Degree Of Left Ventricular Dilatation Research Articles

Secondary Mitral Regurgitation and Transcatheter Mitral Valve Therapies: Do They Have a Role in Advanced Heart Failure with Reduced Ejection Fraction?

Transcatheter mitral valve repair should be considered for patients with severe secondary mitral regurgitation with symptomatic heart failure with reduced ejection fraction for symptom improvement and survival benefit. Patients with a higher severity of secondary mitral regurgitation relative to the degree of left ventricular dilation are more likely to benefit from transcatheter mitral valve repair. A multidisciplinary Heart Team should participate in patient selection for transcatheter mitral valve therapy.

The Dysfunctional Right Ventricle in Dilated Cardiomyopathies: Looking from the Right Point of View

Dilated cardiomyopathies (DCMs) are a heterogenous group of primary myocardial diseases, representing one of the leading causes of heart failure, and the main indication for heart transplantation. While the degree of left ventricular dilation and dysfunction are two key determinants of adverse outcomes in DCM patients, right ventricular (RV) remodeling and dysfunction further negatively influence patient prognosis. Consequently, RV functional assessment and diagnosing RV involvement by using an integrative approach based on multimodality imaging is of paramount importance in the evaluation of DCM patients and provides incremental prognostic and therapeutic information. Transthoracic echocardiography remains the first-line imaging modality used for the assessment of the RV, and newer techniques such as speckle-tracking and three-dimensional echocardiography significantly improve its diagnostic and prognostic accuracy. Nonetheless, cardiac magnetic resonance (CMR) is considered the gold standard imaging modality for the evaluation of RV size and function, and all DCM patients should be evaluated by CMR at least once. Accordingly, this review provides a comprehensive overview of the anatomy and function of the RV, and the pathophysiology, diagnosis, and prognostic value of RV dysfunction in DCM patients, based on traditional and novel imaging techniques.

Degree of left ventricular dilatation at end-diastole: Correlation and prognostic utility of quantitative volumes by 2D-echocardiography versus linear dimensions in patients with asymptomatic aortic regurgitation.

Guideline recommendations for aortic valve replacement (AVR) in asymptomatic patients with chronic aortic regurgitation (AR) have historically focused on linear dimensions without normalization for the body surface area (BSA). Values for grading the severity of end-diastolic volume dilatation by 2D echocardiography remain to be established. We retrospectively analyzed 543 consecutive asymptomatic patients with pure chronic moderate/severe AR (mean age 66±17years, 37.7% males). Applying the ASE/EACVI guidelines, BSA-indexed LV end-diastolic volume (LVEDVi) and indexed LV end-diastolic diameter (LVEDDi) were assessed. Then, we identified 192 patients with at least mild LV end-diastolic dilatation by volumetric or linear measurements. The outcome endpoint was the combination of cardiac death, hospitalization for acute heart failure or AVR during a median follow-up of 4.5±3.6years. Multivariable Cox regression analyses including age, LV ejection fraction (EF) and AR severity showed an independent prognostic value of the LVEDDi and LVEDVi (P<.001 and P<.01, respectively). Congruent severe LVEDDi and LVEDVi dilatation was associated with a higher event rate compared to discordant severe LV end-diastolic dilatation or nonsevere LV dilatation (P=.001) even after landmark analysis (P=.02). In patients with EF>50%, only the LVEDVi showed and independent prognostic value (P<.001). In a cohort of asymptomatic patients with AR, the presence of severe LV volume and diameter dilatation on the basis of the cutoff values proposed by current recommendations and normalized for BSA may be instrumental in the identification of patients at increased risk of clinical progression regardless of EF.

Soluble (pro)renin receptor in elderly chronic heart failure patients.

