Heart Of Failure Research Articles

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.

Failing hearts increasingly metabolize ketone bodies, and enhancing ketosis improves heart failure (HF) remodeling. Circulating ketones are elevated by fasting/starvation, which is mimicked with a high-fat, low-carbohydrate "ketogenic diet" (KD). While speculated that KD improves HF through increased ketone oxidation, some evidence suggests KD paradoxically downregulates cardiac ketone oxidation despite increased ketone delivery. We sought to clarify the significance of cardiac ketone metabolism during KD in HF. Mice were subjected to transverse aortic constriction with apical myocardial infarction (TAC-MI) and fed either low-fat (LF) control or KD. Cardiac-specific mitochondrial pyruvate carrier 2 (csMPC2-/-) mice were used as a second model of heart failure. In both mice, feeding a KD improved HF, determined by echocardiography, heart weights, and gene expression analyses. Although KD increases plasma ketone bodies, gene expression for ketone metabolic genes is decreased in the hearts of KD-fed mice. Cardiac-specific β-hydroxybutyrate dehydrogenase 1 (csBDH1-/-), the first enzyme in ketone catabolism, mice were also studied and crossed with the csMPC2-/- mice to create double knockout (DKO) mice. These mice were aged to 16 weeks and switched to LF or KD, and KD was able to completely normalize the hearts of both csMPC2-/- and DKO mice, suggesting that ketone metabolism is unnecessary for improving heart failure with ketogenic diet. These studies were then repeated, and mice injected with U-13C-β-hydroxybutyrate to evaluate ketone metabolism. KD feeding significantly decreased the enrichment of the TCA cycle from ketone body carbons, as did the BDH1-deletion in DKO mice. Gene expression and respirometry suggests that KD instead increases cardiac fat oxidation. In conclusion, these results suggest that ketogenic diet decreases cardiac ketone metabolism and does not require ketone metabolism to improve heart failure.

Current status and future directions in pediatric ventricular assist device.

A ventricular assist device (VAD) is a form of mechanical circulatory support that uses a mechanical pump to partially or fully take over the function of a failed heart. In recent decades, the VAD has become a crucial option in the treatment of end-stage heart failure in adult patients. However, due to the lack of suitable devices and more complicated patient profiles, this therapeutic approach is still not widely used for pediatric populations. This article reviews the clinically available devices, adverse events, and future directions of design and implementation in pediatric VADs.

A TRPV1 common missense variant affected the prognosis of ischemic cardiomyopathy.

The purpose was to identify the Transient receptor potential (TRP) superfamily gene variants associate with the prognosis of ischemic cardiomyopathy (ICM). A whole-exome sequencing study involving 252 ICM and 252 healthy controls participants enrolled from March 2003 to November 2017. Optimal sequence kernel association test and Cox regression dominant was conducted to identify the cause genes of TRP with ICM and association of common SNPs with prognosis of ICM. Rs224534 was verified in the replication population. Besides, the expression of TRPV1 was detectable in human failed heart ventricular tissues. The TRPs was not associated with the risk of ICM (P > .05). Rs224534 was significantly associated with the prognosis of ICM (Hazard ratio, 2.27, 95%CI: 1.31–3.94; P = 3.7 × 10–3), in the replication cohort, (hazard ratio 1.47, 95%CI: 1.04–2.07; P = 2.9 × 10–2), and in combined cohort hazard ratio 1.62 (95%CI: 1.21–2.18; P = 1.1 × 10–3). The common SNP of TRPV1 (rs224534) is associated with the prognosis of ICM, and homozygote rs224534-AA showed an unfavorable prognosis of ICM in the dominant model tested. Genotyping the variant may benefit to further progress judgment of ICM.

Can Percutaneous Coronary Intervention Revive a Failing Heart?

