Left Ventricular Structural Remodeling Research Articles

Pleiotropic Effects of Long-Term Monotherapy with Rosuvastatin in Dogs with Moderate Heart Failure

Objective: The objective of this study was to investigate the potential pleiotropic effects of rosuvastatin (RSV) in the left ventricular (LV) myocardium of dogs with moderate heart failure (HF). Methods: LV tissue was obtained from HF dogs randomized to 3 months therapy with low-dose RSV (n = 7), high-dose RSV (n = 7) or to no therapy (Control, n = 7) and from 7 normal dogs. mRNA and protein expression of prohypertrophic mediator NGFI-A binding protein 1 (Nab1), phosphatase and tensin homolog (PTEN), phosphoinositide-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) were measured, as well as that of proinflammatory cytokine interleukin-6 (IL-6), bone marrow-derived stem cell markers cKit and Sca1, vascular endothelial and fibroblast growth factors (VEGF and FGF) and nitric oxide synthase (NOS) isoforms. Results: Nab1, PTEN, PI3K, mTOR and IL-6 increased in the controls. High-dose RSV reduced expression of Nab1, PTEN, PI3K, mTOR and IL-6 to near-normal levels. cKit and Sca1 significantly increased, while VEGF and FGF decreased in the controls compared to the normal dogs. RSV therapy further increased expression of cKit, Sca1, VEGF and FGF. High-dose RSV normalized the expression of NOS isoforms. Conclusion: These pleiotropic effects of RSV may account, in part, for the observed beneficial effect of RSV on LV function and structural remodeling.

Analysis of left ventricular remodelling in patients treated with cardiac resynchronisation therapy

ObjectiveMatrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors...

Relationship Between the Temporal Profile of Plasma microRNA and Left Ventricular Remodeling in Patients After Myocardial Infarction

microRNAs (miRs) are small noncoding RNAs that recognize and bind to mRNAs and inhibit protein translation or degrade mRNA. Studies in animal models have suggested that miRs play a translational or posttranslational regulatory role in myocardial growth, fibrosis, viability, and remodeling. However, whether specific temporal changes in miRs occur in patients during the left ventricular (LV) remodeling process that follows a myocardial infarction (post-MI) remains unknown. The current pilot study tested the hypotheses that plasma miRs could be reliably measured in post-MI patients and that there is a relationship between temporal changes in specific miRs and post-MI LV structural remodeling. LV end-diastolic volume (echocardiography) and plasma miR were measured in age-matched referent controls (CTLs, n=12) and post-MI patients (n=12) from day 2 through day 90 post-MI. Selected miRs (miR-1, miR-21, miR-29a, miR-133a, and miR-208) were measured using quantitative reverse transcription-polymerase chain reaction and normalized for endogenous small nuclear RNA U6. After MI, LV end-diastolic volume increased progressively compared with CTL; this was accompanied by time-dependent changes in specific miRs. For example, miR-21 initially decreased 2 days post-MI (0.3 ± 0.1-fold versus CTL; P<0.05), increased 5 days post-MI (2 ± 1-fold versus CTL; P<0.05), and returned to CTL values at later post-MI time points. In contrast, miR-29a increased 5 days post-MI (4 ± 1-fold versus CTL; P<0.05) and then decreased to CTL at later time points. miR-208 increased 5 days post-MI (3 ± 1-fold versus CTL; P<0.05) and remained elevated up to 90 days post-MI. A time-dependent change in miRs occurred in post-MI patients, including an early and robust increase in miRs that has affected myocardial growth, fibrosis, and viability. Thus, serially profiling miRs in the plasma of post-MI patients may hold both mechanistic and prognostic significance.

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.

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

It is uncertain if downregulation of β-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400μgkg(-1)h(-1) over 16days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute β-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G(sα)) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G(iα2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G(sα)-protein expression.