Overactivation of renin-angiotensin system (RAS) is one of the main pathophysiological features in the evolution of chronic heart failure (CHF). The (pro)renin receptor ((P)RR) represents an important player in a tissue renin-angiotensin system (tissue RAS), which mediates tissue injury through fibrosis and hypertrophy of the affected organs in CHF patients. In our study we used plasma samples from 556 elderly subjects with CHF and 198 healthy participants in order to evaluate prognostic and diagnostic potential of s(P)RR in setting of CHF. The patients with CHF showed significantly higher plasma levels of s(P)RR than the healthy volunteers (p=0.0005). We observed association between higher s(P)RR plasma concentrations and lower left ventricular ejection fraction and higher degree of left ventricular dilatation on baseline echocardiography examination of the CHF patients. Elderly CHF patients with higher baseline s(P)RR plasma concentration were at same risk for death, stroke and hospitalization due to heart failure worsening at mean follow-up from forty-eight months in comparison to low s(P)RR counterparts.

Circulating MicroRNAs as Novel Potential Biomarkers for Left Ventricular Remodeling in Postinfarction Heart Failure.

Circulating microRNAs (miRNAs) have been proposed as potential biomarkers for left ventricular remodeling in postinfarction heart failure (HF). However, the diagnostic reproducibility of the use of circulating miRNAs may be affected by the temporal expression of miRNAs following myocardial infarction (MI). In the current study, using a MI-induced HF rat cohort (4-, 8-, and 12-week post-MI groups), we investigated the temporal expression of plasma miRNAs during the development of left ventricular remodeling. The plasma miRNA expression profile was obtained using miRNA sequencing. The expression of candidate miRNAs in plasma and tissues was examined with real-time PCR. Target genes of candidate miRNAs were predicted using a parallel miRNA-messenger RNA expression profiling approach. The value of plasma miRNAs as biomarkers for left ventricular remodeling was evaluated in patients with postinfarction HF (n = 32) and control patients with stable angina and without significant coronary lesions and HF (n = 16) with real-time PCR. Although the expression levels of miR-20a-5p, miR-340-5p, and let-7i-5p were temporally regulated in plasma, myocardium, and peripheral blood mononuclear cells, the expression levels of plasma miRNAs, especially miR-20a-5p, were associated with the development of left ventricular remodeling in the postinfarction HF rat cohort. The target genes of these 3 miRNAs were associated with the mechanistic target of rapamycin, nuclear factor-κB, tumour necrosis factor, apoptosis, and p53 signaling pathways. Additionally, the plasma levels of miR-20a-5p, miR-340-5p, and let-7i-5p were significantly increased in patients with postinfarction HF. However, only the expression levels of miR-20a-5p presented significant positive correlations with left ventricular internal end diastolic dimension and left ventricular end diastolic volume. In conclusion, the expression levels of plasma miR-20a-5p were significantly associated with the degree of left ventricular dilatation, and plasma miR-20a-5p may be a potential biomarker for postinfarction left ventricular remodeling.

Microvascular leakage in acute myocardial infarction: characterization by histology, biochemistry, and magnetic resonance imaging.

Cardiac microvascular obstruction (MVO) after ischemia-reperfusion (I/R) has been well studied, but microvascular leakage (MVL) remains largely unexplored. We characterized MVL in the mouse I/R model by histology, biochemistry, and cardiac magnetic resonance (CMR) imaging. I/R was induced surgically in mice. MVL was determined by administrating the microvascular permeability tracer Evans blue (EB) and/or gadolinium-diethylenetriaminepentaacetic acid contrast. The size of MVL, infarction, and MVO in the heart was quantified histologically. Myocardial EB was extracted and quantified chromatographically. Serial CMR images were acquired from euthanized mice to determine late gadolinium enhancement (LGE) for comparison with MVL quantified by histology. I/R resulted in MVL with its severity dependent on the ischemic duration and reaching its maximum at 24-48 h after reperfusion. The size of MVL correlated with the degree of left ventricular dilatation and reduction in ejection fraction. Within the risk zone, the area of MVL (75 ± 2%) was greater than that of infarct (47 ± 4%, P < 0.01) or MVO (36 ± 4%, P < 0.01). Contour analysis of paired CMR-LGE by CMR and histological MVL images revealed a high degree of spatial colocalization (r = 0.959, P < 0.0001). These data indicate that microvascular barrier function is damaged after I/R leading to MVL. Histological and biochemical means are able to characterize MVL by size and severity while CMR-LGE is a potential diagnostic tool for MVL. The size of ischemic myocardium exhibiting MVL was greater than that of infarction and MVO, implying a role of MVL in postinfarct pathophysiology.NEW & NOTEWORTHY We characterized, for the first time, the features of microvascular leakage (MVL) as a consequence of reperfused myocardial infarction. The size of ischemic myocardium exhibiting MVL was significantly greater than that of infarction or no reflow. We made a proof-of-concept finding on the diagnostic potential of MVL by cardiac magnetic resonance imaging.

