Progressive Left Ventricular Hypertrophy Research Articles

Myocardial work alterations with progressive left ventricular hypertrophy in patients with hypertension.

Left ventricular (LV) hypertrophy (LVH) is frequently observed in patients with hypertension (HTN). LV myocardial work (MW) has recently emerged as a non-invasive method to assess systolic myocardial deformation relative to afterload conditions. The authors investigated the characteristics of myocardial work with different degrees of LVH in HTN patients. From December 2020 to February 2024, 255 HTN patients and 26 healthy controls undergoing transthoracic echocardiography were included in the current study. Hypertension patients were divided into quintile groups based on left ventricular mass index (LVMI), for the first to fourth LVMI quantiles, global work index (GWI) and global constructive work (GCW) were higher compared to the control group, but the difference was not statistically significant. In the sixth LVMI quantile, GWI and GCW showed a significant decrease. The restricted cubic splines showed that both GWI and GCW exhibited an inverted U-shaped relationship with LVMI. A LVMI of >151.39g/m2 could accurately predict reduction both in GWI and GCW (Sensitivity: 0.78, Specificity: 0.89, AUC: 0.90, P <.001; Sensitivity: 0.81, Specificity: 0.92, AUC: 0.92, P <.001, respectively). As LVH progressed in HTN patients, both GWI and GCW initially demonstrated an increase, followed by a subsequent decrease. Myocardial work provides additional insights into assessment of cardiac function in HTN patients.

Abstract 12381: De Novo Multiple Myeloma in a Patient With Transthyretin Amyloid Cardiomyopathy

Background: The development of de novo multiple myeloma in a patient with transthyretin amyloid cardiomyopathy (ATTR-CM) is rare and is often associated with poor prognosis. Early and definitive diagnosis is crucial to improve survival. Case: A 63-year-old male was evaluated for heart failure. He had a history of hypertension, sick sinus syndrome status post dual chamber pacemaker, non-sustained ventricular tachycardia requiring ablation in addition to bilateral carpal tunnel syndrome, spontaneous biceps tendon rupture, and lumbar spinal stenosis. Transthoracic echocardiogram showed progressive severe left ventricular hypertrophy with a septal thickness of 2.0cm with a normal left ventricular ejection fraction. Decision-Making: Given his history, an amyloid evaluation was performed. Serum and urine assessment for light chain amyloidosis revealed elevated kappa free light chains with kappa/lambda free light chain ratio of 19.30. Bone marrow biopsy at that time showed normocellular bone marrow with less than 3% plasma cells. An abdominal fat pad biopsy was inconclusive. A cardiac MRI was unobtainable given non-compatible pacemaker leads and a technetium-99m pyrophosphate scintigraphy was deferred given his abnormal light chains. An endomyocardial biopsy was performed and revealed wild-type ATTR deposition by mass spectrometry. Serum genetic test confirmed the absence of TTR gene mutation. The patient was started on Tafamadis. Six months later, he was noted to have progressive elevation in kappa free light chains on serial evaluation and underwent a repeat bone marrow biopsy. This showed plasma cell myeloma with 25-30% marrow cellularity and flow cytometry consistent with kappa light chain multiple myeloma. He was started on Daratumumab, Lenalidomide, and Dexamethasone. This resulted in normalization of his free light chain ratio and morphologic remission on repeat bone marrow biopsy. Conclusion: In patients who are found to have monoclonal gammopathy, an endomyocardial biopsy is crucial to evaluate for amyloid cardiomyopathy. These patients should also be monitored for the progression to multiple myeloma.

Hypertension in Patients Receiving Dialysis: A Review of the Current Clinical Approach

