Fabry cardiomyopathy may present with left ventricular hypertrophy (LVH) and enzyme replacement therapy (ERT) aims to slow its progression in affected patients. LVH progression may be observed despite ERT and the aim of this study was to identify predictors of adverse LV remodeling under treatment. Methods This multicentric study included consecutive Fabry patients receiving ERT and for whom a clinical follow-up (FU) with echocardiography (TTE) of at least 5 years was available. The first TTE was performed at the time of ERT start and disease progression was defined as an increase in LV mass index between the first and the last available FU TTE. Results Sixty-one patients (median age 35 years [23–48] and 40 (66%) men) were included with a median FU of 10.5 years [7.2–12.2]. Progression was seen in 33 (54%) patients with an annual increase in LV mass index of 1.8 g/m2/year [0.7–3.2] (vs −0.8 g/m2/year [−1.6 to 0.4] in the non-progression group). Presence of LVH (&gt;95 g/m2 in women or &gt;115 g/m2 in men) at the start of ERT was the only morphological baseline parameter significantly associated with progression after adjustment for age, gender and baseline arterial hypertension (OR 22.5, 95% CI 2.7–188.3, p=0.004). Over the FU duration, patients with baseline LVH (n=22) had higher increase in LV diastolic diameter (2.3±4.9 mm vs 0.9±4.1, p=0.009), a lower increase in relative wall thickness (−1.7±14.1% vs 4.6±9.8%, p=0.04), and a higher increase in LV mass index (22±22 g/m2 vs 0±17 g/m2, p=0.001), as compared with patients with no baseline LVH. While no difference was seen in the evolution of the LV ejection fraction, a faster decline in diastolic function was observed in patients with baseline LVH, with a higher increase in E/e' ratio (5.9±7.4 vs 1.1±2.8, p=0.001) and in left atrial diameter (4.7±5.4 mm vs 1.8±5.2 mm). Baseline characteristics All (n=61) No LVH (n=39) LVH (n=22) p Age (years) 35 [23–48] 17 [21–36] 50 [44–54] &lt;0.001 Male gender 40 (66%) 22 (56%) 18 (82%) 0.79 Arterial hypertension 10 (17%) 3 (8%) 7 (31%) 0.03 LV mass index (g/m2) 105±43 79±18 150±38 &lt;0.001 Mitral E/e' ratio 7.8±5.0 6.7±2.0 9.9±7.8 0.02 Conclusion Over a median FU of over 10 years, LV wall thickness, LV mass and LV diastolic function remained stable under ERT, providing the treatment was started, early, i.e. before development of LVH. If LVH is already present at baseline, ERT appears to be less effective, with significant progression in LV mass and significantly faster decrease in diastolic function.

Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction

BackgroundAlterations in cardiac energy metabolism contribute to the development and severity of heart failure (HF). In severe HF, overall mitochondrial oxidative metabolism is significantly decreased resulting in a reduced energy reserve. However, despite the high prevalence of HF with preserved ejection fraction (HFpEF) in our society, it is not clear what changes in cardiac energy metabolism occur in HFpEF, and whether alterations in energy metabolism contribute to the development of contractile dysfunction.MethodsWe directly assessed overall energy metabolism during the development of HFpEF in Dahl salt-sensitive rats fed a high salt diet (HSD) for 3, 6 and 9 weeks.ResultsOver the course of 9 weeks, the HSD caused a progressive decrease in diastolic function (assessed by echocardiography assessment of E’/A’). This was accompanied by a progressive increase in cardiac glycolysis rates (assessed in isolated working hearts obtained at 3, 6, and 9 weeks of HSD). In contrast, the subsequent oxidation of pyruvate from glycolysis (glucose oxidation) was not altered, resulting in an uncoupling of glucose metabolism and a significant increase in proton production. Increased glucose transporter (GLUT)1 expression accompanied this elevation in glycolysis. Decreases in cardiac fatty acid oxidation and overall adenosine triphosphate (ATP) production rates were not observed in early HF, but both significantly decreased as HF progressed to HF with reduced EF (i.e. 9 weeks of HSD).ConclusionsOverall, we show that increased glycolysis is the earliest energy metabolic change that occurs during HFpEF development. The resultant increased proton production from uncoupling of glycolysis and glucose oxidation may contribute to the development of HFpEF.