Noninvasive stratification of postinfarction rats based on the degree of cardiac dysfunction using magnetic resonance imaging and echocardiography.

The myocardial infarction (MI) rat model plays a crucial role in modern cardiovascular research, but the inherent heterogeneity of this model represents a challenge. We sought to identify subgroups among the post-MI rats and establish simple noninvasive stratification protocols for such subgroups. Six weeks after induction of MI, 49 rats underwent noninvasive examinations using magnetic resonance imaging (MRI) and echocardiography. Twelve sham-operated rats served as controls. Increased end-diastolic left ventricular (LV) pressure and lung weight served as indicators for congestive heart failure (CHF). A clustering algorithm using 13 noninvasive and invasive parameters was used to identify distinct groups among the animals. The cluster analysis revealed four distinct post-MI phenotypes; two without congestion but with different degree of LV dilatation, and two with different degree of congestion and right ventricular (RV) affection. Among the MRI parameters, RV mass emerged as robust noninvasive marker of CHF with 100% specificity/sensitivity. Moreover, LV infarct size and RV ejection fraction further predicted subgroup among the non-CHF and CHF rats with excellent specificity/sensitivity. Of the echocardiography parameters, left atrial diameter predicted CHF. Moreover, LV end-diastolic diameter predicted the subgroups among the non-CHF rats. We propose two simple noninvasive schemes to stratify post-MI rats, based on the degree of heart failure; one for MRI and one for echocardiography.NEW & NOTEWORTHY In vivo phenotyping of rats is essential for robust and reliable data. Here, we present two simple noninvasive schemes for the stratification of postinfarction rats based on the degree of heart failure: one using magnetic resonance imaging and one based on echocardiography.

Prognostic Significance of Non-Dilated Left Ventricular Size and Mitral Regurgitation in Patients With Dilated Phase of Hypertrophic Cardiomyopathy.

Although a subtype of hypertrophic cardiomyopathy (HCM), dilated phase of HCM (D-HCM) characterized by left ventricular (LV) systolic dysfunction, has been reported to have a poor prognosis, some patients with D-HCM survive for a relatively long period. The degree of LV dilatation and functional mitral regurgitation (MR) are generally thought to be important predictors of poor prognosis in patients with LV systolic dysfunction. However, there is little information available on the relations among LV size, presence of significant MR, and prognosis in D-HCM patients.We retrospectively studied 31 patients with D-HCM to determine whether echocardiographic assessment of LV size and MR provides incremental prognostic information.During a follow-up period of 5.6 ± 4.2 years, there were 13 cardiovascular deaths. When the patients were divided into two groups by LV size at diagnosis of D-HCM, a non-dilated LV group (LV end-diastolic diameter (LVEDD) < 50 mm, n = 9) and a dilated LV group (LVEDD ≥ 50 mm, n = 22), the clinical course in the non-dilated LV group was significantly worse. As for the clinical impact of MR, no patient in the non-dilated LV group showed significant MR and 7 of the patients with dilated LV size showed significant MR during follow-up. Once significant MR was reached, cardiovascular deaths were significantly more frequent in patients with MR.Patients with D-HCM, particularly those with less LV dilatation at diagnosis of dilated phase and with significant MR during follow-up, have a poor prognosis.