Risk Stratification and Serious Ventricular Arrhythmias: The Importance of Left Ventricular Hypertrophic Remodeling in Patients with Depressed Ejection Fraction

Previous studies indicate an association between ventricular arrhythmias and left ventricular (LV) structural and functional remodeling. There has been emphasis on LV systolic dysfunction, yet little is known about LV structural remodeling and arrhythmias. Accordingly, we studied the extent of LV hypertrophy (LVH) as well as the patterns of hypertrophic remodeling and their relation to ventricular tachycardia/fibrillation (VT/VF) in patients with depressed ejection fraction (EF) and an implantable cardioverter-defibrillator (ICD). Of 565 patients who underwent implantation of a single or dual chamber ICD between 2006 and 2009, 127 had echocardiographic evidence of LV dysfunction and were followed in our device clinic. Standard echocardiographic Methods were used. LVH was defined as mass > 95 g/m2 in women and > 115 g/m2 in men. A relative wall thickness partition value of 0.42 was used to differentiate concentric vs. eccentric geometry. Serious ventricular arrhythmias were defined as VT/VF requiring anti-tachycardia pacing and/or ICD discharge. This diagnosis was made and confirmed by ICD interrogation and medical record review. Data are mean +/- SD. In the 127 patients, VT/VF occurred in 29 (23%). The average EF was 29 +/- 9%, LV mass was 115 +/- 33 g/m2, and LV end-diastolic dimension was 58 +/- 8 mm. The average age was 66 +/- 13 years; 78% were male. Clinical characteristics: hypertension: 69%, NYHA functional class I/II: 87%, diabetes: 31%, atrial fibrillation: 34%. VT/VF was significantly more prevalent in the 60 patients with LVH vs. 67 patients with normal LV mass (37% vs. 10%; p=0.0006). There was a trend towards more VT/VF in patients with LV enlargement vs. those with normal LV size (30% vs. 17%; p=ns), and in patients with eccentric hypertrophy vs. those with concentric remodeling/hypertrophy (38% vs. 20%; p=ns). There was no significant difference in clinical characteristics, indication for ICD, ischemic etiology, cardiac medications, and EF in patients with and without VT/VF. In patients with LV systolic dysfunction, we found a significant relationship between serious ventricular arrhythmias requiring device therapy and LVH. There was a trend towards more VT/VF in patients with LV enlargement and/or eccentric hypertrophy vs. those with concentric remodeling/hypertrophy. These data provide a rationale for improving risk stratification of patients with LV systolic dysfunction.

Changing Characteristics and Mode of Death Associated With Chronic Heart Failure Caused by Left Ventricular Systolic Dysfunction

Background— Therapies for patients with chronic heart failure caused by left ventricular systolic dysfunction have advanced substantially over recent decades. The cumulative effect of these therapies on mortality, mode of death, symptoms, and clinical characteristics has yet to be defined. Methods and Results— This study was a comparison of 2 prospective cohort studies of outpatients with chronic heart failure caused by left ventricular systolic dysfunction performed between 1993 and 1995 (historic cohort: n=281) and 2006 and 2009 (contemporary cohort: n=357). In the historic cohort, 83% were prescribed angiotensin-converting enzyme inhibitors and 8.5% were prescribed β-adrenoceptor antagonists, compared with 89% and 80%, respectively, in the contemporary cohort. Mortality rates over the first year of follow-up declined from 12.5% to 7.8% between eras ( P =0.04), and sudden death contributed less to contemporary mortality (33.6% versus 12.7%; P &lt;0.001). New York Heart Association class declined between eras ( P &lt;0.001). QTc dispersion across the chest leads declined from 85 ms (SD, 2) to 34 ms (SD, 1) and left ventricular end-diastolic dimensions declined from 65 mm (SD, 0.6) to 59 mm (SD, 0.5) (both P &lt;0.001). Conclusions— Survival has significantly improved in patients with chronic heart failure caused by left ventricular systolic dysfunction over the past 15 years; furthermore, sudden death makes a much smaller contribution to mortality, and noncardiac mortality is a correspondingly greater contribution. This has been accompanied by an improvement in symptoms and some markers of adverse electric and structural left ventricular remodeling.

