Chronic Left Ventricular Pressure Research Articles

Eccentric hypertrophy impairs outcome after TAVR.

Aortic stenosis (AS) induces cardiac remodeling upon chronic left ventricular (LV) pressure overload. Here, we analyzed the clinical outcome of patients undergoing transcatheter aortic valve replacement (TAVR) for symptomatic AS with regard to varying LV hypertrophy patterns. Moreover, we investigated the genetic influence on development of different hypertrophy patterns, measured by polygenic risk scores (PRS). 1703 patients with severe AS undergoing TAVR were categorized according to LV mass index and relative wall thickness in four subgroups: normal geometry (NG, n = 57), concentric remodeling (CR; n = 388), concentric hypertrophy (CH; n = 993) and eccentric hypertrophy (EH; n = 265). Data was analyzed retrospectively with regard to clinical outcome. In a substudy, 520 patients affected by CH (n = 237), EH (n = 139) or CR (n = 164) were analyzed using two PRS that have been previously associated with hypertrophic and dilated cardiomyopathy. 1year after TAVR, for EH, in contrast to the remaining groups (NG, CR, CH), a significant difference in all-cause mortality was observable (mortality 17.4% EH, 14.0% NG, 12.4% CR, 14.0% CH, p = 0.001). This difference was observed up to 4years (mortality 41.9% EH, 26.9% CH, 28.1% CR, 26.4% NG, p = 0.001). Of note, higher percentiles in a PRS for hypertrophic cardiomyopathy were associated with a reduced likelihood of EH in patients with AS (p = 0.046). The EH group had a statistically significant poorer 1-year and 5-year outcomes than the other groups. PRS might help predict myocardial reactions in patients with aortic stenosis in future.

Abstract 15684: Prognostic Value of Cardiac Damage Staging in Adults With Repaired Coarctation of Aorta

Background: Chronic left ventricular (LV) pressure overload is common in adults with repaired coarctation of aorta (COA). However, there is no validated systematic approach for assessing cardiac remodeling and damage in this population. The purpose of this study was to evaluate the role of cardiac damage staging scheme (validated for calcific aortic stenosis) for prognostication in adults with repaired COA. Methods: Patients were classified using a modified cardiac damage scheme: stage 0 (no cardiac damage), stage 1 (LV damage), stage 2 (left atrial damage), stage 3 (pulmonary vascular/tricuspid valve damage), and stage 4 (right ventricular damage). Results: Of 795 patients (age 36±16 years), 270 (34%) had stage 0, 198 (25%) had stage 1, 225 (28%) had stage 2, 37 (5%) had stage 3, and 65 (8%) had stage 4 cardiac damage. The 795 patients were followed for 7.3 (2.8-9.6) years, and 94 (12%) died, of which 75 (9%) were cardiovascular deaths. Cardiac damage stage was independently associated with all-cause mortality (adjusted HR 1.31, 95% CI 1.22-1.40, per unit increase in stage), and cardiovascular mortality (adjusted HR 1.42, 95% CI 1.28-1.55, per unit increase in stage). The addition of the cardiac damage stage to the base model (clinical and echocardiographic variables) provided significant incremental improvement in the prediction of 5-year risk of all-cause mortality over the base model (net reclassification index 0.39, p<0.001). Hypertension was associated with cardiac damage and mortality. Conclusions: The cardiac damage scheme can be used for risk stratification, and potentially guide therapy in the COA population.

PDE9A deficiency does not prevent chronic-hypoxic pulmonary hypertension in mice.

