Progressive Left Ventricular Research Articles

Heart Failure and Its Management With β‐Blockade: Potential Applications of Once‐Daily Therapy

Heart failure (HF) due to left ventricular (LV) systolic dysfunction is a progressive disease beginning with a primary injury that activates compensatory cardiovascular mechanisms including varying degrees of neurohormonal activation. Within the neurohormonal cascade, activation of the sympathetic nervous system is in part responsible for ongoing myocardial injury, progressive LV remodeling, and functional deterioration eventually leading to symptomatic HF. Large randomized clinical trials of certain β‐blockers added to standard therapies have shown unequivocal benefits in patients with chronic systolic HF resulting in reduced remodeling, fewer total and cardiovascular deaths, and less risk of hospitalization for worsening HF. Evidence‐based clinical guidelines recommend β‐blockers as part of the regimen for patients with systolic HF as well as LV dysfunction following myocardial infarction. Based on published clinical trial results, bisoprolol, carvedilol, and sustained‐release metoprolol succinate are recommended for systolic HF. Carvedilol, propranolol, and timolol are recommended for post‐myocardial infarction LV dysfunction. Unfortunately, these evidence‐based therapies are often underused in actual practice. Various strategies to increase β‐blocker use in HF have been attempted, including in‐hospital initiation of β‐blocker therapy. Simplifying dosing regimens may also improve adherence to prescribed medications. Use of controlled‐release carvedilol may encourage better adherence in patients with LV dysfunction and help overcome at least one barrier to optimal evidence‐based care.

Genetic Disruption of Angiotensin II Type 1a Receptor Improves Long-Term Survival of Mice With Chronic Severe Aortic Regurgitation

Aortic regurgitation (AR) causes left ventricular (LV) volume overload, leading to progressive LV dilatation and dysfunction. In the present study it was examined whether blockade of angiotensin II type 1 receptor (AT1) could improve survival in cases of chronic severe AR. AR was induced by puncturing the aortic valves of wild-type (WT) and AT1a knockout (KO) mice. Mice that survived for 4 weeks after the operation were deemed to be a model of chronic severe AR and were followed up for 50 weeks (WT, n=29; KO, n=31). Baseline measurements made 4 weeks after surgery showed similar LV cavity and function in both genotypes. These conditions progressively worsened in both genotypes, but 16 weeks after baseline, KO mice showed significantly less LV dilatation, hypertrophy and interstitial fibrosis than WT mice. Cardiac mRNA expression of B-type natriuretic peptide and type I collagen was lower in KO than WT mice. The 50-week mortality rate was significantly lower among KO (45.2%) than WT (86.2%) mice, and postmortem findings indicated that the lower mortality was attributable to a lower incidence of congestive heart failure. In cases of chronic severe AR, blockade of AT1 attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival.

Effects of cardiac patches engineered with bone marrow-derived mononuclear cells and PGCL scaffolds in a rat myocardial infarction model

Little is known about the cardioprotective effects against heart failure (HF), the effects on differentiation of bone marrow-derived mononuclear cell (BMMNC), and the biocompatibility of BMMNC-seeded biodegradable poly-glycolide- co-caprolactone (PGCL) scaffolds in a myocardial infarction (MI) animal model. This study hypothesized that implantation of a BMMNC-seeded PGCL scaffold into the epicardial surface in a rat MI model would be biocompatible, induce BMMNC migration into infarcted myocardium, and effectively improve left ventricular (LV) systolic dysfunction. One week after the implantation of a BMMNC-seeded PGCL scaffold, BMMMC showed migration into the epicardial region. Four weeks after implantation, augmented neovascularization was observed in infarcted areas and in infarct border zones. Some BMMNCs exhibited the presence of α-MHC and troponin I, markers of differentiation into cardiomyocytes. In echocardiographic examinations, BMMNC-seeded PGCL scaffold and non-cell-seeded simple PGCL scaffold groups effectively reduced progressive LV dilatation and preserved LV systolic function as compared to control rat MI groups. Thus, BMMNC-seeded PGCL scaffolding influences BMMNC migration, differentiation to cardiomyocytes, and induction of neovascularization, ultimately effectively lessening LV remodeling and progressive LV systolic dysfunction. PGCL scaffolding can be considered as an effective treatment alternative in MI-induced advanced HF.