Rapid changes in genes regulating cardiac remodeling following reversal of LV volume overload

Molecular changes involved in cardiac remodeling following reversal of volume overload are relatively unknown. This study evaluated the expression of genes known to regulate cardiac remodeling following acute reversal of volume overload-induced heart failure. Methods Sprague-Dawley rats underwent sham/aortocaval fistula (ACF) surgery to induce volume overload heart failure for 4 wks (compensatory stage), followed by a reversal procedure in a subset of sham and ACF rats. Left ventricular (LV) structure and function were studied at 2–5d post-reversal by echocardiography while gene expression profiling was studied by qRT-PCR. Results At 5d post-reversal, increased LV end-diastolic dimension in ACF was normalized. Fractional shortening was reduced both in ACF and ACF+Rev compared to that of sham. Increased gene expression of proteins involved in extracellular matrix remodeling (collagen1a1, collagen3a1, elastin, periostin, TIMP-1 and TIMP-2) in ACF was normalized by reversal. On the other hand, hypertrophic marker β-myosin heavy chain was elevated by reversal compared to sham and ACF, while the expression of genes involved in excitation contraction coupling (b1-Adrenergic receptor and SERCA2) were decreased in ACF. Conclusion These results reveal multiple gene changes following hemodynamic reversal, suggesting a role in reverse LV structural and functional remodeling.

Plasma tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1): an independent predictor of poor response to cardiac resynchronization therapy

AimsMatrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT).Methods and resultsA cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy responders were defined as patients who survived, were not transplanted, and increased their basal 6 min walking distance test (6MWDT) by ≥10% or improved their NYHA functional class. Overall, 25 patients (60%) were classed as responders. At 12-month follow-up, six patients (14.2%) had died and one (2.4%) patient had been transplanted. Compared with responders, non-responders had higher levels of TIMP-1 (277 ± 59 vs. 216 ± 46 ng/mL, P = 0.001), MMP-2 (325 ± 115 vs. 258 ± 56 ng/mL, P = 0.02), and creatinine (1.76 ± 0.8 vs. 1.25 ± 0.3 mg/dL, P = 0.01). In a multivariate analysis, TIMP-1 was the only independent predictor of non-response to CRT [OR 0.97, 95% (CI 0.96–0.99) P = 0.005]. TIMP-1≥248 ng/mL predicted non-response with 71% sensitivity and 72% specificity.ConclusionTIMP-1 is an independent predictor of non-response in patients treated with CRT.

IL-10 Inhibits Inflammation and Attenuates Left Ventricular Remodeling After Myocardial Infarction via Activation of STAT3 and Suppression of HuR

Persistent inflammatory response has adverse effects on left ventricular (LV) function and remodeling following acute myocardial infarction. We hypothesized that suppression of inflammation with interleukin (IL)-10 treatment attenuates LV dysfunction and remodeling after acute myocardial infarction. After the induction of acute myocardial infarction, mice were treated with either saline or recombinant IL-10, and inflammatory response and LV functional and structural remodeling changes were evaluated. IL-10 significantly suppressed infiltration of inflammatory cells and expression of proinflammatory cytokines in the myocardium. These changes were associated with IL-10-mediated inhibition of p38 mitogen-activated protein kinase activation and repression of the cytokine mRNA-stabilizing protein HuR. IL-10 treatment significantly improved LV functions, reduced infarct size, and attenuated infarct wall thinning. Myocardial infarction-induced increase in matrix metalloproteinase (MMP)-9 expression and activity was associated with increased fibrosis, whereas IL-10 treatment reduced both MMP-9 activity and fibrosis. Small interfering RNA knockdown of HuR mimicked IL-10-mediated reduction in MMP-9 expression and activity in NIH3T3 cells. Moreover, IL-10 treatment significantly increased capillary density in the infarcted myocardium which was associated with enhanced STAT3 phosphorylation. Taken together, our studies demonstrate that IL-10 suppresses inflammatory response and contributes to improved LV function and remodeling by inhibiting fibrosis via suppression of HuR/MMP-9 and by enhancing capillary density through activation of STAT3.

MR study of the effect of infarct size and location on left ventricular functional and microstructural alterations in porcine models

To investigate the effect of infarct size and location on left ventricular (LV) functional and microstructural alterations in well-established porcine models. Myocardium infarction was induced in mini-pigs at apical septum (Group 1, n = 6) or basal lateral wall (Group 2, n = 6) by permanent occlusion of the left anterior descending or left circumflex coronary artery, respectively. In vivo cardiac magnetic resonance (CMR) was performed 4 and 13 weeks later. Hearts were then excised and examined by ex vivo diffusion tensor imaging (DTI) for myocardium structural changes in infarct, adjacent and remote regions. LV ejection fractions correlated negatively with infarct sizes. Between week 4 and 13, Group 1 exhibited more changes in end-systolic volume, LV mass, and ejection fraction, although it showed a smaller infarct volume percentage. Ex vivo results revealed the decreased water diffusion fractional anisotropy and increased diffusivities in infarct region in correlation with infarct size, but with no significant difference between the two groups. However, LV myocardial double-helical fiber architecture was found to alter in Group 1, shifting more towards left-handed direction as compared to controls. Postinfarct LV functional and structural remodeling is affected by both infarct size and location.