Inhibition of cyclic guanosine monophosphate (cGMP)‐specific phosphodiesterases (PDEs) is a cornerstone of pulmonary arterial hypertension (PAH)‐specific therapy. PDE9A, expressed in the heart and lung tissue, has the highest affinity for cGMP of all known PDEs. PDE9A deficiency protects mice against chronic left ventricular (LV) pressure overload via increased natriuretic peptide (NP)‐dependent cGMP signaling. Chronic‐hypoxic pulmonary hypertension (CH‐PH) is a model of chronic right ventricular (RV) pressure overload, and previous studies have demonstrated a protective role for NPs in the murine model. Therefore, we hypothesized that PDE9A deficiency would promote NP‐dependent cGMP signaling and prevent RV remodeling in the CH‐PH model, analogous to findings in the LV. We exposed wild‐type and PDE9A‐deficient (Pde9a −/−) C57BL/6 mice to CH‐PH for 3 weeks. We measured RV pressure, hypertrophy, and levels of lung and RV cGMP, PDE9A, PDE5A, and phosphorylation of the protein kinase G substrate VASP (vasodilatory‐stimulated phosphoprotein) after CH‐PH. In wild‐type mice, CH‐PH was associated with increased circulating ANP and lung PDE5A, but no increase in cGMP, PDE9A, or VASP phosphorylation. Downstream effectors of cGMP were not increased in Pde9a −/− mice exposed to CH‐PH compared with Pde9a +/+ littermates, and CH‐PH induced increases in RV pressure and hypertrophy were not attenuated in knockout mice. Taken together, these findings argue against a prominent role for PDE9A in the murine CH‐PH model.

Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure.

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Determinants of Left Ventricular Diastolic Function and Exertional Symptoms in Adults With Coarctation of Aorta.

Coarctation of aorta (COA) results in chronic left ventricular (LV) pressure overload and subsequently leads to LV diastolic dysfunction and heart failure over time. The goal of COA intervention is to prevent these complications. The timing of COA interventions is based on the presence of these COA severity indices: doppler mean COA gradient, systolic blood pressure, upper-to-lower-extremity SBP gradient, aortic isthmus ratio, presence of collaterals, and exercise-induced hypertension. Although these indices are physiologically intuitive, the relationship between these indices and LV diastolic dysfunction and exertional symptoms has not been studied. The purpose of this study was to evaluate the association between the indices of COA severity and LV diastolic function and symptoms. In this cross-sectional study, multivariate linear and logistic regression analyses were used to assess the correlation between indices of COA severity, LV diastolic function (average e' and E/e'), and exertional symptoms (NYHA II-IV and peak oxygen consumption). Of all the COA indices analyzed in 546 adult COA patients, aortic isthmus ratio had the strongest correlation with e' (β [95% CI]: 3.11 [2.02-4.31]; P=0.014) per 1 cm/second; E/e' (-13.4 [-22.3 to -4.81]; P=0.009) per 1 unit; peak oxygen consumption (4.05 [1.97-6.59] per 1% change, P=0.019), and NYHA II to IV symptoms (odds ratio, 2.16 [1.65-3.18]; P=0.006). Of all the COA severity indices stipulated in the guidelines, aortic isthmus ratio had the strongest correlation with LV diastolic function and exertional symptoms. As LV diastolic dysfunction typically precede heart failure symptoms, we anticipate that the results of this study will improve and simplify patient selection for COA intervention and potentially improve long-term outcomes.

Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH2-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3-/-) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3-/- mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3+/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3-/- TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3-/- TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

TCT-723 Pulmonary Arterial Proportional Pulse Pressure: A Hemodynamic Predictor of Right Ventricular Dysfunction and Early Outcomes Following Transcatheter Aortic Valve Replacement

Among patients with severe aortic stenosis, chronic left ventricular pressure overload can be transmitted to the pulmonary vascular bed, resulting in right ventricular failure and adverse cardiovascular outcomes. In this study, we investigated the role of the pulmonary arterial proportional pulse

Invasive assessment of microvascular function in patients with valvular heart disease.