Abstract P193: Anti-fibrotic and Anti-oxidant Actions of a Muscadine Grape Extract Supplement on Hypertension-induced Cardiac Damage

Approximately 75 million U.S. adults suffer from hypertension, an independent risk factor for pathological cardiac hypertrophy. The current study examines the effects of a muscadine grape extract formulation (MGE; Piedmont Research &amp; Development Corp.) with anti-oxidant, anti-inflammatory, and anti-proliferative properties on hypertension-induced cardiac damage in Sprague-Dawley rats receiving a 4-week Ang II infusion (24 μg/kg/h). We previously showed that MGE in the drinking water had no effect on blood pressure or systolic function in normotensive or hypertensive rats; however, MGE ameliorated the Ang II-induced decrease in diastolic function and increase in cardiomyocyte cross-sectional area. In the current study, MGE supplementation of Ang II-treated rats decreased interstitial cardiac fibrosis, reducing collagen III staining in the myocardium (0.9 ± 0.2% control, 6.8 ± 1.0% Ang II, and 2.8 ± 0.4% Ang II/MGE; p&lt;0.01). MGE alone had no effect on any parameters assessed. The positive correlation between collagen and diastolic function with Ang II compared to control (p&lt;0.01) was significantly abrogated by co-administration of MGE. TGFβ is a critical cytokine that stimulates cardiac fibrosis. The Ang II-mediated increase in cardiac TGFβ mRNA was attenuated by MGE (relative gene expression: 1.0 ± 0.1 control, 2.0 ± 0.4 Ang II, 1.1 ± 0.2 Ang II/MGE; p&lt;0.05) as was downstream pSmad2 protein in cardiomyocytes (% nuclei: 26.1 ± 6 control, 53.8 ± 9.6 Ang II, 27.6 ± 5.5 Ang II/MGE; p&lt;0.05) and cardiac fibroblasts (2.3 ± 1.1 control, 11.7 ± 4.9 Ang II, 2.2 ± 0.5 Ang II/MGE; p&lt;0.05). NADPH oxidase is a primary contributor to cardiac oxidative stress and excess ROS production can lead to activation of pro-fibrotic pathways. MGE significantly reduced the Ang II-induced increase in p22phox mRNA (relative gene expression: 1.0 ± 0.1 control, 1.9 ± 0.1 Ang II, 1.0 ± 0.1 Ang II/MGE; p&lt;0.0001) and protein (relative density: 1.0 ± 0.2 control, 5.4 ± 1.6 Ang II, 2.9 ± 1.0 Ang II/MGE; p&lt;0.05), a subunit required for NADPH oxidase activity. These results indicate that MGE ameliorates cardiac fibrosis by targeting NADPH oxidase and the TGFβ pro-fibrotic pathway, suggesting that MGE supplementation may be an effective, natural therapeutic for hypertension-induced cardiac damage.

Resistance training attenuates salt overload-induced cardiac remodeling and diastolic dysfunction in normotensive rats.

Elevated salt intake induces changes in the extracellular matrix collagen, leading to myocardial stiffness and impaired relaxation. Resistance training (RT) has been used as a remarkably successful strategy in the treatment of heart disease. Therefore, the aim of this study was to investigate the effects of RT on preventing pathological adaptation of the left ventricle (LV) induced by salt overload. Male Wistar rats (10 weeks old) were distributed into four groups (n=8/group): control (CO), control+1% salt (CO+SALT), RT and RT+1% salt (RT+SALT). The RT protocol consisted of 4×12 bouts of squat training, 5/week for 8 weeks, with 80% of one repetition maximum (1RM). Echocardiographs were analyzed and interstitial collagen volume fraction (CVF) was determined in the LV. The 1RM tests in the RT and RT+SALT groups increased 145 and 137%, respectively, compared with the test performed before the training program. LV weight-to-body weight ratio and LV weight-to-tibia length ratio were greater in the RT and RT+SALT groups, respectively, compared with the CO group. Although there was no difference in the systolic function between groups, diastolic function decreased 25% in the CO+SALT group compared with the CO group measured by E/A wave ratio. RT partially prevented this decrease in diastolic function compared with the CO+SALT group. A 1% salt overload increased CVF more than 2.4-fold in the CO+SALT group compared with the CO group and RT prevented this increase. In conclusion, RT prevented interstitial collagen deposition in LV rats subjected to 1% NaCl and attenuated diastolic dysfunction induced by salt overload independent of alterations in blood pressure.

Abstract P166: The Effect of a Muscadine Grape Extract on Angiotensin II-Induced Hypertension and Cardiac Damage

Muscadine grapes, indigenous to the southeastern United States, are a dietary source of polyphenols, such as ellagic acid, quercetin, and resveratrol, which have both anti-inflammatory and antioxidant properties. Preclinical studies show that ground muscadine grape skins and seeds have anti-cancer effects, suggesting that supplementation with a muscadine grape extract (MGE) may serve as a chemotherapeutic or chemopreventive agent. As cancer patients often present with hypertension, diabetes, and other vascular pathologies, it is imperative to determine the effect of a muscadine grape supplement on these underlying comorbidities. The goal of this study was to determine whether MGE administered in the drinking water will exacerbate or improve hypertension and cardiac damage. Sprague-Dawley rats receiving a 4-week infusion of Ang II via subcutaneous osmotic mini-pump (24 μg/kg/h) had a significant increase in systolic blood pressure (123.1 ± 2.3 mm Hg in control vs. 213.1 ± 6.8 mm Hg in Ang II-treated; n=8; p &lt; 0.0001). MGE supplementation had no effect on blood pressure or gross cardiac hypertrophy in either normotensive or hypertensive rats. Additionally, MGE did not alter stroke volume or cardiac output, measured by VEVO ultrasound. However, MGE ameliorated the Ang-II induced decrease in diastolic function, as measured by the E/E’ ratio (19.9 ± 0.8 in control, 28.1 ± 1.1 in Ang II-treated rats, 22.3 ± 2.0 in Ang II/MGE-treated rats; p &lt; 0.05). Co-treatment with MGE also significantly reduced the Ang II-mediated increase in cardiomyocyte cross-sectional area (340.5 ± 12.0 μm 2 in control, 423.2 ± 17.1 μm 2 in Ang II-treated rats, and 342.6 ± 13.2 μm 2 in Ang II/MGE-treated rats, p &lt; 0.01). MGE supplementation of Ang II-treated rats decreased interstitial cardiac fibrosis, measured by Picrosirius red staining (1.0 ± 0.1% in control, 2.0 ± 0.2% in Ang II-treated rats and 1.4 ± 0.1% in Ang II/MGE-treated rats, p &lt; 0.05). These results demonstrate that treatment with MGE does not exacerbate hypertension or hypertension-induced cardiac damage but ameliorates cardiac hypertrophy, suggesting that MGE supplementation has an acceptable safety profile for use as an anti-cancer agent in hypertensive patients and may be used to treat cardiac hypertrophy and damage.

Abstract 402: Mutation-Specific Activation of CaMK-II in Hypertrophic Cardiomyopathy

Approximately 5-10% of all Hypertrophic Cardiomyopathy (HCM) mutations reside within cardiac troponin T (cTnT). Residue Arg92 of cTnT represents a mutational hotspot, including Arg92Leu (R92L) and Arg92Trp (R92W). Interestingly, patients expressing these substitutions that differ by only a single amino acid present with distinct phenotypes and disease severity. Studying the differential effects of the R92 mutations on Ca 2+ homeostasis revealed an age-dependent increase in phospholamban (PLB) phosphorylation at Thr17 (targeted by CaMKII) only in R92W mice. Thus, we hypothesized a mutation-specific role of CaMKII in cTnT-linked HCM progression and tested this hypothesis via genetic partial inhibition of CaMKII (AC3I peptide) in both R92W and R92L transgenic mice. A progressive increase in PKA-mediated PLB-Ser16 phosphorylation was observed in the AC3I/RW mice, leading to an increase in SERCA2 activity. This improved Ca 2+ re-uptake activity was coupled with a decrease in atrial mass, indicative of a decrease in diastolic filling pressure. Thus, the R92W mutation initiates downstream pathophysiologic activation of CaMKII, leading to progressive cardiomyopathic remodeling. Partial inhibition of CaMKII in R92W mice resulted in the alteration of the natural history of HCM, indicating a potential therapeutic target for patients expressing the mutation. In contrast, AC3I/RL mice showed no change in SERCA2 activity or atrial morphology, suggesting a CaMKII-independent progression to disease for R92L-linked HCM. Finally, R92L and R92W mice were treated with diltiazem hydrochloride, an L-type Ca 2+ channel blocker, and diastolic function monitored over time. R92W mice showed improvement in diastolic function with treatment while R92L mice showed a progressive decrease in diastolic function. These findings suggest that closely related mutations, even at the same residue, can have discrete molecular effects that result in mutation-specific ventricular remodeling and these observations can be incorporated in targeted disease management.

Impact of adverse left ventricular remodeling on sudden cardiac death in patients with hypertrophic cardiomyopathy.

Adverse left ventricular (LV) remodeling predicts heart failure symptoms and overt LV dysfunction in patients with hypertrophic cardiomyopathy (HCM), but its influence on the occurrence of sudden cardiac death (SCD) is unknown. The aim of this study was to investigate the effect of adverse LV remodeling on SCD risk in patients with HCM. Adverse LV remodeling increases SCD in HCM patients. This study included 41 patients with HCM who experienced SCD; each case was matched with 3 controls based on age, gender, and time of first contact. In this population of 164 patients, predictors of SCD were identified using univariable and multivariable logistic regression and expressed as odds ratio (OR) with 95% confidence interval (CI). Baseline characteristics, such as New York Heart Association (NYHA) class, systolic and diastolic left ventricular function, left ventricular wall thickness, left atrial size, atrial fibrillation, and established risk factors for SCD were similar in cases and controls. Independent predictors of SCD during follow-up (median follow-up, 7.7 ± 6.5 years) were: increase in NYHA class (OR: 8.7 [95% CI: 2.5-30.5], P = 0.001), decrease of fractional shortening (per % decrease, OR: 1.09 [95% CI: 1.03-1.14], P = 0.001), and decrease of diastolic function (OR: 3.5 [95% CI: 1.2-10.2], P = 0.02). This study shows that SCD risk in HCM increases when adverse remodeling occurs. Because cases and controls were similar at baseline, these findings emphasize the importance of vigilant follow-up of HCM patients and could aid clinical decision making concerning implantable cardioverter-defibrillator implantation, especially in patients with moderate risk for SCD.

Depressed Systolic Function after a Prolonged and Strenuous Exercise

Prolonged and strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Although a consensus exists regarding the decrease in diastolic function, the existence of a decrease in systolic function by a PSE remains controversial, probably due to the transient tachycardia and changes in loading conditions observed upon the completion of exercise. Therefore, the objective was to evaluate LV systolic function before and after a PSE using two-dimensional speckle tracking echocardiography not only at rest but also during incremental tests to adjust heart rates (HR). Sixteen healthy young men (23 ± 3 yr old) performed a 3-h period of intensity-controlled upright cycling. LV strain (S), systolic strain rate (SR), rotation, and systolic rotational rate were evaluated by two-dimensional speckle tracking echocardiography before and after a 3-h period of PSE at rest and during incremental tests. Posttest evaluation was performed once the HR had returned to the pretest value. Under resting conditions, parameters of systolic function were either unchanged or increased after the PSE. However, during the incremental test, all LV systolic SR and apical rotational rates were decreased after PSE (radial SR at workload 3 (W3): 2.21 ± 0.12.s(-1) vs 1.87 ± 0.10.s(-1), P < 0.01 and apical rotational rate at W3: 128 ± 28 deg.s(-1) vs 105 ± 26 deg.s(-1), P < 0.05). Regression analyses between LV systolic SR and HR showed lower y-intercepts without differences in slopes, suggesting a decrease of both global and regional systolic functions irrespective of HR after the PSE. Our findings based on LV S and SR data during incremental tests demonstrate that the 3-h period of PSE induces LV systolic dysfunction.

Endurance exercise training attenuates fibrosis and collagen cross‐linking in myocardium of aged F344BNF1 rats

The objective of the study was to determine if endurance exercise training (ET) could attenuate the age‐related increase in fibrosis and collagen cross‐linking in the myocardium of the heart, which is thought to be a cause of the age‐related decline in diastolic function. Fisher 344 × Brown Norway F1 rats underwent ET from late middle age into senescence. Genes for collagen synthesis and degradation were assessed by polymerase chain reaction. Matrix metalloproteinase (MMP) activity was assessed using EnzChek Gelatinase/Collagenase Assay kit, and collagen cross‐linking was determined indirectly by immunohistochemical staining for advanced glycation end‐products. Tissue inhibitor of matrix metalloproteinase‐1 (TIMP1) gene expression, TIMP and MMP1 protein expression, and MMP activity increased with age but with no ET effect. ET attenuated the age‐related increase in fibrosis and collagen cross‐linking, while increasing survival rate. This could have attenuated the age‐related decline in myocardial compliance and in turn have helped attenuate the decrease in diastolic function generally seen with aging. This work was supported by an operating grant from CIHR (MOP 57808).

Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease

This cross-sectional study aimed to analyse myocardial deformation in patients with Fabry disease (FD) in order to evaluate speckle tracking as a method for non-invasive determination of myocardial fibrosis. Myocardial fibrosis is common in Fabry cardiomyopathy and is associated with disease progression and severe prognosis. In 101 consecutive Fabry patients (39.8 ± 12.9 years; 42 males), the quantitative measurement of myocardial fibrosis with magnetic resonance imaging was compared with regional myocardial deformation assessed by speckle-tracking imaging. Patients were analysed in relation to per cent of late-enhancement (LE)-positive areas of left-ventricular (LV) mass. Fifty-two patients (51%) displayed LE with a mean volume of 1.2 ± 1.8% of total LV mass. Predominantly basal lateral and posterior segments were affected. Patients with LE had lower global systolic longitudinal strain than those without (LE -14.8 ± 3.5% and -18.9 ± 2.1%, respectively; P < 0.001). Loss of global deformation, quantified by speckle tracking, was predominantly caused by basal posterior (P = 0.049) and lateral (P = 0.005) segments and global systolic strain correlated with the amount of LE (r = 0.543; P < 0.001). Patients with severe LE (>2%, n = 22) showed the lowest deformation values (-5.9 ± 8.4%) in basal postero-lateral segments when compared with those with mild (<2%; n = 30, -7.1 ± 7.5%) or no LE (n = 49, -16.3 ± 3.3%). These changes were accompanied by thinning of the posterior wall and a decrease in diastolic function, whereas ejection fraction and LV end-diastolic diameter were not different. Receiver operating characteristic analysis revealed that the systolic strain of basal postero-lateral segments was the most powerful predictor to distinguish between patients with and without LE (sensitivity = 90%; specificity = 97%, area under the curve = 0.913; P < 0.001). Late enhancement is associated with lower longitudinal strain in the fibrotic wall segments. Speckle tracking can be used as a tool for the indirect evaluation of LE in FD.

Abstract P081: Voltage-Gated TTX-Sensitive Nav1.1 Brain Sodium Channels Are Important for Cardiac Contractile Function

Background: Mutations in voltage gated brain sodium channel Nav1.1 have been linked to many disorders, including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). Recent studies have identified TTX- sensitive Nav1.1 brain sodium channels in the SA node and ventricular T-tubules of the heart, though their role in cardiac function is still controversial. We tested the functional significance of Nav1.1 sodium channels in the heart by creating a novel knock-in of human epilepsy GEFS+ mutation SCN1A-R1648H at the Scn1a locus of a C57BL/6J X 129 mouse. Method: In vivo 2-D echocardiography was performed on 2 week old (juvenile) and 8 week old (adult) wild-type and heterozygote (Scn1aRH/+) mice after extracardiac neuronal block through intraperitoneal injections of atropine and propranolol (2.5mg/kg each). Calcium and contractility studies on adult ventricular cardiomyocytes isolated from the wild type and Scn1aRH/+ mice paced at 0.5Hz were followed by administration of TTX (100nM, a brain sodium channel inhibitor) and pacing at 2Hz. qRT-PCR and Western blot of the isolated cells and whole heart samples was also done. Results: A decrease in Nav1.1 gene expression in the Scn1aRH/+ juvenile (by 31%, 0.69 of 1) and adult (by 60%, 0.4 of 1) whole heart samples and isolated cells (p&lt;0.05) was seen. Echocardiography revealed concentric hypertrophy in the juvenile Scn1aRH/+ mice by a significant increase in LV mass, LV mass/body weight ratio, and relative wall thickness (p&lt;0.05). In the adult Scn1aRH/+ mice, systolic isovolumic contraction time (IVCT) was reduced (p=0.03) and decrease in diastolic function was evident through significant decreases in isovolumic relaxation time (IVRT) and E’/A’ ratio, and increase in E/E’ ratio. Isolated adult ventricular Scn1aRH/+ cardiomyocytes showed significant reduction in percent sarcomere shortening, maximum rate of contraction and relaxation, and time to peak contraction, exaggerated with TTX and pacing at 2Hz (p&lt;0.5). Conclusions: Our study demonstrates the importance of voltage gated TTX-sensitive Nav1.1 brain sodium channels in cardiac contractile function and their possible role in cardiac complications in epilepsy.

Cardiac and Vascular Consequences of Pre‐Hypertension in Youth

Hypertension is associated with increased left ventricular mass (LVM) and carotid intima-media thickness (cIMT), which predict cardiovascular (CV) events in adults. Whether target organ damage is found in pre-hypertensive youth is not known. The authors measured body mass index, blood pressure, fasting glucose, insulin, lipids and C-reactive protein, LVM/height(2.7) (LVM index), diastolic function, cIMT, carotid stiffness, augmentation index, brachial artery distensibility, and pulse wave velocity (PWV) in 723 patients aged 10 to 23 years (29% with type 2 diabetes mellitus). Patients were stratified by blood pressure level (normotensive: 531, pre-hypertensive: 65, hypertensive: 127). Adiposity and CV risk factors worsened across blood pressure group. There was a graded increase in cIMT, arterial stiffness, and LVM index and decrease in diastolic function from normotension to pre-hypertension to hypertension. In multivariable models adjusted for CV risk factors, status as pre-hypertension or hypertension remained an independent determinant of target organ damage for LVM, diastolic function, internal cIMT, and carotid and arterial stiffness. Pre-hypertension is associated with cardiovascular target organ damage in adolescents and young adults.

The effect of repeated ischaemic periods on left ventricular dynamics during percutaneous coronary intervention

To study online left ventricular (LV) dynamic effects of transmural ischaemia and reperfusion during consecutive balloon coronary occlusions in the setting of percutaneous coronary intervention (PCI). In 10 consecutive unselected patients with stable angina (seven males, mean age 62 ± 3 years) who underwent elective PCI, LV dynamics were continuously recorded using a pressure-conductance catheter to simultaneously measure pressure and volume (PV-loop). The effects of a prolonged balloon coronary occlusion (148 ± 19 s) and a second occlusion on various LV function parameters were studied, as well as recovery of these parameters after reperfusion. Ischaemia caused an immediate (<5 s) decrease in diastolic function, followed by a decrease in contractile function, indicated by a rightward shift of the PV-loop, and a decreased dP/dtmax and ejection fraction. All parameters recovered within two minutes after reperfusion. The second occlusion caused a more rapid and more pronounced decrease in systolic and global LV function, while the 12-lead ECG showed less ST-segment deviation. Online LV pressure-volume measurements during elective PCI show that prolonged balloon coronary occlusion causes a phased ischaemic response of diastolic dysfunction, and then systolic dysfunction with more pronounced deterioration during a consecutive ischaemic period, paradoxical to the ischaemic electrocardiographic signs.