Hemodynamic Characteristics and Progression to Heart Failure in Regurgitant Lesions

Mitral and aortic valvular regurgitation are two lesions that share the common denominator of left ventricular (LV) volume overload. Both lesions, in severe cases, can result in progressive LV dilatation, systolic dysfunction, and clinical heart failure in the absence of correction. Despite these similarities, the pathophysiology of LV adaptation to the volume-overload states created by mitral regurgitation (MR) and aortic regurgitation (AR) is distinctly different, as are the clinical sequelae and outcomes. This article reviews the mechanisms of disease, compensation, and eventual decompensation in both disorders.

Goals and guidelines for treating hypertension in a patient with heart failure

Hypertension promotes left ventricular (LV) hypertrophy and myocardial remodeling and is frequently present in patients with systolic or diastolic heart failure. Control of hypertension in both of these settings may attenuate progressive LV hypertrophy and remodeling and improve clinical outcomes. Guidelines for the management of heart failure recommend that hypertension should be treated in all patients with preclinical heart failure as well as in those with heart failure with reduced or preserved LV systolic function. Consistent with national hypertension guidelines, the goal for blood pressure control in hypertensive patients with heart failure is less than 140/90 mm Hg, but lower targets (< 130/80 mm Hg) may be desirable in those with concomitant diabetes mellitus or renal disease. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and beta-adrenoreceptor antagonists are first-line options for hypertension treatment in heart failure. Calcium channel antagonists and the alpha blocker doxazosin should be avoided. Episodes of recurrent pulmonary edema and hypertension may also indicate underlying severe renovascular disease that may respond to percutaneous renal artery intervention.

New Molecular Mechanism in Diastolic Heart Failure

In contrast to systolic heart failure (SHF), for which knowledge of pathophysiology and therapy has advanced rapidly over the past decade, little is known about diastolic heart failure (DHF). The article by van Heerebeek et al1 in this issue of Circulation that describes an abnormal distribution of titin isoforms in DHF may herald a new approach to understanding the pathophysiology of this syndrome. Article p 1966 Recognition of 2 forms of heart failure is not new; almost 70 years ago, Fishberg2 described “those forms of cardiac insufficiency which are due to inadequate diastolic filling of the heart (hypodiastolic failure) [and] the far more common ones in which the heart fills adequately but does not empty to the normal extent (hyposystolic failure)” (p 23). This distinction has stood the test of time, because there is a growing consensus that these 2 clinical syndromes differ in epidemiology, demographics, and origin. Because DHF and SHF represent subgroups of patients with heart failure, they share many clinical features, notably the hemodynamic findings, but it is now clear that they are caused by different pathophysiological mechanisms. Hearts in SHF are characterized by eccentric hypertrophy, progressive left ventricular (LV) dilation, and abnormal LV systolic properties, whereas in DHF, the hearts generally exhibit concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function.3,4 In addition, cardiomyocyte size, shape, and molecular composition differ in these 2 syndromes. Diastolic dysfunction refers to mechanical and functional abnormalities present during relaxation and filling, whereas DHF refers to clinical syndromes in which patients with heart failure have little or no ventricular dilatation and significant, often dominant diastolic dysfunction. Diastolic dysfunction can be quantified with indices of LV pressure decline and filling. Abnormal pressure decline is characterized by decreased peak −dP/dt, prolonged isovolumic time constant (τ), and …

Predictors of Remodeling in the CRT Era: Influence of Mitral Regurgitation, BNP, and Gender