Ethanol-Associated Cardiomyocyte Apoptosis and Left Ventricular Dilation Are Unrelated to Changes in Myocardial Telomere Length in Rats

AimThe aim of this work was to determine whether ethanol-associated myocardial apoptosis and cardiac dilation are related to myocardial telomere shortening in rats. Methods and ResultsSprague-Dawley (SD) rats received either drinking water with (ethanol: n = 19) or without (control: n = 19) 5% (v/v) ethanol ad libitum, for 4 months. Left ventricular (LV) dimensions and function (echocardiography and isolated perfused heart preparations), cardiomyocyte apoptosis (terminal deoxynucleotide transferase–mediated dUTP nick-end labeling), and leukocyte and myocardial telomere length (real-time polymerase chain reaction) were determined at the end of the study. Ethanol administration resulted in a marked increase in cardiomyocyte apoptosis (ethanol 0.85 ± 0.13% vs control 0.36 ± 0.06%; P = .0021) and LV dilation (LV end-diastolic diameter: ethanol 8.20 ± 0.14 mm vs control 7.56 ± 0.11 mm [P = .0014]; volume intercept at 0 mm Hg (V0) of the LV end-diastolic pressure-volume relationship: ethanol 0.40 ± 0.03 mL vs control 0.31 ± 0.02 mL [P = .020]). However, there were no changes in systolic chamber function as indexed by LV endocardial fractional shortening or the slope of the LV systolic pressure-volume relationship (end systolic elastance). The percentage of myocardial apoptosis was correlated with the degree of LV dilation (% apoptosis vs LV EDD: r = 0.39; n = 38; P = .021; vs V0: r = 0.44; n = 19; P = .046). No differences in leukocyte or cardiac telomere length were noted between the ethanol and control groups. Furthermore, cardiac telomere length was not associated with indexes of LV dilation (LVEDD and V0) or cardiomyocyte apoptosis. ConclusionsChronic ethanol-associated myocardial apoptosis and adverse remodeling occurs independently from changes in cardiac telomere length. Telomere shortening may not be a critical mechanism responsible for cardiomyocyte apoptosis and adverse cardiac remodeling.

Murine pressure overload models: a 30-MHz look brings a whole new "sound" into data interpretation.

Transverse aortic constriction (TAC) and angiotensin II (ANG II) subcutaneous osmotic pump infusion are frequently used murine models of pressure overload hypertrophy. The aim of this paper is to investigate time- and stressor-dependent functional and structural changes using echocardiographic B-mode, M-mode, and Doppler characterization. Ten-week-old male C57BL6/J wild-type mice received 4-wk ANG II (1.5 mg·kg(-1)·day(-1), n = 19) or saline (n = 10) infusion followed by echocardiography (Vevo2100, Visual Sonics), or underwent TAC (n = 63) or a sham operation (n = 30). In the TAC protocol, echocardiography was performed after 2 wk (n = 22 TAC, n = 10 sham), after 4 wk (n = 20 TAC, n = 10 sham), and after 10 wk (n = 21 TAC, n = 10 sham). ANG II infusion was associated with a mixed pressure and volume overload, with a variable contribution of volume overload caused by aortic valve insufficiency (grade 0.5-3.5/4). The degree of aortic valve insufficiency correlated with the degree of left ventricular dilation (r(2) = 0.671, P < 0.001). After TAC, all hypertrophic remodeling patterns known in human disease were observed: 1) low-flow, low-gradient with preserved ejection fraction (EF); 2) concentric hypertrophy with normal EF and flow; 3) concentric hypertrophy with moderately decreased EF and/or flow; 4) eccentric hypertrophy with normal EF and flow; 5) eccentric hypertrophy with moderately decreased EF and/or flow; and 6) eccentric hypertrophy with severely depressed EF. Eccentric remodeling was time dependent, with 5% of mice developing this phenotype at 2 wk, 39% at 4 wk, and 59% at 10 wk. Comprehensive echocardiographic analysis allows identification of homogeneous subgroups of mice subjected to hypertrophic stress, reducing variability in experimental results and facilitating clinical translation.

