Heart failure due to chronic experimental aortic regurgitation

1994 ◽  
Vol 267 (2) ◽  
pp. H556-H562 ◽  
Author(s):  
N. M. Magid ◽  
G. Opio ◽  
D. C. Wallerson ◽  
M. S. Young ◽  
J. S. Borer
Keyword(s):  
Heart Failure ◽  
Aortic Regurgitation ◽  
Systolic Dysfunction ◽  
Disease Process ◽  
Experimental Models ◽  
Left Ventricular ◽  
Sham Operation ◽  
Systolic Performance ◽  
Baseline Values ◽  
Chronic Aortic Regurgitation

Previously reported experimental models of aortic regurgitation generally have manifested normal systolic performance and have not developed heart failure [Magid et al. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H226–H233, 1992]. To determine whether more severe chronic experimental aortic regurgitation would generate systolic malperformance, heart failure, and emulate the human disease process, 11 New Zealand White rabbits underwent surgical induction of aortic regurgitation and 5 control animals underwent sham operation. Doppler echocardiography was performed serially for up to 3 yr, and pathological studies were performed at necropsy. Left ventricular internal dimension at end diastole increased 80% (P < 0.00002) and left ventricular weight increased 250% (P < 0.0002) in aortic regurgitant rabbits (regurgitant fraction 52 +/- 13%) compared with baseline values. Six of 11 aortic regurgitant animals died with pathological evidence of congestive heart failure at 1.5 +/- 0.8 yr postoperatively; 2 of these developed severe systolic malperformance, manifest as fractional shortenings of 15 and 19% at 1.6 and 1.7 yr, respectively. Five of 11 aortic regurgitant animals survived until killed at 2.9 +/- 0.1 yr. Thus moderate-to-severe chronic aortic regurgitation in rabbits frequently results in heart failure and systolic dysfunction and may usefully model chronic aortic regurgitation and heart failure in humans.

Left ventricular diastolic and systolic performance during chronic experimental aortic regurgitation

1992 ◽  
Vol 263 (1) ◽  
pp. H226-H233 ◽  
Author(s):  
N. M. Magid ◽  
D. C. Wallerson ◽  
J. S. Borer ◽  
A. Mukherjee ◽  
M. S. Young ◽  
...  
Keyword(s):  
Aortic Regurgitation ◽  
Time Course ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Sham Operation ◽  
Functional Responses ◽  
Volume Load ◽  
Systolic Performance ◽  
Chronic Aortic Regurgitation

To study the time course of left ventricular structural and functional responses to chronic aortic regurgitation, aortic regurgitation was surgically induced in rabbits, and Doppler echocardiography was performed preoperatively and serially postoperatively for up to 2.5 yr. Twenty-five New Zealand White rabbits underwent surgical induction of aortic regurgitation and 13 control animals underwent sham operation. Left ventricular endocardial and epicardial surfaces were digitized from M-mode echocardiograms to measure the rates of change of cavity dimensions and wall thicknesses during diastolic relaxation and systolic contraction. Aortic regurgitant animals developed left ventricular dilatation and eccentric hypertrophy that remained relatively stable throughout the follow-up period. Compared with baseline values, left ventricular mass increased 120% and left ventricular internal dimension at end diastole increased 40%, whereas posterior wall thickness at end diastole and fractional shortening remained relatively stable. Left ventricular diastolic performance was enhanced at 6 mo after operation, a finding associated with increased volume load and heart rate following induction of aortic regurgitation. Diastolic performance was then reduced at 12 mo after operation and demonstrated no further decline throughout the remainder of the follow-up period. In contrast, left ventricular systolic performance was not altered following operation and remained preserved until the final assessment at up to 2.5 yr. Thus alterations in diastolic performance occurred without impairment of systolic performance during long-term follow-up of chronic experimental aortic regurgitation.

Abstract 4876: LAMP2 Cardiomyopathy is a Particularly Adverse Phenocopy of Sarcomeric Hypertrophic Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Barry Maron ◽  
William C Roberts ◽  
Michael Arad ◽  
Carolyn Y Ho ◽  
Tammy S Haas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Sudden Death ◽  
Heart Transplantation ◽  
Systolic Dysfunction ◽  
Ventricular Tachyarrhythmia ◽  
Young Patients ◽  
Disease Process ◽  
Left Ventricular ◽  
Asymptomatic Patients