Background We analyzed quantitative echocardiographic data from a large heart failure cohort receiving medical and cardiac resynchronization therapy (CRT) to determine baseline predictors of progressive left ventricular (LV) enlargement. Methods and Results Quantitative echocardiograms were obtained at baseline and after 6 months in 776 outpatients with chronic heart failure who participated in MIRACLE (Multicenter InSync Randomized Clinical Evaluation) and MIRACLE-ICD (Multicenter InSync ICD Randomized Clinical Evaluation). We used multivariable regression to determine clinical, therapeutic, and echocardiographic characteristics that predicted a subsequent change in left ventricular end-diastolic volume (LVEDV). Over 6 months, LVEDV increased in 308 (40%) and decreased in 468 (60%) patients. Baseline mitral regurgitation and levels of plasma brain natriuretic peptide (BNP) independently predicted LV enlargement, whereas CRT predicted a decrease in LVEDV (all P < .01). In all models tested, male gender was an independent risk factor for progressive LV enlargement ( P < .0001). Conclusion Men show more prominent LV dilation than women in chronic heart failure despite medical and device therapy. Rates of LV remodeling are influenced further by mitral regurgitation, plasma BNP, and CRT. Future studies should take these clinical factors into account when determining the influence of genetic factors and novel therapies on ventricular remodeling in chronic heart failure.

Sustained augmentation of cardiac α1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes

We previously reported that transgenic (TG) mice with cardiac-restricted alpha(1A)-adrenergic receptor (alpha(1A)-AR)-overexpression showed enhanced contractility, but no hypertrophy. Since chronic inotropic enhancement may be deleterious, we investigated if long-term, cardiac function and longevity are compromised. alpha(1A)-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dt(max): 14,567+/-603 to 11,610+/-915 mmHg/s, P<0.05, A1A1 line: 170-fold overexpression; and 13,625+/-826 to 8322+/-682 mmHg/s, respectively, P<0.05, A1A4 line: 112-fold overexpression, at 2 and 6 months, respectively). Both TG lines developed LV fibrosis, but not LV dilatation or hypertrophy, despite activation of hypertrophic signaling pathways. Microarray and real time RT-PCR analyses revealed activation of matricellular protein genes, including those for thrombospondin 1, connective tissue growth factor and tenascin C, but not transforming growth factor beta1. Life-span was markedly shortened (mean age at death: 155 days, A1A1 line; 224 days, A1A4 line compared with NTLs: >300 days). Telemetric electrocardiography revealed that death in the alpha(1A)-AR TG mice was due to cardiac standstill preceded by a progressive diminution in QRS amplitude, but not by arrhythmias. The QRS changes and sudden death could be mimicked by alpha(1)-AR activation, and reversed preterminally by alpha(1)-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac alpha(1A)-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes. To our knowledge this is the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.

Histone Acetyltransferase Activity of p300 Is Required for the Promotion of Left Ventricular Remodeling After Myocardial Infarction in Adult Mice In Vivo

Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4-dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this. These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.

Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction

Section 5: Management of Asymptomatic Patients With Reduced Left Ventricular Ejection Fraction

Differential right and left ventricular diastolic tolerance to acute afterload and NCX gene expression in Wistar rats

This study evaluated right ventricular (RV) and left ventricular (LV) diastolic tolerance to afterload and SERCA2a, phospholamban and sodium-calcium exchanger (NCX) gene expression in Wistar rats. Time constant tau and end diastolic pressure-dimension relation (EDPDR) were analyzed in response to progressive RV or LV afterload elevations, induced by beat-to-beat pulmonary trunk or aortic root constrictions, respectively. Afterload elevations decreased LV- tau, but increased RV-tau. Whereas LV- tau analyzed the major course of pressure fall, RV- tau only assessed the last fourth. Furthermore, RV afterload elevations progressively upward shifted RV EDPDR, whilst LV afterload elevations did not change LV-EDPDR. SERCA2a and phospholamban mRNA were similar in both ventricles. NCX-mRNA was almost 50 % lower in RV than in LV. Left ventricular afterload elevations, therefore, accelerated the pressure fall and did not induce diastolic dysfunction, indicating high LV diastolic tolerance to afterload. On the contrary, RV afterload elevations decelerated the late RV pressure fall and induced diastolic dysfunction, indicating small RV diastolic tolerance to afterload. These results support previous findings relating NCX with late Ca(2+) reuptake, late relaxation and diastolic dysfunction.

Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

Growing evidence suggests that thyroid dysfunction may contribute to progression of cardiac disease to heart failure. We investigated the effects of a therapeutic dose of thyroid hormones (TH) on cardiomyopathic (CM) hamsters from 4 to 6 mo of age. CM hamsters had subclinical hypothyroidism (normal thyroxine, elevated TSH). Left ventricular (LV) function was determined by echocardiography and hemodynamics. Whole tissue pathology and isolated myocyte size and number were assessed. TH treatment prevented the decline in heart rate and rate of LV pressure increase and improved LV ejection fraction. The percentage of fibrosis/necrosis in untreated 4-mo-old CM (4CM; 15.5 +/- 2.2%) and 6-mo-old CM (6CM; 21.5 +/- 2.4%) hamsters was pronounced and was reversed in treated CM (TCM; 11.9 +/- 0.9%) hamsters. Total ventricular myocyte number was the same between 4- and 6-mo-old controls but was reduced by 30% in 4CM and 43% in 6CM hamsters. TH treatment completely prevented further loss of myocytes in TCM hamsters. Compared with age-matched controls, resting and maximum coronary blood flow was impaired in 4CM and 6CM hamsters. Blood flow was completely normalized by TH treatment. We conclude that TH treatment of CM hamsters with subclinical hypothyroidism normalized impaired coronary blood flow, which prevented the decline in LV function and loss of myocytes.

Changes in Ventricular Size and Function in Patients Treated With Valsartan, Captopril, or Both After Myocardial Infarction

Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone. Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates. Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.

Global Left Ventricular Remodeling with the Acorn Cardiac Support Device: Hemodynamic and Angiographic Findings in Dogs with Heart Failure

Preventing progressive left ventricular (LV) remodeling is paramount in the treatment of heart failure. In recent years, several surgical approaches have been implemented with the objective of improving LV function through amelioration of progressive LV remodeling. These included surgical reduction of LV size, the so-called Batista procedure, dynamic cardiomyoplasty and mitral valve repair to limit or eliminate functional mitral regurgitation. While the Batista procedure and dynamic cardiomyoplasty have for all practical purposes been abandoned, the lessons learned from these procedures gave rise to a new generation of devices aimed at preventing progressive LV dilation and restoring LV shape by passive mechanical containment of the failing LV. One such device is the Acorn Cardiac Support Device (CSD) or the CorCap. Studies in dogs with intracoronary microembolization-induced moderate and advanced heart failure have shown that long-term monotherapy with the CSD not only prevents progressive LV dilation but, in effect, partially reverses this phenotype. These studies have also shown that the CSD restores, albeit in part, progressive LV chamber sphericity and attenuates functional mitral regurgitation. These benefits were accompanied by improvement in global LV function along with improvements of remodeling at the cellular level. The findings were largely responsible for initiating safety and feasibility clinical trials with the CSD and ultimately, the initiation of the Acorn efficacy trial that was completed in 2004. This review will focus on studies conducted in dogs with heart failure and, specifically on hemodynamic, angiographic and echocardiographic results from these studies that provided support for the CSD as a successful technology targeting "reverse LV remodeling" for the treatment of heart failure.