Coronary artery disease (CAD) remains the most common cause of heart failure with reduced ejection fraction; despite its prevalence, there is limited evidence to guide physicians in managing patients with CAD with percutaneous revascularization. The REVIVED-BCIS2 trial (ClinicalTrials.gov identifier: NCT01920048) represents the first randomized trial to assess the value of percutaneous coronary intervention in addition to optimal medical therapy in patients with ischaemic left ventricular systolic dysfunction and stable CAD. In this article, we review the results of the REVIVED-BCIS2 trial and compare them to the ClinicalTrials.gov Identifier: NCT00023595 trial (ClinicalTrials.gov Identifier: NCT00023595), which investigated the benefit of surgical revascularization on such patients. Finally, we suggest a pathway for physicians managing patients with ischaemic left ventricular systolic dysfunction based on the current evidence and highlight potential avenues for future research.

A carbon nanotubes based in situ multifunctional power assist system for restoring failed heart function

BackgroundEnd-stage heart failure is a major risk of mortality. The conductive super-aligned carbon nanotubes sheets (SA-CNTs) has been applied to restore the structure and function of injured myocardium through tissue engineering, and developed as efficient cardiac pacing electrodes. However, the interfacial interaction between SA-CNTs and the surface cells is unclear, and it remains challenge to restore the diminished contraction for a seriously damaged heart.ResultsA concept of a multifunctional power assist system (MPS) capable of multipoint pacing and contraction assisting is proposed. This device is designed to work with the host heart and does not contact blood, thus avoiding long-term anticoagulation required in current therapies. Pacing electrode constructed by SA-­CNTs promotes the epithelial-mesenchymal transition and directs the migration of pro-regenerative epicardial cells. Meanwhile, the power assist unit reveals an excellent frequency response to alternating voltage, with natural heart mimicked systolic/diastolic amplitudes. Moreover, this system exhibits an excellent pacing when attached to the surface of a rabbit heart, and presents nice biocompatibility in both in vitro and in vivo evaluation.ConclusionsThis MPS provides a promising non-blood contact strategy to restore in situ the normal blood-pumping function of a failed heart.

Could Cellular Therapy Rescue the Chronically Failing Heart?

Purpose Myocardial infarction (MI) results in permanent cardiomyocyte loss, frequently leading to heart failure with 50% 5-year mortality. At subacute time points following MI, animal studies have shown ‘remuscularization’ of the damaged heart with human embryonic stem cell (hESC)-derived cardiomyocytes. We recently improved outcomes by co-delivering hESC-derived epicardium. Clinically, the main challenge remains chronic heart failure. However, hESC-cardiomyocytes alone, in the chronically infarcted heart show no benefit. We hypothesized that co-delivering hESC-epicardium or a species-matched therapy could regenerate the chronically infarcted heart. Methods 3 separate pilot studies on chronically infarcted rodents were conducted: I) Vehicle-control ii) P1/P2 neonatal rat cardiomyocytes (NRVM) iii) hESC-epicardium & cardiomyocytes (Epi+CM). Rats underwent temporary left anterior descending artery ligation, resulting in MI. At 28days post-MI, animals with fractional shortening (FS%) Results Overall, Vehicle-control persistently decreased in cardiac function, whilst species-matched therapy (NRVM) had sustained functional recovery. Initially, combination therapy (EPI+CM) sharply declined, with a trend towards recovery by 3months. Infarct sizes between groups were similar. At 3months, Epi+CM's cardiac graft size=1.2±1.3% of LV whilst NRVM=2.7±1.9% of LV. Both NRVM and Epi+CM grafts displayed increased sarcomeric alignment, maturation, connexin-43 organization and neovascularization, compared to previous reports. Conclusion Our serial observations of within-group trends showed functional recovery for species-matched therapy (NRVM), whereas combination cellular therapy (Epi+CM) attenuated cardiac dysfunction at 3months. hESC-combination cell therapy holds clinical promise for ‘remuscularising’ chronically infarcted hearts and needs validation in a randomized preclinical study.

Mechanical circulatory support systems: evolution, the systems and outlook.