The aim of this study was to investigate microvascular function in patients with valvular heart disease (VHD), which causes chronic left ventricular volume and/or pressure overload, therefore change in coronary microvascular hemodynamics. We prospectively enrolled 30 patients with VHD considered for surgery (10 aortic stenosis, 12 aortic regurgitation, and eight mitral regurgitation) and 30 controls. Intracoronary physiological assessments were performed in the unobstructed left anterior descending artery using a pressure-temperature sensor guidewire at rest and hyperemia. The index of microcirculatory resistance (IMR) was similar between the two groups (16.2±6.5 vs. 16.2±8.5, P=0.997), whereas coronary flow reserve (CFR) was lower in the VHD group compared with the controls (3.2±1.4 vs. 4.3±1.7, P=0.005). Resting and hyperemic coronary distal pressure, and hyperemic mean transit time were similar between VHD and controls, whereas resting mean transit time was significantly shorter (0.70±0.29 vs. 0.89±0.39, P=0.035) and baseline resting microvascular resistance was significantly lower in the VHD group compared with the controls (58.1±25.4 vs. 78.1±36.7, P=0.011). Patients with aortic stenosis showed numerically higher IMR values than aortic regurgitation, mitral regurgitation, and controls, although this was not statistically significant (20.4±6.9, P=0.14). CFR was significantly correlated with log high-sensitivity cardiac troponin T levels in patients with VHD (r=-0.523, P=0.004). CFR was reduced in patients with VHD compared with controls, despite similar microvascular function as assessed by IMR. This appeared to be mainly because of an increased resting coronary flow accompanied by a decreased resting coronary microvascular resistance rather than microvascular disease.

Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice.

BackgroundA disintegrin‐like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13), the von Willebrand factor–cleaving enzyme, decreases leukocyte and platelet recruitment and, thus, reduces thrombosis and inflammation. Recombinant human ADAMTS13 (rhADAMTS13) is a novel drug candidate for ischemia/reperfusion injury and has shown short‐term benefits in mouse models of myocardial injury, but long‐term outcome has not been investigated.Methods and ResultsWe evaluated the impact of rhADAMTS13 on cardiac remodeling, scarring, and contractile function, under chronic left ventricular pressure overload. The role of von Willebrand factor and the effect of rhADAMTS13 treatment were studied. This model of heart failure, based on ascending aortic constriction, produces a coronary inflammatory response and microvascular dysfunction, resulting in fibrotic remodeling and cardiac failure. Mice were treated with either rhADAMTS13 or vehicle and assessed for coronary vascular inflammation and ventricular function at several postsurgical time points, as well as for cardiac fibrosis after 4 weeks. Early upon induction of pressure overload under rhADAMTS13 treatment, we detected less endothelial‐lumen–associated von Willebrand factor, fewer platelet aggregates, and decreased activated transforming growth factor‐β1 levels than in vehicle‐treated mice. We observed significant preservation of cardiac function and decrease in fibrotic remodeling as a result of rhADAMTS13 administration.ConclusionsHerein, we show that rhADAMTS13 decreases coronary vascular dysfunction and improves cardiac remodeling after left ventricular pressure overload in mice. We propose that this effect may, at least in part, be the result of decreased von Willebrand factor–mediated recruitment of platelets, a major source of the activated profibrotic cytokine transforming growth factor‐β1. Our study further supports the therapeutic potential of rhADAMTS13 for conditions characterized by inflammatory cardiac damage that results in fibrosis.

Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates contractile dysfunction of pressure-overloaded heart in mice.

IntroductionChronic left ventricular (LV) pressure overload causes relative ischemia with resultant LV dysfunction. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we thus examined whether LIPUS also ameliorates contractile dysfunction in LV pressure-overloaded hearts.Methods and resultsChronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. LIPUS was applied to the whole heart three times in the first week after TAC and was repeated once a week for 7 weeks thereafter (n = 22). Animals in the control groups received the sham treatment without LIPUS (n = 23). At 8 weeks after TAC, LV fractional shortening was depressed in the TAC-Control group, which was significantly ameliorated in the TAC-LIPUS group (30.4±0.5 vs. 36.2±3.8%, P<0.05). Capillary density was higher and perivascular fibrosis was less in the LV in the TAC-LIPUS group than in the TAC-Control group. Myocardial relative ischemia evaluated with hypoxyprobe was noted in the TAC-Control group, which was significantly attenuated in the TAC-LIPUS group. In the TAC-LIPUS group, as compared with the control group, mRNA expressions of BNP and collagen III were significantly lower (both P<0.05) and protein expressions of VEGF and eNOS were significantly up-regulated associated with Akt activation (all P<0.05). No adverse effect related to the LIPUS therapy was noted.ConclusionsThese results indicate that the LIPUS therapy ameliorates contractile dysfunction in chronically pressure-overloaded hearts through enhanced myocardial angiogenesis and attenuated perivascular fibrosis. Thus, the LIPUS therapy may be a promising, non-invasive treatment for cardiac dysfunction due to chronic pressure overload.