Chronic hibernating myocardium in sheep can occur without degenerating events and is reversed after revascularization

Our goal was to show that blunting of myocardial flow reserve is mainly involved in adaptive chronic myocardial hibernation without apparent cardiomyocyte degeneration. Sheep chronically instrumented with critical multivessel stenosis and/or percutaneous transluminal coronary angioplasty (PTCA)-induced revascularization were allowed to run and feed in the open for 2 and 5 months, respectively. Regional myocardial blood flow (MBF) with colored microspheres, regional and global left ventricular function and dimensions (2D echocardiography), and myocardial structure were studied. In sheep with a critical stenosis, a progressive increase in left ventricular end-diastolic and end-systolic cavity area and a decrease in fractional area change were found. Fraction of wall thickness decreased in all left ventricular wall segments. MBF was slightly but not significantly decreased at rest at 2 months. Morphological quantification revealed a rather small but significant increase in diffusely distributed connective tissue, cardiomyocyte hypertrophy, and presence of viable myocardium of which almost 30 % of the myocytes showed depletion of sarcomeres and accumulation of glycogen. The extent of myolysis in the transmural layer correlated with the degree of left ventricular dilation. Structural degeneration of cardiomyocytes was not observed. Balloon dilatation (PTCA) of one of the coronary artery stenoses at 10 weeks revealed recovery of fraction of wall thickness and near normalization of global subcellular structure at 20 weeks. These data indicate that chronic reduction of coronary reserve by itself can induce ischemic cardiomyopathy characterized by left ventricular dilatation, depressed regional and global function, adaptive chronic myocardial hibernation, reactive fibrosis and cardiomyocyte hypertrophy in the absence of obvious degenerative phenomena. Reduction of myocardial flow reserve due to chronic coronary artery stenosis in sheep induces adaptive myocardial hibernation without involvement of degenerative phenomena.

Differences in classification of left ventricular size measured by diameter and volume with contrast echocardiography

Background: Left Ventricular (LV) size is commonly assessed at echocardiography by measurement of the End-Diastolic Diameter (EDD) in the parasternal long axis view. However, this has recognized limitations, and volumetric measurement from apical views is considered superior, particularly with the use of echocardiographic contrast to improve endocardial border definition. We sought to determine the agreement in classification of LV size by these different measures in a large population of patients undergoing clinically indicated echocardiography. Methods: Data were analyzed retrospectively from consecutive patients (n=2008, 61% male, age 62±13 years) who received echocardiographic contrast for LV opacification over 3 years in a single institution. Repeat studies were not included. LVEDD was measured, and LV End-Diastolic Volume (LVEDV) calculated using Simpson's biplane method. Both measures were indexed to body surface area (BSA) and categorized according to ASE guidelines as normal, mild, moderate or severely dilated. Results: There was a good overall correlation between LVEDD and LVEDV (Spearman's rho 0.74, p<0.001). However, when patients were categorized by indexed (i) LV diameter and volume there was poor agreement in classification (kappa = 0.200). Of 320 patients with severely dilated LVEDVi, only 43 were similarly classified by LVEDDi. Furthermore, 173 patients (54%) with a severely dilated LVEDVi had an LVEDDi in the normal range. View this table: Classification of LV size Conclusion: Agreement between different recommended measures of LV size is limited, even with significant LV dilation. The use of LVEDDi as the sole measure of ventricular size risks under-diagnosing or underestimating the degree of LV dilation. This has implications for reporting in circumstances where accurate assessment of LV size is important, such as timing of surgery in asymptomatic valve disease or classification of cardiomyopathy.