Cardiovascular disease is a leading cause of morbidity and mortality in end-stage renal disease (ESRD). Hypertension plays a major contributory role, resulting in progressive left ventricular hypertrophy, and increasing the risk of sudden cardiac death. The prevalence and pathophysiological mechanisms differ fundamentally from the non-dialysis-dependent population. Sodium restriction can be as effective as antihypertensive medication in mitigating the haemodynamic effects resulting from impaired sodium handling. Tailoring dialysate sodium may enhance diffusion and facilitate greater sodium elimination where dietary measures alone prove ineffective. Unlike hypertension in the wider population, volume overload plays a major pathophysiological role in ESRD. Probing dry weight in patients on dialysis who are seemingly euvolaemic enables clinically significant blood pressure (BP) reduction, and translates to improvements in markers of future cardiovascular morbidity and mortality. Pharmacotherapy remains an important aspect in controlling hypertension in dialysis. Although no large-scale studies have identified the optimal medical therapy, numerous meta-analyses and randomised control trials (RCT) have demonstrated the efficacy of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB), calcium channel blockers, β-blockers, and hydralazine/isosorbide dinitrate in the treatment of hypertension in ESRD. Whether the beneficial haemodynamic properties of mineralocorticoid receptor antagonists outweigh the risk of hyperkalaemia is the subject of ongoing RCTs. Numerous meta-analyses have demonstrated that adequate pharmacological control of BP translates to improved cardiovascular morbidity and mortality. The fluctuation of volume status in the inter/intra-dialytic period complicates the diagnosis of hypertension in ESRD. As with patients not receiving dialysis, 24-hour blood pressure monitoring appears to have the greatest sensitivity in diagnosing hypertension and predicting outcomes from hypertension. Where resources are limited, home BP monitoring appears to have the greatest value.

Abstract 15210: Association of Circulating Biomarkers With Progressive Left Ventricular Remodeling and Hypertrophy in Patients With Aortic Stenosis: Results From the Progressa Study

Introduction: Aortic stenosis (AS) is associated with progressive left ventricular (LV) remodeling and hypertrophy, ultimately leading to cardiac decompensation. Measurement of circulating biomarkers may be useful to identify AS patients with higher risk of maladaptive LV remodeling, a potent marker of the transition to heart failure. We hypothesized that multiple circulating biomarkers are associated with faster progression of LV hypertrophy in patients with AS. Methods: One hundred and forty-six asymptomatic AS patients (66±13years, 75% male) prospectively enrolled in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography to measure AS severity, LV mass indexed to body surface area (LVMi) and LV relative wall thickness (RWT). The annualized changes in LVMi and RWT were calculated between baseline and last follow-up visit (mean follow-up of 2.5±1.88 years). Results: At baseline, 16% of patients had mild (i.e. peak aortic jet velocity [Vpeak] 2.0-2.9 m/s),76% moderate (Vpeak 3.0-3.9 m/s), and 8% severe (Vpeak ≥4.0 m/s) AS, mean LVMi and RWT were 106±23 g/m 2 and 0.47±0.07 respectively. Among biomarkers, baseline level of triglycerides, D-dimer and tumor antigen 125(Ca-125) were significantly associated with LVMi progression rate (β:0.16,p≤0.05), (β:0.18,p≤0.05) and(β:-0.20,p≤0.05) respectively. Soluble (ST2) protein and alkaline phosphatase (ALP) were the only factors independently associated with the annualized change in RWT. In multivariate analysis adjusted for age, gender, comorbidities, AS severity, cardiac biomarkers; triglycerides and D-dimers remained significantly associated with faster progression rate of LVMi (all, p≤0.05), while lower level of CA125 remained significantly associated with LVMi annualized change (β=-0.21, p=0.01). After similar multivariate adjustment, higher levels of ST2 and ALP remained significantly associated with faster progression rate of RWT (all, p≤0.05). Conclusion: Several blood biomarkers were independently associated with faster progression of LV remodeling and hypertrophy in patients with AS. A multiple biomarker approach may be useful to assess LV health and predict the risk of early phases of heart failure in AS.

Abstract 15680: Impact of Heart Failure on Peri-Procedural Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement

Introduction: Transcatheter aortic valve replacement (TAVR) is rapidly becoming commonplace for hemodynamically significant aortic stenosis (AS). Heart failure (HF) is a common comorbidity in aortic stenosis patients. Prolonged elevated left ventricular pressures result in progressive left ventricular hypertrophy and remodeling which in turn predisposes to the HF. Since many who undergo TAVR for AS could have HF, we aimed to assess periprocedural outcomes in this population. Methods: We utilized the National Inpatient Sample from 2016-2019 to identify 217,575 hospitalized adults who underwent TAVR for AS. These hospitalizations were further stratified based on the presence of HF. A multivariate regression model was used to adjust for confounders and analyze the variables. Results: Of those who underwent TAVR for AS, 146,770 (67.4%) had HF. Those with HF had a higher proportion of males (47.3% vs 41.6%; p&lt;0.001). Figure 1 shows the Forrest plot for multivariate analysis of peri-procedural complications when adjusted for patient demographics, comorbidities, and hospital characteristics. When adjusted similarly, patients with HF who underwent TAVR had longer length of stay (LOS) by 0.89 days (p&lt;0.001) and had additional hospital costs (HC) of $13,297 (p&lt;0.001). Conclusions: Patients undergoing TAVR with co-existing HF had significantly worse outcomes in terms of LOS, HC, atrial flutter, AKI, sepsis, pneumonia, and endotracheal intubation. Patients with severe AS may have altered myocardial contractility and periprocedural hemodynamic shifts may be poorly tolerated due to structural and functional impairments that persist even after correction of afterload. Despite the risk of periprocedural outcomes, the benefit of ventricular unloading particularly in those with preserved or mildly reduced ejection fraction should not be overlooked.

Cardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies.

Fabry disease is an X-linked inherited metabolic disorder due to the pathogenic mutation of the GLA gene, which codes lysosomal enzyme alpha-galactosidase A. The resultant accumulation of glycosphingolipids causes various systemic symptoms in childhood and adolescence, and major organ damage in adulthood. Cardiac involvement is important as the most frequent cause of death in Fabry disease patients. Progressive left ventricular hypertrophy with varying degrees of contractile dysfunction as well as conduction abnormalities and arrhythmias are typical cardiac features, and these findings can be evaluated in detail via non-invasive modalities, such as an electrocardiogram, echocardiography and cardiac magnetic resonance. In addition, specific therapies of enzyme replacement therapy and pharmacological chaperone therapy are available, and their beneficial effects on cardiac involvement have been reported. This minireview highlights recent evidence concerning non-invasive modalities for assessing cardiac involvement in Fabry disease and the effects of enzyme replacement therapy and pharmacological chaperone therapy on the findings of those modalities.

Primary Cilia and Their Role in Acquired Heart Disease.

Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia’s role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia’s role in adult cardiac pathology, especially heart failure.

Impaired cardiopulmonary test performance as a marker of early functional impairment in patients with Anderson-Fabry disease

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease characterized by progressive glicosphingolipid accumulation in multiple organs, due to α-galactosidase a deficiency [1]. It is considered a rare disease although newborn genetic screening showed non-negligible prevalence (∼1:3.900) [1]. Cardiac manifestations include progressive Left Ventricular (LV) Hypertrophy (LVH), which may be extreme and provoke both reduced stroke volume and dynamic LV outflow tract obstruction [2-6].

Reduced global longitudinal strain as a marker for early detection of Fabry cardiomyopathy.

Fabry cardiomyopathy (FC) is characterized by progressive left ventricular hypertrophy (LVH). Conventional echocardiography is not sensitive in detecting preclinical FC before the development of LVH. We aim to investigate whether myocardial deformation analysis is useful to detect preclinical FC before LVH. One hundred and sixty patients carrying mutated gene were prospectively enrolled, including 86 patients without LVH and 74 patients with LVH. Another 33 healthy individuals were also included for comparison. Standard transthoracic two-dimensional, Doppler, tissue Doppler echocardiography and deformation analysis were performed. The mean age of the overall 193 subjects was 48 ± 15 years, with 51% men. Fabry patients with LVH were older, more often to be men. They also had the worst diastolic function as evidenced by the largest left atrium, lowest E/A, and highest E/e' ratio. The global longitudinal strain (GLS) deteriorated with the development of LVH (control vs. LVH- patients vs. LVH+ patients = -21.2 ± 2.7 vs. -19.0 ± 2.9 vs. -16.5 ± 4.2%, P < 0.001). Despite similar LV systolic, diastolic function, and LV mass, LVH- Fabry patients still had a reduced GLS as well as regional longitudinal strains at mid-to-apical, anterior, and inferolateral wall when compared to healthy subjects. The basal longitudinal strain was consistently worse in male patients than in female patients, irrespective of LVH. Reduced GLS could be a marker of early FC before the development of LVH.