Intrinsic Wave Propagation of Myocardial Stretch, A New Tool to Evaluate Myocardial Stiffness: A Pilot Study in Patients with Aortic Stenosis and Mitral Regurgitation

Left ventricular (LV) filling following atrial contraction generates LV myocardial stretch that propagates from base to apex with a speed proportional to myocardial elasticity. The aim of this study was to test the hypothesis that intrinsic velocity propagation of myocardial stretch (iVP) would be altered in patients with valvular disease and chronic LV pressure overload or volume overload, which may adversely affect mechanical properties of the LV tissue. A second aim was to compare iVP with flow propagation velocity in the chamber. Sixty subjects were prospectively recruited: 20 with severe aortic stenosis (AS), 20 with severe degenerative mitral regurgitation (MR), and 20 normal control subjects. LV iVP was measured using ultrahigh-frame rate tissue Doppler (350-460frames/sec) and flow propagation velocity by color flow M-mode imaging. Follow-up data (up to 2years) were retrieved from medical records. iVP was highest in patients with AS (2.2±0.7m/sec), intermediate in those with MR (1.6±0.5m/sec), and lowest in control subjects (1.4±0.2m/sec; P<.0001). Fourteen patients with AS and eight withMR had iVP>1.8m/sec. Overall, iVP correlated with age, LV morphology, severity of aortic valve obstruction, and measures of LV preload and afterload. At follow-up, patients with high iVP had lower survival free of major adverse cardiac events (P=.002). Flow propagation velocity was similar between groups and correlated poorly with iVP (r=0.26, P=.10). A significant number of patients with severe AS and severe MR had rapid transmission of myocardial stretch, indicating increased myocardial stiffness. This information was not conveyed by measurement of flow propagation. Larger studies are needed to investigate the clinical utility of this novel measurement.

Abstract 13160: Low-intensity Pulsed Ultrasound Enhances Angiogenesis and Ameliorates Contractile Cardiac Function in Pressure-Overloaded Hearts in Mice

Introduction: Chronic pressure overload causes relative ischemia with resultant left ventricular (LV) dysfunction. Because the number of patients with chronic heart failure of ischemic origin is increasing worldwide, development of novel therapeutic strategies for those patients are needed. We have previously demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. We also have recently reported that the LIPUS ameliorates post-MI LV remodeling in a mouse model of acute myocardial infarction (AMI). In the present study, we thus examined whether LIPUS also ameliorates contractile cardiac function in pressure-overloaded hearts in mice. Methods and Results: Chronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. The heart was treated with either placebo or LIPUS three times in the first week after TAC and was subsequently repeated once a week for 8 weeks. At 8 weeks, LV fractional shortening (LVFS) was significantly depressed in the placebo group, which was significantly ameliorated in the LIPUS group (36.2±3.8 vs. 30.4±0.5%, P&lt;0.05). Capillary density in the LV was significantly higher in the LIPUS group than in placebo group (4229±455 vs. 3243±143 /mm 2 , P&lt;0.05). Perivascular fibrosis was attenuated in the LIPUS group compared with the placebo group (P&lt;0.05). The mRNA expression of BNP and Collagen III (Iα) was lower in the LIPUS group than in the placebo group (both P&lt;0.05). Western blot analysis revealed that VEGF, eNOS and Hif-1α were significantly up-regulated in the LIPUS group (all P&lt;0.05 vs. placebo). Akt was also significantly activated in the LIPUS group (P&lt;0.05 vs. placebo). No adverse effect related to LIPUS therapy was noted. Conclusions: These results indicate that the LIPUS therapy ameliorates contractile cardiac function in pressure overload-induced cardiac dysfunction, for which enhanced myocardial angiogenesis may be involved. Thus, the LIPUS therapy may be a promising, non-invasive therapeutic strategy for the treatment of cardiac dysfunction due to pressure overload.