Reversal of Maladaptive Gene Program in Left Ventricular Myocardium of Dogs with Heart Failure Following Long-Term Therapy with the Acorn Cardiac Support Device

Progressive left ventricular (LV) dilation is a characteristic feature of heart failure and is associated with poor long-term prognosis. One of the characteristic changes that occur in the failing heart is a change in gene expression wherein fetal genes that were turned off shortly after birth are re-activated in heart failure and may play a key role in the progressive worsening of the heart failure state. This review discusses reversal of maladaptive gene expression in dogs with chronic heart failure treated long-term with the Acorn Cardiac Support Device (CSD); a passive mechanical device designed to prevent progressive LV enlargement and to restore normal LV chamber geometry. Studies in our laboratories have shown that, in addition to preventing LV dilation and improving LV ejection fraction, long-term therapy with the CSD reverses the maladaptive gene program observed in LV myocardium of dogs with heart failure. Therapy with the CSD was associated with up-regulated mRNA expression for alpha-myosin heavy chain and down-regulated mRNA expression of A- and B- type natriuretic peptides, cytokines and favorably modulated cytoskeletal proteins. These findings provide an explanation for mechanisms that may be partly responsible for the improvement in LV systolic and diastolic function seen in dogs with heart failure after long-term CSD therapy.

Left Ventricular Histomorphometric Findings in Dogs with Heart Failure Treated with the Acorn Cardiac Support Device

Progressive left ventricular (LV) dilation in the setting of heart failure is associated with increased mortality and morbidity. The Acorn Cardiac Support Device (CSD, Acorn Cardiovascular, Inc., St. Paul, MN) is a preformed polyester device that is surgically placed over the cardiac ventricles, anchored to the AV-groove and tailored anteriorly to fit snugly over the epicardial surface of the heart. The CSD was shown to prevent progressive LV enlargement and, indeed, reduce LV size and attenuate global LV remodeling in both animal models of experimentally-induced heart failure as well as in patients with advanced heart failure. This review will examine the CSD from two histologic perspectives namely, (1) the interaction of the CSD with the epicardial surface of the heart and (2) the effects of long-term therapy with the CSD on cellular remodeling. The review will be based on available pre-clinical data generated in dogs with coronary microembolization-induced heart failure that underwent long-term (3 and 6 months) monotherapy with the CSD. The data will show that long-term implantation leads to encapsulation of the CSD by connective tissue that matures with time and that does not invade the underlying myocardium. Furthermore that implantation of the CSD has no adverse impact on epicardial coronary vessel. At the cellular level, existing data will show that long-term monotherapy with the CSD is associated with reduced cardiomyocyte hypertrophy, reduced volume fraction of replacement and interstitial fibrosis, normalization of capillary density and oxygen diffusion distance and attenuation of cardiomyocyte apoptosis. The outcomes strongly argue in favor of a structural modification of the failing myocardium by CSD therapy that is consistent with "reverse cellular remodeling".

Isolated Left Ventricular Noncompaction of the Myocardium as a Cause of Embolic Superior Mesenteric Artery Occlusion

Isolated noncompaction of the left ventricular (LV) myocardium is a rare congenital disorder resulting from an arrest of the compaction process of the myocardial trabeculae during normal embryogenesis. It is characterized by the presence of prominent LV myocardial trabeculations and deep intertrabecular recesses that are in continuity with the LV cavity. The most common clinical presentation includes progressive LV dysfunction, life-threatening tachyarrhythmias, and the risk for severe cardioembolic events. We describe a case where isolated noncompaction of the LV myocardium was diagnosed after an embolic occlusion of the superior mesenteric artery in a 40-year-old Caucasian woman.

Cardiac Changes Associated With Growth Hormone Therapy Among Children Treated With Anthracyclines

The objective was to assess the cardiac effects of growth hormone (GH) therapy. Anthracycline-treated childhood cancer survivors frequently have reduced left ventricular (LV) wall thickness and contractility, and GH therapy may affect these factors. We examined serial cardiac findings for 34 anthracycline-treated childhood cancer survivors with several years of GH therapy and baseline cardiac z scores similar to those of a comparison group (86 similar cancer survivors without GH therapy). LV contractility was decreased among GH-treated patients before, during, and after GH therapy (-1.08 SD below the age-adjusted population mean before therapy and -1.88 SD 4 years after therapy ceased, with each value depressed below normal). Contractility was higher in the control group than in the GH-treated group, with this difference being nearly significant. The GH-treated children had thinner LV walls before GH therapy (-1.38 SD). Wall thickness increased during GH therapy (from -1.38 SD to -1.09 SD after 3 years of GH therapy), but the effect was lost shortly after GH therapy ended and thickness diminished over time (-1.50 SD at 1 year after therapy and -1.96 SD at 4 years). During GH therapy, the wall thickness for the GH-treated group was greater than that for the control group; however, by 4 years after therapy, there was no difference between the GH-treated group and the control group. GH therapy among anthracycline-treated survivors of childhood cancer increased LV wall thickness, but the effect was lost after therapy was discontinued. The therapy did not affect the progressive LV dysfunction.

A novel model of cryoinjury-induced myocardial infarction in the mouse: a comparison with coronary artery ligation

Mouse myocardial infarction (MI) models are frequently used research tools. The most commonly applied model is coronary artery ligation. However, coronary ligation often gives rise to apical aneurysmatic infarcts of variable size. Other infarct models include cryoinfarction, which produces reproducible infarcts of the anterior wall. Thus far, this model has not been extensively described in mice. Therefore, we developed a murine cryoinfarction model and compared it with coronary ligation. Studies were performed under isoflurane anesthesia with a follow-up of 4 and 8 wk. Cryoinfarction was induced using a 2- or 3-mm cryoprobe. Two-dimensional guided M-mode echocardiography was used to assess fractional shortening and left ventricular (LV) dimensions at baseline and end point. At end point, hemodynamics were assessed using a 1.4-Fr Millar catheter. Pressure-diameter relations were constructed by combining echocardiography and hemodynamic data. Histological and morphometric analyses of infarct and remote areas were performed. At 4 wk, 3-mm cryoinfarction resulted in decreased LV fractional shortening as well as decreased global LV contractility and relaxation, which was comparable with coronary ligation. No adverse remodeling was observed at this time point, in contrast with the ligation model. However, progressive LV remodeling occured between 4 and 8 wk after cryoinfarction with a further decline in hemodynamic parameters and LV pump function. Histologically, cryoinfarction resulted in highly reproducible, transmural, cone-shaped infarcts with reperfusion at the macrovascular level. These results indicate that the cryoinfarction model represents the anterior myocardial infarct with modest adverse remodeling and may thus be representative for infarcts encountered in clinical practice.

Distinct Upregulation of Extracellular Matrix Genes in Transition From Hypertrophy to Hypertensive Heart Failure

Cardiac hypertrophy in response to pressure overload is initially beneficial but eventually leads to heart failure, a major cause of morbidity and mortality in the Western countries. Although abnormalities in left ventricular (LV) diastolic filling are early features associated with pressure overload-induced LV hypertrophy, the molecular mechanisms regulating transition to diastolic heart failure are poorly understood. We analyzed global changes in gene expression in 12-, 16-, and 20-month-old spontaneously hypertensive rats (SHR) and their age-matched controls, Wistar Kyoto rats, using DNA microarrays. In SHR, a progressive LV hypertrophy was associated with increased expression of hypertrophy-associated genes including contractile protein and natriuretic peptide genes. Echocardiography indicated that 16-month-old SHR had features of diastolic dysfunction leading to diastolic failure at age 20 months without significant changes in LV systolic function. Comparison analysis revealed that the extracellular matrix genes strikingly dominated the list of altered genes after transition to the heart failure, whereas there was no major shift in gene expression patterns involved in calcium homeostasis and neurohumoral activation, as well as myofilament contractile and cytoskeletal proteins. The microarray analysis also revealed differential gene expression of several novel factors, such as thrombospondin-4 and matrix Gla protein, as well as unknown expressed sequence tags. Our data show that transition from LV hypertrophy to diastolic hypertensive heart failure is almost exclusively associated with progressive remodeling of the extracellular matrix and provide new insights into the pathogenesis of hypertrophy by suggesting existence of novel regulators of LV remodeling.