Short-term electrophysiological effects of losartan, bisoprolol, amlodipine, and hydrochlorothiazide in hypertensive men

Background and aim. Hypertension-induced left ventricular structural remodelling associates with repolarization abnormalities. We investigated if antihypertensive drugs can modulate ventricular repolarization.Methods. A total of 183 hypertensive men received for 4 weeks drugs (losartan 50 mg, bisoprolol 5 mg, amlodipine 5 mg, hydrochlorothiazide (HCTZ) 25 mg) in a randomized order, separated by 4-week placebo periods. Electrocardiograms (ECG) were recorded at the end of placebo and drug periods. Measurements of repolarization duration (QT intervals), repolarization heterogeneity (T-wave peak to T-wave end (TPE) intervals), and T-wave morphology (T-wave principal component analysis (PCA) ratio, T-wave morphology dispersion (TMD), and total cosine R-to-T (TCRT)) during each drug were compared to placebo measurements.Results. Losartan and bisoprolol shortened maximum and mean rate-adjusted QT intervals as well as mean TPE interval, decreased TMD, and increased TCRT. Losartan also shortened precordial maximum TPE interval and decreased PCA ratio. Amlodipine had no repolarization effects, whereas HCTZ prolonged precordial maximum TPE interval and mean TPE interval.Conclusion. Losartan and bisoprolol have beneficial short-term ECG repolarization effects. Amlodipine seems to have no repolarization effects. HCTZ seems to prolong the ECG TPE interval, potentially reflecting increased repolarization heterogeneity. These findings show that antihypertensive drugs may relatively rapidly and treatment-specifically modulate ECG markers of ventricular repolarization.

Inhibition of matrix metalloproteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction

Osteopontin (OPN) plays an important role in left ventricular (LV) remodeling after myocardial infarction (MI) by promoting collagen synthesis and accumulation. This study tested the hypothesis that MMP inhibition modulates post-MI LV remodeling in mice lacking OPN. Wild-type (WT) and OPN knockout (KO) mice were treated daily with MMP inhibitor (PD166793, 30 mg/kg/day) starting 3 days post-MI. LV functional and structural remodeling was measured 14 days post-MI. Infarct size was similar in WT and KO groups with or without MMP inhibition. M-mode echocardiography showed greater increase in LV end-diastolic (LVEDD) and end-systolic diameters (LVESD) and decrease in percent fractional shortening (%FS) and ejection fraction in KO-MI versus WT-MI. MMP inhibition decreased LVEDD and LVESD, and increased %FS in both groups. Interestingly, the effect was more pronounced in KO-MI group versus WT-MI (P < 0.01). MMP inhibition significantly decreased post-MI LV dilation in KO-MI group as measured by Langendorff-perfusion analysis. MMP inhibition improved LV developed pressures in both MI groups. However, the improvement was significantly higher in KO-MI group versus WT-MI (P < 0.05). MMP inhibition increased heart weight-to-body weight ratio, myocyte cross-sectional area, fibrosis and septal wall thickness only in KO-MI. Percent apoptotic myocytes in the non-infarct area was not different between the treatment groups. Expression and activity of MMP-2 and MMP-9 in the non-infarct area was higher in KO-MI group 3 days post-MI. MMP inhibition reduced MMP-2 activity in KO-MI with no effect on the expression of TIMP-2 and TIMP-4 14 days post-MI. Thus, activation of MMPs contributes to reduced fibrosis and LV dysfunction in mice lacking OPN.