Anomalous Left Coronary Artery from the Pulmonary Artery with a Large Patent Ductus Arteriosus: Aversion of a Catastrophe

We present an infant who had an anomalous left coronary artery arising from the pulmonary artery (ALCAPA) and a large patent ductus arteriosus (PDA), who was diagnosed before a potentially catastrophic closure of PDA. In the presence of normal left ventricular function and the absence of coronary artery collaterals, it is difficult to diagnose ALCAPA. A disproportionate degree of left ventricular dilation and severity of mitral valve regurgitation relative to the degree of PDA shunt, and echogenic papillary muscles on an echocardiogram should raise a suspicion of coronary artery anomalies. The infant underwent surgical ligation of PDA with translocation of coronary arteries and had an uneventful recovery.

Prognostic Implications of Left Ventricular Dilation in Patients With Nonischemic Heart Failure: Interactions With Restrictive Filling Pattern and Mitral Regurgitation

The aim of this study was to evaluate whether small left ventricular (LV) volumes increase the negative prognostic impact of a restrictive filling pattern (RFP) and that of mitral regurgitation (MR) in patients with nonischemic heart failure (HF). The Meta-analysis Research Group in Echocardiography (MeRGE) is a meta-analysis that collated individual patient data from several prospective echocardiography outcome studies. This analysis was restricted to 10 studies and 601 patients with nonischemic HF. The role of MR was tested in a subgroup of 252 patients. A total of 106 deaths occurred during a median follow-up of 32 months. At multivariate analysis, RFP (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.54-11.23; P=.005) and New York Heart Association class III or IV (HR, 2.15; 95% CI, 1.33-3.47; P=.001) were the independent predictors of poor prognosis, and there was no statistically significant interaction between LV dilation and RFP. Moderate/severe MR was associated with poorer outcome in the group of patients with normal volumes, whereas it was not a significant predictor of mortality in patients with any degree of LV dilation. In patients with nonischemic HF, RFP is the most important indicator of poor prognosis, irrespective of the degree of LV dilation. Normal LV volumes increase the negative prognostic impact of moderate to severe MR.

Increased enddiastolic wall stress precedes left ventricular hypertrophy in dilative heart failure—Use of the volume-based wall stress index

IntroductionTo examine a potential interrelation of left ventricular (LV) wall stress and hypertrophy, we assessed increased wall stress in patients with suspected non-ischemic dilative cardiomyopathy and addressed the question whether increased LV wall stress is involved in the development of LV hypertrophy. MethodsWe studied 502 consecutive patients in whom LV mass, LV enddiastolic (LVEDV) and endsystolic volume (LVESV) was determined using cardiac magnetic resonance (CMR). Based on a thick-walled sphere, we introduced a myocardial and cavity volume-based wall stress index. Follow up CMR examinations were obtained in a representative subgroup of 71 patients. ResultsLV mass was correlated with LVEDV (r=0.517, P<0.001) and LVESV (r=0.510, P<0.001). Despite LV hypertrophy, LV mass was not sufficient to compensate for LV dilatation resulting in an increased wall stress. Increased LV enddiastolic wall stress was found in 227 patients (45 %) and increased endsystolic wall stress in 198 (39 %). In patients with normal LV enddiastolic wall stress ≤4kPa at time of enrolment, no changes of LV mass occurred during follow up (142±46g vs. 141±47g). In contrast, patients with initially increased LV enddiastolic wall stress >4kPa developed greater LV hypertrophy (141±48g vs. 158±60g, P=0.0247). ConclusionsLV wall stress can be derived from CMR measurements of LV myocardium and cavity using the volume-based wall stress index. Increased LV enddiastolic wall stress leads to LV hypertrophy. Beyond a certain degree of LV dilatation, the extent of hypertrophy does not compensate LV dilatation. The ensuing increased wall stress promotes dilatation and consecutively hypertrophy with an unfavorable prognosis. It is proposed to use the volume-based wall stress index as new diagnostic criterion in heart failure.

Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling

Although past studies observed the changes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in end-stage heart failure (HF) patients, a consistent and clear pattern of type-specific MMPs and/or TIMPs has yet to be further defined. In this study, proteomic approach of human protein antibody arrays was used to compare MMP and TIMP expression levels of left ventricular (LV) myocardial samples from end-stage HF patients due to dilated cardiomyopathy (DCM) with those from age- and sex- matched non-failing patients. Western blot analysis, immunohistochemistry and ELISA were used for validation of our results. We observed that MMP-10 and -7 abundance increased, accompanied by decreased TIMP-4 in DCM failing hearts (n= 8) compared with non-failing hearts (n= 8). The results were further validated in a cohort of 34 end-stage HF patients derived from three forms of cardiomyopathies. Cardiac and plasma MMP-10 levels were positively correlated with the LV end-diastolic dimension in this HF cohort. In addition, we observed that insulin-like growth factor-2 promoted MMP-10 production in neonatal rat cardiomyocytes. In conclusion, this study demonstrated a selective up-regulation of MMP-10 and -7 along with a discordant change of TIMP-4, and a positive correlation between MMP-10 levels and the degree of LV dilation in end-stage HF patients. Our findings suggest that type-specific dysregulation of MMPs and TIMPs is associated with LV remodelling in end-stage HF patients, and MMP-10 may act as a novel biomarker for LV remodelling.

Left-Ventricular Remodeling After Myocardial Infarction Is Associated with a Cardiomyocyte-Specific Hypothyroid Condition

Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice. Pathological remodeling of the noninfarcted part of the LV was evident from cardiomyocyte hypertrophy, interstitial fibrosis, and impairment of contractility. These changes were maximal and stable from the first week onward, as was the degree of LV dilation. A strong induction of D3 activity was found, which was similarly stable for the period examined. Plasma T(4) levels were transiently decreased at 1 wk after MI, but T(3) levels remained normal. The high D3 activity was associated with increased D3 mRNA expression at 1 but not at 4 and 8 wk after MI. Immunohistochemistry localized D3 protein to cardiomyocytes. In vivo measurement of TH-dependent transcription activity in cardiomyocytes using a luciferase reporter assay indicated a 48% decrease in post-MI mice relative to sham-operated animals, and this was associated with a 50% decrease in LV tissue T(3) concentration. In conclusion, pathological ventricular remodeling after MI in the mouse leads to high and stable induction of D3 activity in cardiomyocytes and a local hypothyroid condition.

Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure

It has been reported that angiotensin converting enzyme (ACE) 2, a homologue of ACE, has direct effects on cardiac function. However, the role of ACE2 in the development of human heart failure is not fully understood. We evaluated the expression of the ACE2 gene by means of real-time RT-PCR in myocardium from 14 patients with end-stage heart failure. The amount of ACE2 mRNA positively correlated with left ventricular (LV) end-diastolic diameter (r(2)=0.56, p<0.01) but did not significantly correlate with LV ejection fraction or plasma brain natriuretic peptide levels. In conclusion, our data show that the up-regulation of the ACE2 gene in the LV myocardium of patients with severe heart failure was associated with the degree of LV dilatation and may thereby constitute an important adaptive mechanism to retard the progression of adverse LV remodeling.