Viral Vector-Based Targeting of miR-21 in Cardiac Nonmyocyte Cells Reduces Pathologic Remodeling of the Heart.

Systemic inhibition of miR-21 has proven effective against myocardial fibrosis and dysfunction, while studies in cardiac myocytes suggested a protective role in this cell type. Considering potential implications for therapy, we aimed to determine the cell fraction where miR-21 exerts its pathological activity. We developed a viral vector-based strategy for gene targeting of nonmyocyte cardiac cells in vivo and compared global to cardiac myocyte-specific and nonmyocyte-specific deletion of miR-21 in chronic left ventricular pressure overload. Murine moloney virus and serotype 9 of adeno-associated virus were engineered to encode improved Cre recombinase for genetic deletion in miR-21fl/fl mice. Pericardial injection of murine moloney virus-improved Cre recombinase to neonates achieved highly selective genetic ablation of miR-21 in nonmyocyte cardiac cells, identified as cardiac fibroblasts and endothelial cells. Upon left ventricular pressure overload, cardiac function was only preserved in mice with miR-21 deficiency in nonmyocyte cardiac cells, but not in mice with global or cardiac myocyte-specific ablation. Our data demonstrate that miR-21 exerts its pathologic activity directly in cardiac nonmyocytes and encourage further development of antimiR-21 therapy toward cellular tropism.

Valvular endothelial cells: Guardians or destroyers of aortic valve integrity?

Atherosclerosis and calcific aortic valve disease (CAVD) are two distinct, morbid processes that share similar pathophysiological events. Both diseases are characterized by recruitment of immune cells, activation of inflammatory pathways, proliferation/differentiation of resident elements, remodeling of extracellular matrix and calcium deposition [ 1 Bentzon J.F. Otsuka F. Virmani R. Falk E. Mechanisms of plaque formation and rupture. Circ. Res. 2014; 114: 1852-1866 Crossref PubMed Scopus (1057) Google Scholar , 2 Yutzey K.E. et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2387-2393 Crossref PubMed Scopus (180) Google Scholar ]. However, while the actual impact of intimal calcification on plaque stability is still controversial [ [3] Otsuka F. Sakakura K. Yahagi K. Joner M. Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed?. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 724-736 Crossref PubMed Scopus (281) Google Scholar ], no uncertainty exists about the clinical harmful consequences of calcium deposition within the aortic valve. As a matter of fact, progressive stiffness of calcified leaflets leads to reduction of aortic valve area, which results in chronic left ventricular pressure overload. Clinical manifestations of the advanced disease are syncope, angina and inevitable progression towards end-stage heart failure. Aging is the major risk factor for CAVD and this explains way the disease prevalence is growing in the countries with the highest life expectancy (about 3% of Americans aged 75 and over are affected) [ [4] Mozaffarian D. et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015; 131: e29-322 Crossref PubMed Scopus (5504) Google Scholar ]. Nevertheless, several basic and clinical science studies performed in the last two decades clearly demonstrated that arterial and valve calcification should be considered as an active, finely regulated biological process, which is mainly characterized by the activation of osteogenic programs and/or the lost of anti-calcific defense mechanisms within the vascular/valve tissue [ 2 Yutzey K.E. et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2387-2393 Crossref PubMed Scopus (180) Google Scholar , 5 Demer L.L. Tintut Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 715-723 Crossref PubMed Scopus (240) Google Scholar ]. These new data are of great relevance since nowadays the only treatments available to cure CAVD consist of invasive therapeutic strategies (namely surgical or transcatheter aortic valve replacement) and there is a substantial need of new pharmacological targets. Valvular interstitial cells suppress calcification of valvular endothelial cellsAtherosclerosisVol. 242Issue 1PreviewCalcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. We previously proposed that valvular endothelial cells (VECs) replenish injured adult valve leaflets via endothelial-to-mesenchymal transformation (EndMT); however, whether EndMT contributes to valvular calcification is unknown. We hypothesized that aortic VECs undergo osteogenic differentiation via an EndMT process that can be inhibited by valvular interstitial cells (VICs). Full-Text PDF Open Access

Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice.

BackgroundRecent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload.MethodsMice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined Dnmt3a/3b ablation (DKO) was characterized on cardiomyocyte-specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham) or with left ventricular pressure overload induced by transverse aortic constriction (TAC). Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing.ResultsDKO cardiomyocytes showed virtual absence of targeted Dnmt3a and Dnmt3b mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice.ConclusionThe absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that de novo DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload.

Thallium-201 gated single-photon emission tomography for assessing left ventricular volumes and function in patients with aortic valve stenosis: Comparison with echocardiography as the reference standard

BackgroundAortic valve stenosis (AS) is characterized by chronic left ventricular pressure overload, leading to left ventricular hypertrophy (LVH). We assessed correlations in left ventricular volumes and function between echocardiography and quantitative gated SPECT (QGS) in patients with AS. Methods and resultsThe study population consisted of 28 patients with AS defined as a peak velocity of >3.0m/s and 28 age- and sex-matched control subjects. Patients with AS had a peak pressure gradient of 73.4±24.5mmHg and a larger LVM index compared to control subjects (115.5±29.2g/m2 vs 78.3±12.1g/m2, p<0.01). There were good correlations in end-diastolic volume and end-systolic volume between echocardiography and QGS in patients with AS as well as control subjects. Bland–Altman plot for end-systolic volume showed a significant negative slope of −0.51 in patients with AS. There was a good correlation in ejection fraction between the 2 methods in patients with AS as well as control subjects. However, Bland–Altman plots showed significant negative slopes of −0.40 in patients with AS and −0.74 in control subjects. ConclusionsOur data suggested that QGS was a useful method for assessing left ventricular volumes and function even in patients with AS. Cardiologists should recognize its specific characteristics.

Ablation of Mineralocorticoid Receptors in Myocytes But Not in Fibroblasts Preserves Cardiac Function

Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2±4.4%) as compared with control mice (54.3±2.5%; P<0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload.

Protective Effects of Recombinant Human Erythropoietin against Pressure Overload-Induced Left Ventricular Remodeling and Premature Death in Mice

Chronic left ventricular (LV) pressure overload induced by hypertension is one of the most common causes of heart failure. Earlier reports have shown the cardioprotective effects of erythropoietin (EPO). In the present study, we tested the hypothesis that recombinant human EPO exerts a protective effect against pressure-overload induced LV remodeling. Mice subjected to transverse aortic constriction (TAC) (n = 70) were randomly assigned to the treatment with phosphate buffer solution (PBS) (TAC-PBS) or EPO (2,000 U/kg twice a week) (TAC-EPO). At 8 weeks after TAC, LV weight was comparably increased in both TAC groups compared with sham-operated mice (Sham) (both P < 0.001). The treatment with EPO improved the survival of TAC mice as compared with treatment with PBS (80 vs. 47%, P < 0.01), which was associated with reductions in the extent of myocardial fibrosis and the number of TUNEL positive cardiomyocytes (both P < 0.05). Echocardiography revealed that TAC increased LV chamber diameter and decreased LV fractional shortening compared with Sham (P < 0.05), which was ameliorated by the treatment with EPO (P < 0.05). In TAC-EPO as compared to TAC-PBS, phosphorylation of STAT3, Akt and eNOS was all increased, while phosphorylation of p38 was decreased (all P < 0.05). Importantly, the expression level of VEGF and the capillary density in LV myocardium were similar among the 3 groups. These results suggest that recombinant human EPO ameliorates the cardiac remodeling and the premature death associated with chronic LV pressure overload through the mechanisms independent of angiogenesis.