Mutations in the X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a morphologic phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM) in young patients, characterized by extreme left ventricular (LV) hypertrophy and pre-excitation. However, the natural history of this newly recognized cardiomyopathy is incompletely resolved. Seven young asymptomatic patients with LAMP2 cardiomyopathy were identified at ages 8 to 15 years; 6 were male. LV hypertrophy was particularly marked (septal thickness 25– 65 mm; mean 42±17) in the presence of nondilated LV cavity. On each ECG, Wolff-Parkinson-White pre-excitation pattern was associated with markedly increased voltages (74±38mm for R- or S-wave). Over the 7±3 year follow-up from initial cardiac diagnosis, all 7 patients experienced particularly adverse disease consequences associated with progressive LV wall thinning and cavity dilatation and systolic dysfunction (ejection fraction, 29±7%) by the ages of 12 – 24 years (mean 20). Of the 7 patients, 5 either died of progressive heart failure, had heart transplantation or were considered for a donor heart; 2 others had sudden death events, including one fatal ventricular tachyarrhythmia refractory to defibrillator therapy and one appropriate defibrillator shock in an asymptomatic female survivor. Pathologic examination of hearts at autopsy showed histopathologic findings compatible with both HCM due to sarcomere protein mutations (i.e., extensive myocyte disarray, intramural small vessel disease, myocardial replacement scarring), and also evidence of a storage disease process (i.e., clusters of myocytes with vacuolated sarcoplasm within fibrotic areas). Heart weights, 1266 and 1425 grams, are the most substantial recorded for hypertrophic cardiomyopathies. LAMP2 cardiomyopathy is a uniformly profound, and particularly deleterious disease entity, causing refractory heart failure with systolic dysfunction as well as sudden death in young patients < 25 years of age. This novel phenocopy of sarcomeric HCM underscores the power of molecular diagnosis for predicting prognosis, and should also raise consideration for intervention with early heart transplantation.

Left ventricular sphericity index predicts systolic dysfunction in rats with experimental aortic regurgitation

2014 ◽  
Vol 116 (10) ◽  
pp. 1259-1262 ◽  
Author(s):  
Meliza Goi Roscani ◽  
Bertha Fulan Polegato ◽  
Suzana Erico Tanni Minamoto ◽  
Ana Paula Mena Lousada ◽  
Marcos Minicucci ◽  
...  
Keyword(s):  
Aortic Regurgitation ◽  
Sham Group ◽  
Systolic Dysfunction ◽  
Multiple Regression Model ◽  
Left Ventricular ◽  
Sham Operation ◽  
Sphericity Index ◽  
Male Wistar Rats ◽  
Fractional Shortening

Although an increased left ventricular (LV) diastolic diameter (DD) and a decreased ejection fraction have been used as markers for the surgical replacement of an insufficient aortic valve, these signals may be observed when irreversible myocardium damage has already occurred. The aim of this study was to determine whether change in LV geometry predicts systolic dysfunction in experimental aortic regurgitation. Male Wistar rats underwent surgical acute aorta regurgitation (aorta regurgitation group; n = 23) or a sham operation (sham group; n = 12). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 16 wk. At the end of protocol, the LV, lungs, and liver were dissected and weighed. During the follow-up, no animal developed overt heart failure. There was a correlation between the LV sphericity index and reduced fractional shortening ( P < 0.001) over time. A multiple regression model showed that the LVDD-sphericity index association at 8 wk was a better predictor of decreased fractional shortening at week 16 ( R2 = 0.50; P < 0.001) than was the LVDD alone ( R2 = 0.39; P = 0.001). LV geometry associated with increased LVDD improved the prediction of systolic dysfunction in experimental aortic regurgitation.

scholarly journals Right versus left ventricular remodeling in heart failure due to chronic volume overload: pressure-volume and proteome analysis

2021 ◽  
Author(s):  
Tereza Havlenova ◽  
Petra Skaroupkova ◽  
Matus Miklovic ◽  
Matej Behounek ◽  
Martin Chmel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Volume Overload ◽  
Left Ventricular ◽  
Cytoskeletal Proteins ◽  
Sham Operation ◽  
Stroke Work ◽  
Specific Regulation

Abstract Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV. The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. RV reacts to ACF relatively more than LV due to concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

Abstract 15863: Macrophage Foxp1 is a Regulator of Pathologic Cardiac Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shuichi Yoneda ◽  
Saptarsi M Haldar ◽  
Jessica Jenkins ◽  
Yunmei Wang ◽  
Teruo Inoue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Disease Process ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Control Male ◽  
Pathologic Cardiac Hypertrophy

Introduction: Pathologic cardiac hypertrophy is a maladaptive response to neurohormonal and hemodynamic stress that is a hallmark of human heart failure. While inflammation has been implicated in pathologic hypertrophy, the molecular mechanisms underlying innate immune dysregulation in this disease process are incompletely defined. We have previously demonstrated that the forkhead transcription factor Foxp1 controls monocyte differentiation and suppresses inflammatory activation of macrophages. In this study, we hypothesized that monocyte/macrophage Foxp1 regulates pathologic cardiac hypertrophy. Methods: Macrophage-specific Foxp1 over-expressing (macFoxp1tg=anti-inflammatory) vs. non-tg controls, as well as macrophage-specific Foxp1 knockdown (macFoxp1ko=pro-inflammatory) vs. Cre-control male mice were subject to chronic angiotensin II (AII) infusion (1.8 mcg/kg/min via subcutaneous osmotic mini-pump) for 4 weeks. Results: AII-mediated cardiac hypertrophy (heart mass and cardiomyocyte cross-sectional area), left ventricular (LV) systolic dysfunction, LV dilation, interstitial fibrosis and macrophage (Mac-3+ cells) accumulation were significantly attenuated in macFoxp1tg mice compared to non-tg controls. In contrast, AII-mediated cardiac hypertrophy, LV systolic dysfunction and cavity dilation were significantly exacerbated in macFoxp1ko mice compared to Cre controls. There were no differences in systemic blood pressure between these groups, corroborating a load-independent role for macrophage Foxp1 in cardiac hypertrophy. Conclusion: These studies identify macrophage Foxp1 as a novel negative regulator of pathologic cardiac hypertrophy in vivo. Modulation of Foxp1 signaling may provide a novel strategy for prevention and treatment of heart failure.

scholarly journals Early Detection of Left Ventricular Systolic Dysfunction in Asymptomatic Patients with Chronic Aortic Regurgitation by two Dimensional Speckle Tracking Echocardiography

2019 ◽  
Vol 14 (2) ◽  
pp. 35-42
Author(s):  
Thamer I. Al-Jawahiri ◽  
Amal N. Al-Marayati,
Keyword(s):  
Early Detection ◽  
Aortic Regurgitation ◽  
Speckle Tracking ◽  
Speckle Tracking Echocardiography ◽  
Heart Diseases ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Two Dimensional ◽  
Asymptomatic Patients ◽  
Chronic Aortic Regurgitation

Background: Early detection of subclinical left ventricular (LV) systolic dysfunction is crucial and could influence patients' prognosis by aiding the clinician to candidate patients for better management. Objective: To detect early LV systolic dysfunction in asymptomatic patient with chronic aortic regurgitation by two dimensional speckle tracking echocardiography.  Methods:  Sixty one asymptomatic patients with chronic aortic regurgitation, with no ischemic heart diseases (by coronary angiography) or conductive heart diseases, no diabetes mellitus, no hypertension, and no other valvular heart diseases (group 1) and fifty age and sex-matched healthy subjects (group 2) were enrolled into the study. Group (1) was further classified into 3 sub-groups according to 4 chosen parameters from the published guidelines of American Society of Echocardiography (ASE) into: Mild AR, Moderate AR, and Severe AR.   All patients and controls underwent echocardiographic examination including conventional echocardiography, tissue Doppler study and Two Dimensional (2-D) Speckle Tracking Echocardiography. Results: GLS showed the highest sensitivity and specificity in detection of subtle LV systolic dysfunction in moderate AR. In moderate AR,a cut off value of > (-19.62) has sensitivity and specificity of 91.3% and 95.5% respectively, with Positive Predictive Value (PPV) and Negative Predictive Value ( NPV ) of 87.5% and 96.9% respectively, Area under curve (AUC) of 0.981. In all types of AR, GLS had higher NPV than PPV which makes it a powerful screening tool for early detection of subtle LV systolic dysfunction. Conclusion: Global Longitudinal strain measured by 2-D speckle tracking echocardiography is an excellent tool for early detection of subtle LV systolic dysfunction in asymptomatic patients with chronic AR  

Abstract 16343: Sarpogrelate, a Selective Serotonin 2a Receptor Antagonist, Suppresses Pressure Overlaod-induced Cardiac Hypertrophy and Systolic Dysfunction Through Inhibiting Erk1/2/gata4 Pathway

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kana Shimizu ◽  
Masafumi Funamoto ◽  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Receptor Antagonist ◽  
Surface Area ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Diameter ◽  
Sham Operation ◽  
Mrna Levels ◽  
Wide Range

Introduction: Serotonin (5-HT), a neurohormone involved in a wide range of physiological functions, has generated much interest in recent years regarding its potential role in cardiac function. It is reported that sarpogrelate, a selective 5-HT2A receptor antagonist, possesses cardioprotective effect against myocardial infarction, however, the precise molecular mechanism of the effect is still unclear. In this study, we examined the effect of sarpogrelate on pressure overload-induced development of heart failure, another heart failure model. Methods: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli. Cardiomyocytes were stained with anti-actinin antibody and the surface area of the cells were measured. The phosphorylation levels of ERK1/2 and GATA4 were assessed by western blotting. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Results: Sarpogrelate significantly suppressed an increase in the surface area of cardiomyocytes induced not only by 5-HT, but also by phenylephrine, angiotensin II and ET-1. Sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. In a mice model of heart failure, echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. One mg/kg sarpogrelate also suppressed TAC-induced increase in HW/BW ratio, myocardial cell diameter and the mRNA levels of ANF and BNP. Moreover, 1 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2/GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.

scholarly journals The left ventricular remodeling assessment by cardiac magnetic resonance in chronic aortic regurgitation; implications for outcome

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
G Hashimoto ◽  
M Sarano ◽  
H Sato ◽  
B Lopes ◽  
M Fukui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Clinical Outcome ◽  
Aortic Regurgitation ◽  
Composite Endpoint ◽  
Left Ventricular ◽  
Lv Remodeling ◽  
Chronic Aortic Regurgitation

Abstract Background Chronic aortic regurgitation (AR) causes left ventricular (LV) volume overload resulting in progressive LV remodeling, which negatively affect clinical outcome. Clinical Guidelines recommend assessment of LV remodeling by echocardiography, but little is known about comparative remodeling quantification by cardiac magnetic resonance (CMR) and association with outcomes. Purpose To assess LV remodeling in AR by CMR, compared with echocardiographic measures and determine its impact on clinical outcome. Methods Patients with native, ≥moderate, chronic AR by echocardiography who underwent CMR exam within 90 days of diagnosis from January 2012 to February 2020 were enrolled. The endpoint was a composite of death, heart failure hospitalization, and heart failure symptom exacerbation during follow-up. Results The 178 patients included had median age (IQR) of 58 years (44–69), and most (88%, n=158) presented with no or minimal symptoms (NYHA class I/II). At diagnosis symptomatic vs. no/minimal symptoms patients presented with much more advanced LV remodeling by CMR (EDVI 133 [83–151] vs. 96 [80–123] p=0.024, ESVI 66 [46–85] vs. 42 [30–58], P=0.001) while echocardiography showed limited differences (EDVI 76 [57–93] vs. 65 [54–87] p=0.507, ESVI 38 [30–58] vs. 27 [20–42], p=0.072). During follow-up (3.3 years [1.6–5.8]), aortic valve replacement (AVR) was performed in 49 patients. In patients with no/minimal symptoms, the composite endpoint occurred in 54 (34%) patients including eight deaths and 30 heart failure hospitalizations. Patients with LV end-systolic volume index (LVESVi) &gt;45 ml/m2 by CMR had higher likelihood for composite endpoint (Panel A) confirmed in multivariate models, adjusting for age, sex, AVR (time-dependent), EuroSCORE2, and LV End-systolic-dimension-index (LVESDi) &gt;25 mm/2, with adjusted hazard ratio 1.84 [1.02–3.33], p&lt;0.044 (Panel B). LVESVi by CMR was at least as powerful in determining clinical outcomes as guideline-recommended Doppler-Echocardiographic variables. Conclusion Assessment of LV remodeling by CMR in patients with clinically significant AR is feasible in routine clinical practice, detects with high sensitivity LV remodeling associated with development of HF symptoms and is independently predictive of clinical outcome. Hence, CMR provides a powerful tool for evaluation and risk stratification of patients with AR. FUNDunding Acknowledgement Type of funding sources: None. Panel A Panel B

scholarly journals Right versus left ventricular remodeling in heart failure due to chronic volume overload

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tereza Havlenova ◽  
Petra Skaroupkova ◽  
Matus Miklovic ◽  
Matej Behounek ◽  
Martin Chmel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Volume Overload ◽  
Left Ventricular ◽  
Cytoskeletal Proteins ◽  
Sham Operation ◽  
Stroke Work ◽  
Specific Regulation

AbstractMechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (pslope: < 0.001). The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. Relatively larger response of ACF RV compared to the LV may be caused by concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

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