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9 ± 8.7 mm and left ventricular ejection fraction was 53.4 ± 6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks—5; sinus node disease—2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

Pretransplant NT-proBNP, Dialysis Vintage, and Posttransplant Mortality in Kidney Transplant Recipients.

End-stage kidney disease and dialysis vintage are characterized by accelerated atherosclerosis, volume overload, and progressive left ventricular hypertrophy, leading to elevated N-terminal probrain natriuretic peptide (NT-proBNP) levels. Pretransplant dialysis vintage is associated with excess mortality after transplantation. We want to study whether pretransplant NT-proBNP is associated with posttransplantation mortality and if it explains the association of dialysis vintage with posttransplantation mortality in kidney transplant recipients (KTR). We measured plasma NT-proBNP on arrival at the hospital before kidney transplantation in 658 KTR between January 1995 and December 2005 in our center. Multivariable Cox regression analyses, adjusted for potential confounders, were used to prospectively study the associations of dialysis vintage and NT-proBNP with all-cause mortality. During median 12.7 (7.8-15.6) years of follow-up after transplantation, 248 (37.7%) KTR died. Dialysis vintage was associated with an increased risk of posttransplant mortality in the fully adjusted model (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.03-1.43; P = 0.02), independent of potential confounders. The association weakened materially and lost significance after further adjustment for NT-proBNP (HR, 1.14; 0.96-1.34; P = 0.14). NT-proBNP was independently associated with all-cause mortality in the fully adjusted model (HR, 1.34; 1.16-1.55; P < 0.001). The association remained independent of adjustment for dialysis vintage (HR, 1.31; 1.13-1.52; P < 0.001). Our study shows that longer dialysis vintage is associated with a higher mortality risk in KTR, and this association might be explained for a considerable part by variation in pretransplant NT-proBNP at the time of transplantation.

P799 The echocardiographic and clinical characteristics of Fabry patients without overt left ventricular hypertrophy but progressing despite on enzyme replacement therapy

Abstract Background Fabry disease (FD) is X-linked genetic disorder caused by the deficiency or absent activity of lysosomal α- galactosidase. When the heart is involved, progressive left ventricular hypertrophy (LVH) is the key feature. Although, LVH is not present in all subjects, some of them progress with LVH despite enzyme replacement therapy (ERT). The present study aimed to evaluate the characteristics of patient of FD without overt LVH, but progresses with their left ventricular mass index (LVMI). Method : This study includes subjects carrying genetic mutations for FD without LVH (n = 12) in a single tertiary center. ‘Decreasing LVMI group (Group1)’ was defined when pre-ERT LVMI minus last LVMI value obtained by echocardiography was positive, and when negative, defined as ‘Increasing LVMI group (Group 2)’. The baseline characteristics and echocardiographic parameters including global strain was analyzed. Result : Total 6 patients were classified as Group 1 and 2 each. The median age at diagnosis for male was 21 vs 27 for each group, and 21 vs 31 for female. The median follow-up duration was 4.0 vs 5.7 yr. The antibody formation for replaced enzyme was 3 for Group 2 and any family member who developed overt LVH was much 1 vs 3 for group 1 vs 2. Initial 3 plane GLS was worse and showed trend to drop in Group 2. Conclusion : In the Fabry patients get worse with their LVMI but still not developed overt LVH despite enzyme replacement therapy, there are some clinical and echo-parameter difference. These findings could suggest insufficient enzyme replacement therapy. Group 1 (n = 6) Group 2 (n = 6) Female/Male 4/2 3/3 Age of at Dx (Female) (median) 21 28 Age of at Dx (Male) (median) 21 31 F/U duration (median) 4.0 yrs 5.7 yrs Antibody formation 0 3 Any Overt LVH family Genotype c.56T &amp;gt; C c.40-11T &amp;gt; A, 782_delG, c.658C &amp;gt; T Initial LVMI (Median) 98.2g/m2 70.9g/m2 Initial GLS (3P) -19 -17.8 Continuously elevated LysoGb3 2 4 Proteinuria &amp;gt;300mg 1 3 (1 preparing HD)

Progression of Hypertrophy and Myocardial Fibrosis in Aortic Stenosis: A Multicenter Cardiac Magnetic Resonance Study.

Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR). Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified. In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8-4.8 g]) demonstrated particularly rapid increases in scar burden (78% [50%-158%] increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%-25%) reduction in left ventricular mass index (P<0.0001) and an 11% (4%-16%) reduction in indexed extracellular volume (P=0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 [26%]; mass, 3.3 g [2.6-8.0 g]) did not change post-AVR (n=10; 3.5 g [2.1-8.0 g]; P=0.23), with no evidence of regression even out to 2 years. In patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01755936 and NCT01679431.

Anemia and coronary artery disease: pathophysiology, prognosis, and treatment.

The mechanisms, pathophysiology, and treatment of anemia in coronary artery disease (CAD) are complex. The hemodynamic changes found in the acute anemic state may contribute to progressive arterial wall and left ventricular hypertrophy if the anemic state persists chronically. We will examine the evidence for anemia as an independent risk factor for CAD events and cardiovascular mortality after percutaneous coronary intervention. We will also investigate the thresholds for appropriate blood transfusion in patients with CAD, as well as the cardiovascular outcomes associated with the utilization of a liberal versus conservative blood transfusion strategy. Although there is evidence supporting the use of intravenous iron replacement in patients with congestive heart failure, we will demonstrate the lack of evidence for iron replacement in patients with CAD. Finally, we will examine the evidence for increased cardiovascular mortality and venous thromboembolic events with the use of erythropoietin-stimulating agents in patients with CAD.

FORECASTING CORONARY EVENTS BASED ON THE ANALYSIS OF THE DYNAMICS OF MORPHOFUNCTIONAL PARAMETERS OF THE CARDIOVASCULAR SYSTEM IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN THE NORTH

In modern society, chronic obstructive pulmonary disease has been isolated relatively recently in an independent nosological unit and, along with cardiovascular diseases, constitutes the leading group of socially significant chronic diseases, being one of the most important medical and social problems of pulmonology. The aim of the study was to determine the possibility of predicting and early diagnosis of coronary heart disease in patients with chronic obstructive pulmonary disease living in the North on the basis of evaluation of morphofunctional parameters of the cardiovascular system. Materials and methods . During the prospective five-year follow- up, an in-depth instrumental examination of 182 patients with chronic obstructive pulmonary disease was conducted to identify the five-year dynamics of the morphofunctional parameters of the cardiorespiratory system at various levels of coronary risk taking into account gender differences. In 66 patients (mean age 64.0 ± 1.1 years) (comparison group), nonfatal coronary events were recorded during follow-up. The conclusion. 1. In the North, cardiac remodeling in patients with chronic obstructive pulmonary disease includes changes in the right divisions due to persistent obstructive disorders and a decrease in pulmonary volume, as well as an increase in left chambers, a decrease in myocardial contractility, and progressive left ventricular hypertrophy. 2. In the course of prophylaxis in case of outpatient examination of patients with chronic obstructive pulmonary disease, it is necessary to determine the criteria for predicting high and very high coronary risk according to the formula d = 0.000108 (Systematic Corоnary Risk Evaluation × “Northern Experience” × frequency of exacerbations of chronic obstructive pulmonary disease × terminal diastolic size of the left ventricle (mm) × systolic blood pressure in the pulmonary artery (mm)) for women and d = 0.000078 (Systematic Coronary Risk Evaluation × frequency of exacerbations of chronic obstructive pulmonary disease × diastolic left ventricular size (mm) × reserve expiratory volume (%)) for men. A high and very high risk can be determined at d≥ 27.5 for women; at d≥ 16.2 for men.

Activated T Lymphocytes are Essential Drivers of Pathological Remodeling in Ischemic Heart Failure.

Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T lymphocytes is unclear. Permanent coronary ligation was performed in adult C57BL/6 mice. When compared with sham-operated mice, mice with HF (8 weeks after ligation) exhibited the following features: (1) significant (P<0.05) expansion of circulating CD3+CD8+ cytotoxic and CD3+CD4+ helper (Th) T lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4+ subsets; (2) significant expansion of CD8+ and CD4+ T cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4+ subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and (3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with expansion of splenic antigen-experienced effector and memory CD4+ T cells. Antibody-mediated CD4+ T-cell depletion in HF mice (starting 4 weeks after ligation) reduced cardiac infiltration of CD4+ T cells and prevented progressive left ventricular dilatation and hypertrophy, whereas adoptive transfer of splenic CD4+ T cells (and, to a lesser extent, cardiac CD3+ T cells) from donor mice with HF induced long-term left ventricular dysfunction, fibrosis, and hypertrophy in naive recipient mice. CD4+ T lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (versus Th1) and Th17 (versus Treg) predominance in failing hearts, and with expansion of memory T cells in the spleen. Cardiac and splenic T cells in HF are primed to induce cardiac injury and remodeling, and retain this memory on adoptive transfer.