Moderate chronic kidney disease and left ventricular hypertrophy after aortic valve replacement for aortic valve stenosis

Left ventricular hypertrophy regression is assumed to be one of the most important goals after aortic valve replacement for aortic stenosis. A moderate decrease in the glomerular filtration rate is associated with a significantly increased risk of left ventricular hypertrophy in hypertensive patients. The effect of moderate kidney disease on left ventricular hypertrophic remodeling in other conditions of chronic left ventricular pressure overload, such as aortic stenosis, remains unknown. Therefore we tested the hypothesis that moderate chronic kidney disease affects left ventricular mass regression in patients undergoing isolated aortic valve replacement for aortic stenosis. In 157 patients with aortic stenosis, left ventricular mass regression was assessed at 18 months after aortic valve replacement. Among them, 73 (46%) had a moderate chronic kidney disease (glomerular filtration rate between 60 and 30 mL/min per 1.73 m(2)). Patients with severely impaired kidney function (glomerular filtration rate of <30 mL/min per 1.73 m(2)) were excluded. After surgical intervention, left ventricular mass was significantly lower from baseline value in both groups, but patients with moderate chronic kidney disease continued to show an increased left ventricular mass (61 +/- 18 vs 50 +/- 16 g/m(2.7), P = .0001). The baseline glomerular filtration rate was significantly related to left ventricular mass at 18 months after surgical intervention (beta = -0.17, r(2) = 0.45, P = .01) and left ventricular mass absolute (beta = 0.18, r(2) = 0.19, P = .03) and relative (beta = 0.20, r(2) = 0.21, P = .02) regression. These associations persisted after adjusting for confounding factors, including hypertension and patient-prosthesis mismatch. After a mean time of 34 +/- 12 months from surgical intervention, congestive heart failure symptoms developed mainly in subjects with moderate chronic kidney disease (adjusted hazard ratio, 1.9; 95% confidence interval, 1.2-3.9; P = .035). Patients with aortic stenosis with concomitant moderate chronic kidney disease present a less evident left ventricular mass regression after aortic valve replacement. Moreover, this condition is related to an increased occurrence of congestive heart failure after surgical intervention.

Impact of Obesity on Left Ventricular Mass and Function in Subjects With Chronic Volume Overload

Previous studies evaluated the effect of obesity on left ventricular (LV) mass and systolic function in healthy subjects and in patients with coexistent chronic LV pressure overload due to hypertension, but no data exist regarding subjects with underlying volume overload. This study assessed the impact of overweight-obesity on LV mass and systolic function in patients with coexistent chronic LV volume overload. In 885 subjects with degenerative aortic regurgitation, a common cause of LV volume overload, LV mass, ejection fraction, and myocardial contractility were determined by echocardiography. LV mass was greater in overweight (193.5 +/- 54.2 g) and further increased in obese subjects (208.4 +/- 63.6 g) in comparison with normal-weight patients (177.7 +/- 54.9 g) (p < 0.0001), and these differences were still evident after adjustment for LV workload, gender, and body size. Despite no differences in ejection fraction, LV myocardial contractility was lower in overweight (92.6 +/- 14.8%) and obese subjects (91.7 +/- 14.4%) than normal-weight individuals (95.6 +/- 16.0%) (p = 0.0058). The magnitudes of these effects were not different from those found in age-, gender-, and body size-matched controls, suggesting additive interaction, rather than synergistic, between overweight-obesity and the underlying condition of volume overload. Multivariate analysis showed that BMI independently predicted LV mass and that the negative effect on LV myocardial contractility was mediated by LV hypertrophy. Overweight and obesity are associated with LV hypertrophy and contractile impairment in patients with underlying chronic LV volume overload.