Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/β-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.

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Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00423.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. H1605-H1617 ◽

Cited By ~ 11

Author(s):

Kristin Wilson ◽

Anuradha Guggilam ◽

T. Aaron West ◽

Xiaojin Zhang ◽

Aaron J. Trask ◽

...

Keyword(s):

Heart Failure ◽

Troponin I ◽

Regulatory Protein ◽

Volume Overload ◽

Left Ventricular ◽

Lv Function ◽

Stroke Work ◽

Sprague Dawley ◽

Diastolic Relaxation ◽

Systolic And Diastolic Function

Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca2+ sensitizer would improve VO-induced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200–240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca2+ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca2+ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4–8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (τ, dP/d tmin) function in ACF and REV. Levo improved Ca2+ sensitivity without altering the amplitude and kinetics of the intracellular Ca2+ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased α-to-β-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function.

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

10.21203/rs.3.rs-399870/v1 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-021-96618-8 ◽

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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Challenges in the diagnosis of peripartum cardiomyopathy: a case series

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytab001 ◽

2021 ◽

Vol 5 (2) ◽

Author(s):

Fabio Chirillo ◽

Anna Baritussio ◽

Umberto Cucchini ◽

Ermanno Toniolli ◽

Angela Polo ◽

...

Keyword(s):

Heart Failure ◽

Multimodality Imaging ◽

Systolic Dysfunction ◽

Case Series ◽

Left Ventricular ◽

Peripartum Cardiomyopathy ◽

Lv Function ◽

Prognostic Information ◽

Clinical Scenarios ◽

Anterolateral Wall

Abstract Background Peripartum cardiomyopathy (PPCM) is usually characterized by overt heart failure, but other clinical scenarios are possible, sometimes making the diagnosis challenging. Case summary We report a case series of four patients with PPCM. The first patient presented with acute heart failure due to left ventricular (LV) systolic dysfunction. Following medical treatment, LV function recovered completely at 1 month. The second patient had systemic and pulmonary thromboembolism, secondary to severe biventricular dysfunction with biventricular thrombi. The third patient presented with myocardial infarction with non-obstructed coronary arteries and evidence of an aneurysm of the mid-anterolateral LV wall. The fourth patient, diagnosed with PPCM 11 years earlier, presented with sustained ventricular tachycardia. A repeat cardiac magnetic resonance, compared to the previous one performed 11 years earlier, showed an enlarged LV aneurysm in the mid-LV anterolateral wall with worsened global LV function. Discussion Peripartum cardiomyopathy may have different clinical presentations. Attentive clinical evaluation and multimodality imaging can provide precise diagnostic and prognostic information.

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Pursuing the non-invasive assessment of cardiac contractility: the added value of pressure-area-strain loop analysis in volume overload-induced heart failure

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.188 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

M Tokodi ◽

BK Lakatos ◽

M Ruppert ◽

A Olah ◽

AA Sayour ◽

...

Keyword(s):

Heart Failure ◽

Mitral Valve ◽

Cardiac Contractility ◽

Volume Overload ◽

Left Ventricular ◽

Stroke Work ◽

Loading Conditions ◽

Innovation And Technology ◽

Pressure Area ◽

Area Strain

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the New National Excellence Programme (ÚNKP-19-3-I) of the Ministry for Innovation and Technology in Hungary, and the Artificial Intelligence Research Field Excellence Programme of the National Research, Development and Innovation Office of the Ministry of Innovation and Technology in Hungary. Background Global longitudinal strain (GLS) by speckle-tracking echocardiography (STE) is a sensitive parameter of left ventricular (LV) systolic function. Nevertheless, GLS is dependent on loading conditions. Through the analysis of pressure-strain loops, myocardial work was recently introduced and tested in different clinical scenarios. Myocardial work incorporates afterload, but still, it neglects changes in preload and LV geometry. Purpose Accordingly, our aim was to test our hypothesis that adding instantaneous LV size to myocardial work calculation can further mitigate the load-dependency of GLS, and therefore, a better correlation with intrinsic myocardial contractility can be achieved. Methods Volume overload-induced heart failure was established by an aortocaval fistula (ACF) in male Wistar rats (n = 12). Age-matched sham-operated animals served as controls (n = 12). STE was performed to assess GLS, which was immediately followed by invasive pressure-volume (P-V) analysis to assess LV pressure and to compute a gold-standard index of cardiac contractility (preload recruitable stroke work [PRSW]). Global myocardial work index (GMWI) was calculated from GLS and the invasively measured LV pressure. To compute GMWI indexed to LV area (GMWIA), the instantaneous power (calculated by multiplying the strain rate and the instantaneous LV pressure) was divided by the instantaneous LV area, and then it was integrated from mitral valve closure until mitral valve opening. Results LV ejection fraction did not differ significantly (ACF vs. controls: 59 ± 4 vs. 65 ± 9%, p = NS), whereas GLS (Figure 1A - representative animals) was slightly decreased in the ACF group (-13.2 ± 2.3 vs. -15.4 ± 1.9%, p < 0.05). In contrast, PRSW, GMWI (Figure 1B - representative animals) and GMWIA (Figure 1C - representative animals) were considerably reduced in ACF compared to controls (57 ± 13 vs. 111 ± 38mmHg, 1383 ± 382 vs. 1928 ± 281mmHg%, 11.6 ± 3.7 vs. 47.9 ± 22.8mmHg%/mm2, all p < 0.01). GLS showed moderate correlation with PRSW (r=-0.550, p < 0.01), whereas GMWI correlated more significantly, but still moderately with the invasively measured LV contractility (r = 0.681, p < 0.001). Correlation between the pressure-area-strain loop-derived GMWIA and P-V analysis-derived PRSW (Figure 1D) was found to be very strong (r = 0.924, p < 0.001). Conclusions In the case of LV volume overload-induced heart failure, our pressure-area-strain loop-derived metric reflected LV contractility better than GLS and even GMWI. Therefore, the incorporation of instantaneous LV size into myocardial work calculation represents a promising clinical tool to assess and monitor intrinsic myocardial function independently of loading conditions. Abstract Figure 1

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Effects of hypoproteinemia-induced myocardial edema on left ventricular function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.3.h937 ◽

1998 ◽

Vol 274 (3) ◽

pp. H937-H944 ◽

Cited By ~ 7

Author(s):

M. Miyamoto ◽

D. E. McClure ◽

E. R. Schertel ◽

P. J. Andrews ◽

G. A. Jones ◽

...

Keyword(s):

Plasma Protein ◽

Protein Concentration ◽

Systolic Dysfunction ◽

Myocardial Edema ◽

Left Ventricular ◽

Control Group ◽

Lv Function ◽

Stroke Work ◽

Plasma Protein Concentration ◽

Total Plasma Protein

In previous studies, we observed left ventricular (LV) systolic and diastolic dysfunction in association with interstitial myocardial edema (IME) induced by either coronary venous hypertension (CVH) or lymphatic obstruction. In the present study, we examined the effects of myocardial edema induced by acute hypoproteinemia (HP) on LV systolic and diastolic function. We also combined the methods of HP and CVH (HP-CVH) to determine their combined effects on LV function and myocardial water content (MWC). We used a cell-saving device to lower plasma protein concentration in HP and HP-CVH groups. CVH was induced by inflating the balloon in the coronary sinus. Six control dogs were treated to sham HP. Conductance and micromanometer catheters were used to assess LV function. Contractility, as measured by preload recruitable stroke work, did not change in control or HP groups but declined significantly (14.5%) in the HP-CVH group. The time constant of isovolumic LV pressure decline (τ) increased significantly from baseline by 3 h in the HP (24.8%) and HP-CVH (27.1%) groups. The end-diastolic pressure-volume relationship (stiffness) also increased significantly from baseline by 3 h in the HP (78.6%) and HP-CVH (42.6%) groups. Total plasma protein concentration decreased from 5.2 ± 0.2 g/dl at baseline to 2.5 ± 0.0 g/dl by 3 h in the HP and HP-CVH groups. MWC of the HP (79.8 ± 0.25%) and HP-CVH groups (79.8 ±0.2%) were significantly greater than that of the control group (77.8 ± 0.3%) but not different from one another. In conclusion, hypoproteinemia-induced myocardial edema was associated with diastolic LV dysfunction but not systolic dysfunction. The edema caused by hypoproteinemia was more than twice that produced by our previous models, yet it was not associated with systolic dysfunction. CVH had a negative inotropic effect and no significant influence on MWC. IME may not have the inverse causal relationship with LV contractility that has been previously postulated but appears to have a direct causal association with diastolic stiffness as has been previously demonstrated.

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Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis

Circulation ◽

10.1161/circ.142.suppl_3.14952 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Mihály Ruppert ◽

Christian Karime ◽

Alex A Sayour ◽

Attila Oláh ◽

Dávid Nagy ◽

...

Keyword(s):

Heart Failure ◽

Systolic Function ◽

Pressure Overload ◽

Volume Overload ◽

Detailed Comparison ◽

Left Ventricular ◽

Lv Function ◽

Arterial Elastance ◽

Lv Remodeling ◽

Av Shunt

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.

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Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction

Clinical Science ◽

10.1042/cs1020009 ◽

2001 ◽

Vol 102 (1) ◽

pp. 9-14 ◽

Cited By ~ 18

Author(s):

Suneel TALWAR ◽

Iain B. SQUIRE ◽

Russell J. O'BRIEN ◽

Paul F. DOWNIE ◽

Joan E. DAVIES ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Acute Myocardial Infarction ◽

Left Ventricular Systolic Dysfunction ◽

Systolic Function ◽

Systolic Dysfunction ◽

Clinic Visit ◽

Left Ventricular ◽

Lv Function ◽

Ventricular Remodelling

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.

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Peripartum Cardiomyopathy Presenting with Predominant Left Ventricular Diastolic Dysfunction: Efficacy of Bromocriptine

Case Reports in Medicine ◽

10.1155/2012/476903 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Piercarlo Ballo ◽

Irene Betti ◽

Giuseppe Mangialavori ◽

Leandro Chiodi ◽

Gherardo Rapisardi ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Systolic Function ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Peripartum Cardiomyopathy ◽

Lv Function ◽

Lv Diastolic Dysfunction ◽

Lv Diastolic Function

Management of patients with peripartum cardiomyopathy (PPCM) is still a major clinical problem, as only half of them or slightly more show complete recovery of left ventricular (LV) function despite conventional evidence-based treatment for heart failure. Recent observations suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. However, no evidence exists regarding its effect on LV diastolic dysfunction, which is commonly observed in these patients. Tissue Doppler (TD) is an echocardiographic technique that provides unique information on LV diastolic performance. We report the case of a 37-year-old white woman with heart failure (NYHA class II), moderate LV systolic dysfunction (ejection fraction 35%), and severe LV diastolic dysfunction secondary to PPCM, who showed no improvement after 2 weeks of treatment with ramipril, bisoprolol, and furosemide. At 6-week followup after addition of bromocriptine, despite persistence of LV systolic dysfunction, normalization of LV diastolic function was shown by TD, together with improvement in functional status (NYHA I). At 18-month followup, the improvement in LV diastolic function was maintained, and normalization of systolic function was observed. This paper might support the clinical utility of bromocriptine in patients with PPCM by suggesting a potential benefit on LV diastolic dysfunction.

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Angiotensin-converting enzyme inhibitor captopril prevents volume overload cardiomyopathy in experimental chronic aortic valve regurgitation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y04-005 ◽

2004 ◽

Vol 82 (3) ◽

pp. 191-199 ◽

Cited By ~ 27

Author(s):

Eric Plante ◽

Martin Gaudreau ◽

Dominic Lachance ◽

Marie-Claude Drolet ◽

Élise Roussel ◽

...

Keyword(s):

Aortic Valve ◽

Angiotensin Converting Enzyme ◽

Enzyme Inhibitor ◽

Systolic Function ◽

Systolic Dysfunction ◽

Volume Overload ◽

Left Ventricular ◽

Lv Function ◽

Mrna Levels ◽

Converting Enzyme

The efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of chronic aortic regurgitation (AR) is not well established and remains controversial. The mechanisms by which ACEIs may protect against left-ventricular (LV) volume overload are not well understood, and clinical trials performed until now have yielded conflicting results. This study was therefore performed to assess the effectiveness of two different doses of the ACEI captopril in a rat model of chronic AR. We compared the effects of a 6-month low-dose (LD) (25 mg/kg) or higher dose (HD) (75 mg/kg) treatment with captopril on LV function and hypertrophy in Wistar rats with severe AR. Untreated animals developed LV eccentric hypertrophy and systolic dysfunction. LD treatment did not prevent hypertrophy and provided modest protection against systolic dysfunction. HD treatment preserved LV systolic function and dimensions and tended to slow hypertrophy. The cardiac index remained high and similar among all AR groups, treated or not. Tissue renin–angiotensin system (RAS) analysis revealed that ACE activity was increased in the LVs of AR animals and that only HD treatment significantly decreased angiotensin II receptor mRNA levels. Fibronectin expression was increased in the LV or AR animals, but HD treatment almost completely reversed this increase. The ACE inhibitor captopril was effective at high doses in this model of severe AR. These effects might be related to the modulation of tissue RAS and the control of fibrosis.Key words: aortic valve, insufficiency, rat, echocardiography, volume overload, ACE inhibitors.

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