Abstract 258: Progressive Diastolic Dysfunction, Perivascular Fibrosis and Left Ventricular Hypertrophy in LDL-Receptor Deficient Mice

Background and Aim: Left ventricular diastolic dysfunction (LVDD) refers to abnormal filling of the left ventricle (LV) due to its impaired relaxation or increased stiffness. Animal models of LVDD are limited and underlying mechanisms remain largely unknown. We aimed to assess LVDD in Ldlr -/- mice using imaging and gene expression measurements. Methods: Sixty-nine Ldlr -/- mice were fed with a western-type diet supplemented with vitamin D 2 (30 U/g/day) for 20 weeks to induce LVDD. Eight normal mice were fed with a normal diet and used as control group. Serial echocardiograms were used to assess cardiac structure and function, histological analyses were done on LV sections, and RT-PCR was performed on LV samples. Results: Echocardiographic results show the development of LVDD over time (P values &lt;0.05), with a modest increase in LV mass/BW and preserved systolic function. There was an increase of perivascular fibrosis (14.9%±1.0% (14.9 to 100) vs 9.0%±1.6%; (9 to 100), respectively, P&lt;0.01) in Ldlr -/- mice compared to controls as detected by Masson’s trichrome staining, which was correlated with increased mRNA expression for TGFß1 and Smad2 and 3 (P&lt;0.05 for all). This was accompanied by numerical increases in Type I and III collagen mRNAs ( Col I : 1.33 (1.03; 1.97) vs 1.03 (0.90; 1.11), P=0.06; Col III : 1.49±0.30 vs 1.00±0.10, P=0.14). The angiotensin II precursor Agt mRNA level was also higher (1.07±0.08 vs 0.72±0.05; P&lt;0.01) in Ldlr -/- mice compared to controls. Conclusion: Taken together, Ldlr -/- mice fed with a western diet supplemented with vitamin D 2 develop progressive LVDD, perivascular fibrosis and mild left ventricular hypertrophy, which represents a new model of lipid-mediated diastolic dysfunction that may be used in future studies for the evaluation of novel treatments.

The Association between Hypoalbuminemia and Intradialytic Hypotension in Heamodialysis Patients

Background: hypoalbuminemia is an important risk factor of hypotension during hemodialysis and progressive left ventricular hypertrophy in patients with chronic kidney disease (CKD). Aim of the study: this study was done to evaluate the relationship between serum albumin and intradialytic hypotension (IDH) and cardiac functions. Patients and Methods: forty patients on regular hemodialysis (HD) were included in the present study. They have been divided into two groups; Group 1: Patients of this group developed recurrent attacks of IDH and Group 2: Patients of this group not developed IDH. The patients have been classified again according to serum albumin level into two groups; Group A: Hypoalbuminemic patients and Group B: Non-hypoalbuminemic patients. Data collected from each patient included: (1) Demographic features (age, gender) and clinical features (blood pressure changes during session, ultrafiltration rate, cardiothoracic ratio, duration of dialysis and Kt/V); (2) Blood chemistry (creatinine, urea, hemoglobin, hematocrit value, total proteins, albumin, triglycerides, cholesterol, AST, ALT, Kt/V, and fasting blood sugar); and (3) Echocardiographic assessment of left ventricular geometry. Results: there was a significant negative correlation between serum albumin and Delta BP in HD patients. Also we found no significant changes in cardiac functions among different studied groups. Conclusion: We concluded that there was a relationship between low serum albumin and intradialytic hypotention and cardiac functions in CKD patients undergoing HD. Recommendations: Regular assessment of serum albumin is mandatory for all HD patients.

Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice.

Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2-3months), middle-aged (14months) and old (20-24months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in-house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P-wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R-wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium-channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R-wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice.

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury.