Prevention Of Left Ventricular Dysfunction Research Articles

Empagliflozin restores autophagy and ameliorates ponatinib-induced cardiomyocyte death

Abstract Background The tyrosine kinase inhibitor ponatinib has proven cardiovascular toxicity, for which no counteractive treatment is available at the moment. Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors are approved drugs treat patients with chronic heart failure of different aetiologies. They play direct anticancer activity in SGLT2-expressing cancer cells, independent of glucose metabolism and through inhibition of oxidative phosphorylation. Ongoing studies are now testing empagliflozin (EMPA) in the prevention of left ventricular dysfunction in patients receiving high cumulative doses of anthracyclines. Aims To determine the effect of EMPA on cardiomyocytes in an in vitro model of PON-induced cardiac toxicity, and to assess underlying cardioprotective mechanisms. Methods and Results We exposed cardiomyocytes to PON (1.7 nM) or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nM) for 24 hours. Compared with vehicle, incubations with PON significantly reduced cell viability at 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, decreased autophagic cells at immunofluorescence assay (1±0.5 vs 6±1 fluorescence intensity/total area, p=0.0006, Figure 1), and increased cell senescence (15±5 vs 4±2 β-gal positivity/tissue area, p<0.02), effects all reverted by EMPA (p<0.01). We observed no significant effects of PON or EMPA on formation of reactive oxygen species. Compared with vehicle, PON significantly reduced serum response factor (SRF)/serum response elements (SRE) binding activity (25±9 vs 218±15 SRE complex abundance, arbitrary units, p<0.001), in parallel with a reduction in cardiac actin expression (0.32±0.06 vs 0.98±0,12 cardiac actin/GAPDH ratio, arbitrary units, p=0.001), which was reversed by EMPA (p=0.001). Conclusion EMPA attenuates PON cardiotoxicity by reducing senescence and enhancing autophagy, apparently independent of antioxidant mechanisms. This study suggests the design of clinical studies aimed at assessing the effects of EMPA on PON-induced cardiotoxicity.Legend to Figure 1.CON, control (vehicle, DMSO); PON, ponatinib; EMPA 100, empagliflozin 100 nM; EMPA 500, empagliflozin 500 nM

697 SGLT2-INHIBITORS PREVENT LEFT VENTRICULAR DISFUNCTION INDUCED BY ANTHRACYCLINE CHEMOTERAPY IN MOUSE MODEL: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background No human studies evaluating the efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2-i) in preventing left ventricular dysfunction induced by anthracycline chemotherapy are available. Current evidence on this topic is based on few studies conducted on mouse models. Objective We investigated this issue through a meta-analysis of echocardiography studies that reported data on difference in left ventricular function between animals assuming SGLT2-i and controls in mouse models of anthracycline-induced cardiomyopathy. Methods The PubMed, OVID-MEDLINE and Cochrane library databases were systematically analysed to search English-language articles published from inception to 31 July 2022. Studies were identified by using Me-SH terms and crossing the following terms: “ sodium glucose cotransporter 2 inhibitors”, “gliflozin”, “anthracycline”, “cardiotoxicity”, “systolic dysfunction” and “echocardiography”. Results The meta-analysis included a total of 106 mice (Sprague Dawley and C57Bl/6 species) with anthracycline-induced cardiomyopathy from 7 studies, 60 mice assuming a SGLT2-i (Empagliflozin:4 studies, Dapagliflozin:2, Canagliflozin:1) and 46 controls. Compared with controls, left ventricle systolic function was significantly better in the pooled SGLT2-i group. Precisely, both fractional shortening (FS: 44,7±3,7 vs 32,6±3,3) and left ventricle ejection fraction (LVEF: 78,2±3,4 vs 64,2±4,9) were higher in the pooled SGLT2-i group than in the controls group, with standard mean difference (SMD) respectively being 2,42±0,56 for FS (CI: 1,326-3,510, p value <0.001) and 2,46±0,61 for LVEF (CI: 1,267-3,656, p value <0.001). Figure 1. Conclusions Our study shows a favourable effect of SGLT2-i in the prevention of left ventricular dysfunction induced by anthracycline chemotherapy in mouse models, suggesting that this pharmacological strategy should also be tested in clinical studies involving human subjects.

Keeping the Heart Fitm2 during Chemotherapy.

Keeping the Heart Fitm2 during Chemotherapy.

Applications of left ventricular strain measurements to patients undergoing chemotherapy.

We aim to summarize the utility of strain in monitoring the effects of cancer therapy-related cardiotoxicity (CTRC) on the development of left ventricular (LV) dysfunction. Serial assessment of cardiac function at baseline and during treatment is recommended in patients undergoing cancer treatment. Historically, the use of left ventricular ejection fraction (LVEF) has been used to monitor for cardiac toxicity from cancer therapies but myocardial mechanic parameters, in particular global longitudinal strain (GLS), have emerged as powerful adjunctive tools. On the basis of longitudinal cohort studies in patients treated with anthracyclines and trastuzumab and retrospective studies of childhood survivors of cancers, strain has been used to detect subclinical LV dysfunction prior to changes in LVEF. Strain parameters decrease during both anthracycline and trastuzumab and these changes can persist after completion of therapy. Baseline GLS and changes in GLS during therapy can be independently prognostic for developing CTRC. Further, GLS has appeared to have an additive predictive value in addition to the traditional clinical parameters and baseline LVEF in the development of cardiotoxicity. The inclusion of strain parameters in clinical decision making and therapeutic planning is an area of intense research. This review seeks to highlight the importance of echocardiographic strain measurements in early detection, treatment and prevention of LV dysfunction from CTRC.

Left Ventricular Dysfunction and Chemotherapeutic Agents.

We aim to summarize the effect of cancer therapy-related cardiotoxicity on the development of left ventricular (LV) dysfunction. We discuss commonly used cancer therapeutics that have the potential for both acute and delayed cardiotoxicity. LV dysfunction from cancer therapies may be found by routine cardiac imaging prior to clinical manifestations of heart failure (HF) and we discuss the current multi-modality approaches for early detection of toxicity with the use of advanced echocardiographic parameters including strain techniques. Further, we discuss the role of biomarkers for detection of LV dysfunction from cancer therapies. Current approaches monitoring and treating LV dysfunction related to cancer therapy-related cardiotoxicity include addressing modifiable cardiovascular risk factors especially hypertension and early initiation of neurohormonal blockade (NHB) with disease-modifying beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. Once LV dysfunction is identified, traditional ACC/AHA guideline-directed therapy is employed. Further, we highlight the use of advanced heart failure therapies including mechanical resynchronization devices, the use of durable ventricular assist devices, and cardiac transplantation as increasingly employed modalities for treatment of severe LV dysfunction and advanced heart failure in the cardio-oncology population. This review seeks to highlight the importance of early detection, treatment, and prevention of LV dysfunction from cancer therapy-related cardiotoxicity.

Diagnosis and Treatment of Bicuspid Aortic Valve Disease

Bicuspid aortic valve disease is the most common congenital cardiac anomaly. The prevalence in the general population is between 0.46% and 1.37%. There is significantly high cardiac morbidity associated with bicuspid aortic valve disease, predomi- nantly due to progressive valve dysfunction (stenosis or regurgitation) that requires surgical intervention for symptom relief or prevention of left ventricular dysfunction, or less commonly, for complications of endocarditis. Bicuspid aortic valve disease is clinically important not only because of valve disease but also because of its association with many vascular abnormalities, such as aortic dilatation and aortic coarctation.

An update on primary findings and new designs in biotherapy studies for acute myocardial infarction.

Treatment of acute myocardial infarction in the future should focus not only on improving acute treatment, as it has been done over the past decades, but also on secondary prevention of left ventricular dysfunction and/or progression to heart failure by preserving left ventricular shape, avoiding left ventricular remodeling and stimulating cardiac regeneration. Biotherapies with adult stem cells and bone marrow-derived endothelial cell progenitors, combined or not with biomaterials, and new drugs are under investigation and will probably be part of routine clinical practice for patients suffering from myocardial infarction in the near future.

Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies. The OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies)

Background: Cardiotoxicity is an important and a common complication of cancer chemotherapeutic drugs. It may not only be associated with significant morbidity and mortality but also often becomes a limiting factor in adequate anti-cancer treatment. Several pharmacological agents are being evaluated for their efficacy in preventing cardiotoxicity of the cancer drugs. Material and methods: Ninety patients with hematological malignancies undergoing chemotherapy and/or autologous hematopoietic stem cell transplantation (HSCT) were recruited in this study and were randomized to receive a combination of enalapril and cardvedilol (intervention arm) or no intervention (control arm). Comprehensive echocardiography and cardiac magnetic resonance imaging (MRI) were performed at baseline and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in left ventricular ejection fraction (LVEF). Results: The mean age of the study subjects was 50 ± 13 years. By the end of the 6 months, there was a significant fall in LVEF in controls (3.28% absolute reduction from baseline) but no change was seen in the intervention group. As a result, at 6 months, LVEF was significantly lower in the control group in comparison to the intervention group (an absolute difference of 3.1% by echocardiography and 3.4% by cardiac MRI, p = 0.035 and 0.09, respectively). The beneficial effect was seen almost exclusively in patients receiving chemotherapy alone (absolute difference in LVEF of 6.38% at 6 months, p = 0.025) and not in those undergoing HSCT (absolute difference of 1.01%, p = 0.56). In addition, compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). Conclusions: The present trial showed that a combination of enalapril and carvedilol might prevent cardiotoxicity in patients undergoing chemotherapy for hematological malignancies.

Exercise training and post-operative prognosis after coronary intervention

Aging is worldwide recognized as a dominant risk factor for most forms of cardiovascular disease [1-3]. However, mechanisms by which it exerts its role and determines poor outcome have been only partially clarified. Numerous evidence indicate that aging is associated with alteration of several mechanisms whose integrity confers protective action on the heart and vasculature [5-9]. Autonomic status derangement, diminished efficacy of ischemic preconditioning, impaired angiogenic responses after ischemic injury, increased oxidative stress, and abnormal left ventricular remodelling after myocardial infarction are all putative mechanisms potentially involved in the vulnerability of cardiovascular system occurring with aging. Interestingly, many of the alterations that take place in the aged heart and vasculature are very similar to those observed in pathologic conditions, such as heart failure (HF), and, most importantly, are at least in part revertible. Exercise training plays a pivotal role in primary and secondary prevention of cardiovascular disease, in counteracting the age-related deterioration of some mechanisms that are crucially involved in the homeostasis of cardiovascular system and that may condition the outcome of cardiovascular disease in the elderly. Moreover, it is associated to reduction of the post-operative atrial fibrillation with reduction of the number of prescribed drugs [10]. Preconditioning represent the strongest form of in vivo protection against myocardial ischemic injury, consisting in brief episodes of myocardial ischemia able to reduce cellular damage subsequent to a more prolonged ischemic injury. Remote preconditioning is the phenomenon by which ischemia in one region of the heart causes protection in a remote region of the heart itself or of another organ, thus suggesting that circulating factors or a neural reflex triggers protection in the remote region. Aging is associated with higher rates of morbidity after coronary intervention and a progressive loss in efficacy of ischemic preconditioning with age has been indicated as a potential mechanism explaining the worse prognosis in the elderly. A diminished norepinephrine release in response to transient ischemic stress has been indicated having role in the loss of preconditioning protection occurring with age. Preinfarction angina is considered one of the strongest clinical equivalent of ischemic preconditioning being associated with both reduction in infarct size and prevention of left ventricular dysfunction. Evidences demonstrate the loss of the protective effect of preinfarction angina with age, resulting in a no more protective effect on both early and late mortality in the elderly after acute cardiac events. In adult and elderly humans, high levels of physical activity preserve the protective role of preinfarction angina against in-hospital mortality and cardiogenic shock after myocardial infarction. More recent data indicate that higher levels of physical activity performed before primary coronary angioplasty may independently predict the reduction of early and late cardiac mortality in older infarcted patients [11]. Accordingly, it has been reported a robust association between physical activity habits of elderly participants prior to coronary artery bypass grafting and survival free from both all-cause and cardiac death, [12]. Interestingly, in these studies, the greatest benefits of exercise on survival were observed in the more sedentary patient groups, thus strongly supporting the importance of implementation of physical activity levels in the elderly also as secondary prevention strategy.

Enalapril and Carvedilol for Preventing Chemotherapy-Induced Left Ventricular Systolic Dysfunction in Patients With Malignant Hemopathies: The OVERCOME Trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies)

This study sought to evaluate the efficacy of enalapril and carvedilol to prevent chemotherapy-induced left ventricular systolic dysfunction (LVSD) in patients with hematological malignancies. Current chemotherapy may induce LVSD. Angiotensin-converting enzyme inhibitors and beta-blockers prevent LVSD in animal models of anthracycline-induced cardiomyopathy. In this randomized, controlled study, 90 patients with recently diagnosed acute leukemia (n = 36) or patients with malignant hemopathies undergoing autologous hematopoietic stem cell transplantation (HSCT) (n = 54) and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echocardiographic and cardiac magnetic resonance (CMR) imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF). The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls, resulting in a -3.1% absolute difference by echocardiography (p = 0.035) and -3.4% (p = 0.09) in the 59 patients who underwent CMR. The corresponding absolute difference (95% confidence interval [CI]) in LVEF was -6.38% (95% CI: -11.9 to -0.9) in patients with acute leukemia and -1.0% (95% CI: -4.5 to 2.5) in patients undergoing autologous HSCT (p = 0.08 for interaction between treatment effect and disease category). Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). Combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger studies. (Prevention of Left Ventricular Dysfunction During Chemotherapy [OVERCOME]; NCT01110824).

Cardiac Overexpression of Monocyte Chemoattractant Protein-1 in Transgenic Mice Prevents Cardiac Dysfunction and Remodeling After Myocardial Infarction

Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.

The Transition From Hypertrophy to Failure

Hypertensive heart disease is a major contributor to cardiovascular morbidity and mortality, especially in African Americans, in whom LV hypertrophy is 2 to 3-fold more common in the general population as compared with whites.1 In the classic paradigm of hypertensive heart disease, concentric hypertrophy (a nondilated, thick-walled left ventricle typically with a normal left ventricular ejection fraction [LVEF]) is a common precursor to LV failure (an increased LV volume with reduced LVEF).2 Although molecular triggers of this transition from concentric hypertrophy to failure have been the subject of intense investigation, there are no previous large, longitudinal cohort studies in humans demonstrating that this progression occurs frequently. The transition from concentric LV hypertrophy to failure has been well demonstrated in animal models including the spontaneously hypertensive rat,3 or after aortic banding4 or transgenic manipulation,5 and also in humans with aortic stenosis6 or familial hypertrophic cardiomyopathy.7 Whether this paradigm faithfully represents the natural history of hypertensive heart disease is not yet known (Figure). An alternative paradigm is that the LV response to elevated blood pressure is either hypertrophy or failure, with transition between the 2 uncommon in the absence of an interval cardiac injury. Potential pathways in progression of hypertensive heart disease. Hypertension can lead to concentric left ventricular hypertrophy (LVH), characterized by nondilated, thick-walled left ventricle (arrow, top left). After “transition to failure,” the LV is dilated with reduced LVEF. Coronary artery disease often via MI is a common contributor to this transition (first horizontal arrow). Whether concentric LVH commonly leads to low EF in absence of an interval MI or significant coronary artery disease is uncertain (second horizontal arrow). If LVH is not common precursor to LV …

Early prevention of left ventricular dysfunction after acute myocardial infarction (AMI) with angiotensin converting enzyme (ACE) inhibitors: A randomized control trial

Early prevention of left ventricular dysfunction after acute myocardial infarction (AMI) with angiotensin converting enzyme (ACE) inhibitors: A randomized control trial

Effect of Angiotensin-Converting Enzyme Inhibitors on Ventricular Remodeling and Survival following Myocardial Infarction

To discuss the effects of angiotensin-converting enzyme (ACE) inhibitors on ventricular remodeling and survival after acute myocardial infarction (AMI). An overview is provided of the pathophysiologic changes produced by AMI and the ventricular remodeling process. ACE inhibitors have been studied for their use in the prevention of ventricular remodeling and reduction in postinfarction mortality. Trials in humans and animals are reviewed, including study methods, results, and limitations. MEDLINE searches identified applicable literature, including experimental trials and review articles. All clinical trials of ACE inhibitors following AMI were reviewed. Morbidity and mortality data evaluating the effect of postinfarction ventricular remodeling are rare. At the time of publication, all available clinical trials studying the effects of ACE inhibitors on postinfarction ventricular remodeling were included, regardless of whether morbidity and mortality were assessed. Data from the Survival and Ventricular Enlargement (SAVE) and Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) trials include almost 10,000 patients. Data were extracted by two independent observers. Data quality and validity were assessed based on sample size, stratification of study population, and statistical power of the studies. ACE inhibitors may prevent the deleterious consequences of AMI, including ventricular remodeling and neurohumoral activation. Ventricular hypertrophy begins acutely following infarction, an early physiologic response to myocardial injury. Hemodynamic benefits from the initial phase of left ventricular hypertrophy include increased ventricular working capacity, normalized systolic wall stress, and maintenance of stroke volume. Although acute dilatation may delay hemodynamic deterioration for six to eight months, it also results in reduced coronary reserve, decreased ventricular compliance, and altered myocardial contractility. With chronic dilatation, the beneficial effects reach a plateau, stroke volume decreases, contractility is reduced, and cardiac failure may ensue. Ventricular hypertrophy is associated with worsened prognosis following infarction and may be the most important single determinant of late prognosis. Ventricular hypertrophy contributes to postinfarction heart failure, angina, and sudden death. Clinical trials show a beneficial effect of the ACE inhibitor captopril on the prevention of left ventricular dysfunction. Although captopril therapy significantly improved survival and myocardial function following AMI in the SAVE trial, these results cannot be generalized to all patient subpopulations. The CONSENSUS II trial demonstrated a decreased survival rate when enalapril was administered within 24 hours of AMI, indicating that timing of therapy may be an important consideration. Captopril therapy may positively affect outcome when initiated 3-16 days following infarction in patients with ejection fractions below 40 percent and who have no signs of ischemia or heart failure. Based on the CONSENSUS II results, enalapril therapy immediately following AMI cannot be recommended. Clinical trials have demonstrated that ACE inhibitors can limit ventricular hypertrophy following AMI, resulting in clinical benefit and improved survival. These effects may be secondary to modulation of neurohumoral activation or the antiischemic effect of ACE inhibitors, which may also reduce the incidence of reinfarction. Early intervention with ACE inhibitors (within 3-16 days of infarction) can slow the progression of cardiovascular disease and improve the survival rate.

Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition

Left ventricular dysfunction can be improved with angiotensin-converting-enzyme inhibition started 1 week after myocardial infarction or later. To see whether earlier intervention may confer greater benefit, a double-blind study was carried out in which 100 patients with Q wave myocardial infarction, but without clinical heart failure, were randomly allocated treatment with captopril 50 mg twice daily or placebo starting 24-48 h after onset of symptoms. Left ventricular volumes were measured regularly during 3 months of treatment and after a 48 h withdrawal period by means of two-dimensional echocardiography. The placebo group showed significant increases in left ventricular end-diastolic (LVEDVI) and end-systolic (LVESVI) volume indices, with the ejection fraction unchanged. By contrast, the captopril group showed a slight but not significant rise in LVEDVI and a significant reduction in LVESVI with ejection fraction increased significantly. At 3 months there was a 4·6% difference in the change in ejection fraction from baseline between the groups (p<0·0001). Most of the treatment benefit was evident at 1 month and there were no changes in left ventricular volumes after 48 h withdrawal of treatment at 3 months. Heart failure requiring treatment with frusemide developed in 7 patients in each group during the study period; 3 of these (1 captopril-treated, 2 placebo-treated) had to be withdrawn from the trial with severe heart failure requiring open treatment. Thus early treatment with captopril is effective in preventing the ventricular dilatation that can occur after Q wave myocardial infarction.

Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat.

To determine whether chronic antihypertensive therapy prevents the progression of cardiac hypertrophy and the deterioration in cardiac performance observed in spontaneously hypertensive rats (SHR) with long-term hypertension, 14-month-old female SHR and normotensive American Wistar rats (NWR) were treated for 10 months with an inhibitor of angiotensin I-converting enzyme, captopril (2 g/liter of drinking water). Captopril reduced the marked left ventricular hypertrophy of 24-month-old SHR (untreated, 4.37 +/- 0.2 mg/g of body weight; treated, 3.01 +/- 0.1 mg/g; P less than 0.02) to levels observed in 6-month-old SHR. Treatment prevented the reductions in baseline and maximal aortic blood flows that occurred in SHR between ages 12 and 24 months yet had no effect on the blood flows of NWR. The diminished maximal stroke volume of untreated SHR was ejected from a significantly increased left ventricular end-diastolic volume, so that the ejection-fraction index was markedly reduced (24-month-old untreated NWR, 84 +/- 3%; untreated SHR, 56 +/- 5%; P less than 0.001). Therapy restores this index in SHR to normal (77 +/- 4%). The relationship between ejection-fraction index, and afterload was also normal in treated SHR. Thus, chronic therapy with captopril produced a marked regression of cardiac hypertrophy and prevented the deterioration of cardiac performance in SHR with long-standing hypertension.