In Search of a Holy Grail

“It came out of nowhere and captured the cardiology community by storm.” The cliche seems very appropriate when describing the impact of cardiac resynchronization therapy (CRT) on the treatment of heart failure. CRT improves survival rate in symptomatic patients 1 and is the only nonsurgical technique that provides substantial and stable reverse remodeling in both symptomatic and asymptomatic patients.2,3 The most surprising fact is that this is accomplished through mechanisms that are still unclear and that are not fully elucidated in experimental models. CRT is the only heart failure therapy with a potential to improve survival rate that is not based on neurohormonal modulation. Finally, it represents a challenge to the imaging community, as it establishes a need to measure something that was previously overlooked—dyssynchrony. Article see p 14 Unfortunately, CRT is not universally successful. One third of CRT patients do not feel better,4 and close to 40% of patients do not experience reverse remodeling, which is important because it predicts survival rate.5 This should not be a surprise—treatment of chronic diseases is rarely homogenously beneficial to all the patients. Nevertheless, in the case of CRT, some extra precautions are necessary. CRT is expensive; placement of electrodes may be difficult; and, even in experienced centers, a significant number of patients may require surgical placement. Finally, it is an expensive, healthcare-intensive therapy with extensive follow-up and occasional complications. Thus, there is an ongoing search for practical methods to predict the outcome of CRT and guide its use. Current guidelines use QRS duration (and symptoms) as the principal determinants for implantation, and as noted, this is fairly successful, with two thirds of such patients demonstrating improvement. The real challenge for clinicians comes in two situations: identifying those patients with narrow QRS who are …

Patterns of Structural and Functional Remodeling of the Left Ventricle in Chronic Heart Failure

Patients with heart failure show a wide variety of alterations in left ventricular (LV) volume, mass, and function. The purpose of this study was to define the common patterns of LV structural and functional remodeling and consider their clinical implications in patients with chronic heart failure. Two-dimensional echocardiograms obtained during the screening phase of a study involving patients (n = 315) with chronic heart failure were used to calculate LV volume, mass, geometry, and ejection fraction (EF). Inclusion required the diagnosis of heart failure in symptomatic patients on medical therapy. Measures of LV size or function were not used as inclusion or exclusion criteria. Plots of EF against LV end-diastolic volume (EDV) showing an inverse curvilinear relation allowed a description of 4 remodeling patterns. Pattern A (n = 66) was defined as normal EDV (<91 ml/m(2)) and normal EF (> or =50%); 65% of these patients showed LV hypertrophy or concentric remodeling. Pattern B (n = 65) was defined as normal EDV and depressed EF; hypertrophy or concentric remodeling was present in 63%. Pattern C (n = 175) was defined as increased EDV and depressed EF; eccentric hypertrophy was present in 94%. Pattern D (n = 9) was defined as increased EDV and normal EF; eccentric hypertrophy was present in 88%. In conclusion, these patterns of remodeling encompass a wide spectrum of geometric changes with different clinical and pathophysiologic features and possibly different management strategies.

Reverse of Left Ventricular Volumetric and Structural Remodeling in Heart Failure Patients Treated With Cardiac Resynchronization Therapy

Patients with heart failure and mechanical dyssynchrony suffer a progressive increase in left ventricular (LV) mass and asymmetrical regional hypertrophy with eventual poor prognosis. The present study sought to investigate whether cardiac resynchronization therapy (CRT) could reverse these abnormalities. The study included 66 consecutive heart failure patients who received CRT. All patients underwent serial evaluation before, 3 months after, and 12 months after CRT. At 12 months after CRT, 50 patients (76%) were echocardiographic volumetric responders, defined as a >15% reduction in LV end-systolic volume. LV end-systolic volume was decreased from 214 +/- 97 ml to 179 +/- 88 ml at 3 months and was further decreased to 158 +/- 86 ml at 12 months after CRT (all p <0.01). LV ejection fraction was improved from 18% +/- 4% to 28% +/- 7% (p <0.001) at 3 months without further change at 12 months after CRT. LV mass was reduced from 242 +/- 52 g to 222 +/- 45 g at 3 months and was further reduced to 206 +/- 50 g at 12 months after CRT (all p <0.01). Improvement of LV geometry was seen as improvements of the end-diastolic (1.64 +/- 0.14 vs 1.77 +/- 0.17, p <0.001) and the end-systolic (1.63 +/- 0.14 vs 1.99 +/- 0.22, p <0.001) sphericity indexes, respectively, at 3 months, without further significant changes at 12 months after CRT. Volumetric responders had a reduction in LV mass from 240 +/- 50 to 210 +/- 38 at 3 months, and LV mass was further reduced to 186 +/- 37 g at 12 months after CRT (all p <0.01). In contrast, nonresponders had a progressive increase in LV mass from 248 +/- 59 g to 258 +/- 54 g at 3 months, and LV mass was further increased to 269 +/- 60 g at 12 months after CRT (all p <0.05). Likewise, only in volumetric responders, regression of the asymmetric hypertrophy of the lateral wall was noted. In conclusion, CRT results in not only volumetric improvement but also in true reverse LV structural remodeling, evidenced by progressive reduction in LV mass and restoration of regional wall symmetry.

P322 Evaluation of the short-term effect of cardiac resynchronization therapy to reserve left ventricular structural remodeling in congestive cardiac failure patients by echocardiography

P322 Evaluation of the short-term effect of cardiac resynchronization therapy to reserve left ventricular structural remodeling in congestive cardiac failure patients by echocardiography

Borderzone Contractile Dysfunction Is Transiently Attenuated and Left Ventricular Structural Remodeling Is Markedly Reduced Following Reperfused Myocardial Infarction in Inducible Nitric Oxide Synthase Knockout Mice

We sought to determine the effect of inducible nitric oxide synthase (iNOS) expression on regional contractile function and left ventricular (LV) remodeling after reperfused myocardial infarction (MI). Inducible nitric oxide synthase is known to contribute to global LV dysfunction after a large MI, but the mechanisms underlying this dysfunction remain unclear. We used immunohistochemistry to investigate the distribution of iNOS expression in wild-type (WT) and iNOS knockout (KO) mice early (day 1) and late (day 28) after reperfused MI. We also used serial cardiac magnetic resonance imaging at baseline and at 1, 7, and 28 days after MI to assess LV volumes, ejection fraction (EF), regional circumferential strain (E(cc)), and day 1 infarct size. At baseline, LV volumes and EF were similar between groups. Day 1 infarct size was also similar between groups. Immunohistochemistry revealed that iNOS expression was abundant throughout the heart in WT mice on day 1 after MI, particularly near the infarct borderzone. On day 7 after MI, E(cc) in KO mice was significantly improved in some borderzone sectors compared with WT. The LV volumes were significantly lower in KO mice at days 7 and 28 compared with WT. The EF on days 7 and 28 was significantly higher in KO mice compared with WT. The circumferential extent of wall thinning was also significantly reduced in KO versus WT mice at days 7 and 28. Expression of iNOS contributes importantly to post-infarction contractile dysfunction and subsequent LV remodeling, suggesting new strategies to combat heart failure resulting from large MI.

Therapy With Cardiac Contractility Modulation Electrical Signals Improves Left Ventricular Function and Remodeling in Dogs With Chronic Heart Failure

This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF). Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption. In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group). In CCM-only treated dogs, LV ejection fraction (EF) increased (27 +/- 1% vs. 33 +/- 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 +/- 1% vs. 23 +/- 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone. In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.

Papel relativo da remodelação geométrica do ventrículo esquerdo, morfológica e funcional do miocárdio na transição da hipertrofia compensada para a falência cardíaca em ratos com estenose aórtica supravalvar

To evaluate the relative contribution of left ventricular (LV) geometric remodeling and of morphological and functional myocardial changes in rats with induced supravalvar aortic stenosis (SAS), in the transition from compensated hypertrophy to congestive heart failure (CHF). Twenty one weeks after induction of SAS, the rats were classified as controls (CG, n=13), without congestive heart failure (SG, n=11), or with congestive heart failure (SG-HF, n=12). All groups were evaluated with echocardiographic, hemodynamic and morphological study of the myocardium. Twenty one weeks after SAS: mass index (SG-HF>SG>CG, p<0.05); systolic pressure (SG-HF= SG>CG, p<0.05); diastolic pressure (SG-HF>SG>CG, p<0.05); systolic and diastolic meridional stress (SG-HF>SG>CG, p<0.05); LV myocyte cross-sectional area (SG-HF>SG>CG, p<0.05) and hydroxyproline content (SG-HF>SG>CG, p<0.05). In the SG-HF group, LV geometric remodeling was characterized by a significant increase in dimensions and relative thickness of the normal wall (excentric remodeling), whereas the SG group presented a concentric remodeling. Indexes of LV performance in the SG-HF group were significantly lower than those of the SG group. The SG-HF and SG groups differed primarily in the LV geometric remodeling and structural myocardial remodeling process, which established a chronically compensated state in the SG group and triggered CHF in the SG-HF group in the presence of equivalent degrees of impaired contractility.