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder of muscle degeneration. Patients with DMD lack expression of the protein dystrophin as a result of mutations in the X-linked dystrophin gene. The loss of dystrophin leads to severe skeletal muscle pathologies as well as cardiomyopathy, which manifests as congestive heart failure and arrhythmias. Like humans, dystrophin-deficient mice (mdx mice) show cardiac dysfunction as evidenced by a decrease in diastolic function followed by systolic dysfunction later in life. We have investigated whether sildenafil citrate (Viagra), a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction present in the mdx mice. By using echocardiography, we show that chronic sildenafil treatment reduces functional deficits in the cardiac performance of aged mdx mice, with no effect on normal cardiac function in WT controls. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. It is recognized that PDE5 inhibitors can have cardioprotective effects in other models of cardiac damage, but the present study reports a prevention and reversal of pathological cardiac dysfunction as measured by functional analysis in a mouse model of DMD. Overall, the data suggest that PDE5 inhibitors may be a useful treatment for the cardiomyopathy affecting patients with DMD at early and late stages of the disease.

Effect of Long Term and Intensive Endurance Training in Athletes on the Age Related Decline in Left and Right Ventricular Diastolic Function as Assessed by Doppler Echocardiography

The aim of this study was to evaluate (1) the effect of endurance training on left ventricular and right ventricular diastolic function and (2) whether the normal aging effect on left ventricular and right ventricular diastolic function is slowed by endurance training. A total of 269 healthy subjects were prospectively enrolled for echocardiographic evaluation. Five groups were defined on the basis of age and athletic activities: (1) young (18 to 39 years) nonathletes (n = 62), (2) veteran (>or=40 years) nonathletes (n = 33), (3) young regular athletes (9 to 18 hours of sports/week; n = 58), (4) young elite athletes (>18 hours of sports/week; n = 63), and (5) veteran athletes (>or=40 years and >or=9 hours of sports/week; n = 53). Pulsed-wave Doppler indexes for diastolic function in the left and right ventricles were obtained at rest. No significant differences were found among the young controls, regular athletes, and elite athletes in left ventricular and right ventricular pulsed-wave and tissue Doppler diastolic parameters. These were also comparable between the veteran athletes and controls. In athletes and controls, similar and significant correlations were found between age and diastolic parameters. Age was the most important determinant in almost all parameters in multivariate analysis, while the influence of the amount of training did not account for >2% of the observed variance in any of these parameters. In conclusion, the amount of endurance training did not alter diastolic parameters in either ventricle in the young. Furthermore, the biventricular decreases in diastolic function observed in healthy, nonathletic subjects with age was also observed in aging athletes' hearts.

Metabolic MRI of myocardial and hepatic triglyceride content in response to nutritional interventions

To discuss the technique and clinical applications of myocardial and hepatic H magnetic resonance spectroscopy to study myocardial and hepatic triglyceride content, in relation to changes in plasma nonesterified fatty acids induced by nutritional interventions. Progressive caloric restriction induces a dose-dependent increase in myocardial triglyceride content and a dose-dependent decrease in diastolic function in lean healthy men. Hepatic triglyceride content shows a differential response to progressive caloric restriction, indicating that redistribution of endogenous triglyceride stores is tissue specific, at least in lean healthy men. A short-term high-fat high-energy diet in healthy men results in major increases in hepatic fat content, whereas it does not influence myocardial triglyceride content or myocardial function. Apparently, there is a differential, tissue-specific partitioning of either triglyceride or fatty acids or both between nonadipose organs such as the human heart and liver during different physiological conditions. Metabolic MRI of myocardial and hepatic triglyceride content is a promising new tool to study the effects of nutritional interventions on myocardial and hepatic lipid metabolism in relation to heart function. Future studies should aim to apply these magnetic resonance techniques to obesity and type 2 diabetes mellitus.