B-type natriuretic peptide and wall stress in dilated human heart

Background Although B-type natriuretic peptide (BNP) is used as complimentary diagnostic tool in patients with unknown thoracic disorders, many other factors appear to trigger its release. In particular, it remains unresolved to what extent cellular stretch or wall stress of the whole heart contributes to enhanced serum BNP concentration. Wall stress cannot be determined directly, but has to be calculated from wall volume, cavity volume and intraventricular pressure of the heart. The hypothesis was, therefore, addressed that wall stress as determined by cardiac magnetic resonance imaging (CMR) is the major determinant of serum BNP in patients with a varying degree of left ventricular dilatation or dysfunction (LVD). Methods A thick-walled sphere model based on volumetric analysis of the LV using CMR was compared with an echocardiography-based approach to calculate LV wall stress in 39 patients with LVD and 21 controls. Serum BNP was used as in vivo marker of a putatively raised wall stress. Nomograms of isostress lines were established to assess the extent of load reduction that is necessary to restore normal wall stress and related biochemical events. Results Both enddiastolic and endsystolic LV wall stress were correlated with the enddiastolic LV volume (r = 0.54, P < 0.001; r = 0.81, P < 0.001). LV enddiastolic wall stress was related to pulmonary pressure (capillary: r = 0.69, P < 0.001; artery: r = 0.67, P < 0.001). Although LV growth was correlated with the enddiastolic and endsystolic volume (r = 0.73, P < 0.001; r = 0.70, P < 0.001), patients with LVD exhibited increased LV wall stress indicating an inadequately enhanced LV growth. Both enddiastolic (P < 0.05) and endsystolic (P < 0.01) wall stress were increased in patients with increased BNP. In turn, BNP concentration was elevated in individuals with increased enddiastolic wall stress (>8 kPa: 587 +/- 648 pg/ml, P < 0.05; >12 kPa: 715 +/- 661 pg/ml, P < 0.001; normal < or =4 kPa: 124 +/- 203 pg/ml). Analysis of variance revealed LV enddiastolic wall stress as the only independent hemodynamic parameter influencing BNP (P < 0.01). Using nomograms with "isostress" curves, the extent of load reduction required for restoring normal LV wall stress was assessed. Compared with the CMR-based volumetric analysis for wall stress calculation, the echocardiography based approach underestimated LV wall stress particularly of dilated hearts. Conclusions In patients with LVD, serum BNP was increased over the whole range of stress values which were the only hemodynamic predictors. Cellular stretch appears to be a major trigger for BNP release. Biochemical mechanisms need to be explored which appear to operate over this wide range of wall stress values. It is concluded that the diagnostic use of BNP should primarily be directed to assess ventricular wall stress rather than the extent of functional ventricular impairment in LVD.

Specific Temporal Profile of Matrix Metalloproteinase Release Occurs in Patients After Myocardial Infarction

Changes in matrix metalloproteinase (MMP) and tissue inhibitors of MMPs (TIMPs) contribute to left ventricular (LV) remodeling after myocardial infarction (MI). We tested the hypothesis that a specific plasma MMP/TIMP profile would emerge after MI and be associated with the degree of LV dilation. LV end-diastolic volume and MMP/TIMP plasma profiles were determined in 53 age-matched control subjects and 32 post-MI patients from day 1 through 180 after MI. LV end-diastolic volume increased by > 38% at day 90 after MI (P < 0.05). MMP-9 increased by > 150% from control at day 1 after MI (P < 0.05) and remained elevated. MMP-8 rose to > 120% at day 3 after MI (P < 0.05) and fell to control values by day 5. TIMP-1 increased by > 60% from control at day 1 after MI (P < 0.05), whereas TIMP-2 increased only at later time points. Cardiac-specific TIMP-4 fell by 40% at day 5 after MI and remained reduced. A persistent or elevated MMP-9 at day 5 was accompanied by a 3-fold end-diastolic volume increase at day 28 (P < 0.05). A specific temporal pattern of MMP/TIMPs occurred in post-MI patients that included an early and robust rise in MMP-9 and MMP-8 and a uniform fall in TIMP-4. These findings suggest that a specific MMP/TIMP plasma profile occurs after MI and holds both prognostic and diagnostic significance.