The joint efforts in the fields of surgery, medicine and biomedical engineering, sponsored by both the government and the industry, have led to the development of mechanical support devices that can provide reliable circulatory support, which can temporarily support a patient's circulation until either the heart recovers or until a new heart can be transplanted or permanently replace a failed heart. Their development has been driven by the shortage of donor organs. Various systems have eventually evolved for short or long-term support of patients suffering from cardiogenic and/or advanced heart failure (HF). Over time, several have been withdrawn from the market due to high rate of thromboembolism and pump-related complications, but many others remained with modern principles of circulatory support proved to be durable and reliable. Hopefully, the ever-evolving technology will yield several devices aimed at their miniaturization, with an energy supply without risk of infection, a system which is simple to implant and to exchange, minimalization of thrombus formation by optimal interior pump design, new antithrombotic medications and a system with demand-based pump activity. It is important to remember that such devices are only implanted to keep a patient alive or in an immediate life-threatening stage. In such circumstances, attribution of aforementioned difficulties to pump limitations or to advanced disease states remains difficult. In the coming years, ventricular assist devices (VADs) could be the most common surgical preference for treating severe HF.

Wish of a Young Failing Heart: Compassionate Listening in Palliative Care.

A young man hospitalized in severe biventricular heart failure, awaiting his third heart transplant, held a wish that he had not expressed to any of the myriad of clinicians involved in his care. It was only at the suggestion of his mother that he, in the hope of having his wish fulfilled, shared his wish with a medical student on the Palliative Care service. Through years of navigating the stressful complexities of her son's medical care, this mother had encountered Palliative care and had come to expect of palliative care, a compassionate presence, compassionate listening, and a compassionate response.

Abstract 13559: Engineered Three-dimensional Cardiac Tissues Maturated by Dynamic Culture in a Rotating Wall Vessel Bioreactor Remodel the Diseased Heart in the Rat Infarction Model

Introduction: To completely repair the distressed heart with few myocytes it may be crucial how to construct massive engineered three-dimensional cardiac tissues (E3DCTs) and integrate them to myocardium after transplant. We hypothesized that E3DCTs maturated by dynamic culture could enhance to remodel diseased left ventricle (LV) in the distressed rat heart. Methods: We made E3DCT by seeding 2.0 х 10 6 human induced pluripotent stem cell derived cardiomyocytes on the 6mm х 6mm PLGA fiber sheet. It was cultured in a rotating wall vessel bioreactor for seven days (RWV group) or culture dishes for the control. After in vitro assessment, these tissues were transplanted to myocardial infarction model nude rats, and 4 weeks after transplantation, we evaluated functional recovery and histology. Results: In the RWV group, thickness of E3DCTs were around 400μm, and cardiomyocytes showed mature phenotype evidenced by significantly higher expression of Troponin T (TnT), sarcomeric α actinin (SAA), connexin 43 (Cx43) and myosin heavy chain 7 (MYH7) with upregulation of mammalian target of rapamycin by Western blots (TnT; 2.1±0.2 vs. 1.0±0.2, SAA; 2.0±0.2 vs. 1.0±0.2, Cx 43; 2.0±0.3 vs. 1.0±0.1, MYH7; 2.0±0.2 vs. 1.0±0.2, p<0.05, respectively) (Figure 1A). Moreover, the concentration of angiogenic cytokines was significantly higher in the RWV group. Four weeks after transplantation, the LV ejection fraction was significantly improved in the RWV group than in the control (47±4.9 vs. 38±6.9%, p<0.01). On histological analysis, transplanted E3DCT reached a thickness of 1mm and vascular-like structures were partially observed inside (Figure 1B). In the RWV group, LV remodeling was significantly attenuated and neovascularization was significantly noted (Figure 1C, 1D). Conclusions: E3DCTs maturated by dynamic culture in a RWV bioreactor could remodel the diseased LV in rat infarction model, proposing potent armamentarium for cardiomyogenesis therapy in failed heart.

Abstract 14321: Administration of Laminin511 Combined With Prostacyclin Agonist Enhances Endogenous Stem Cell Recruitment in Acute Myocardial Infarction Model Rat

Backgroud: Although treatment by endogenous stem cell recruitment is one of the promising therapeutic options for the damaged tissues, the therapeutic efficacy is not enough to repair the severely damaged heart. How to enhance migration of stem cells to injured site and confine them there may be key point to improve the therapeutic effects. In this study, we hypothesized that combined strategy of prostacyclin agonist (ONO1301), which is enhancer in stem cell recruitment, and laminin (LM) 511 as stem cell bed may enhance regeneration processes in failed heart. Methods and Results: To examine the therapeutic effect of ONO1301 and LM511, we administrated ONO1301 and LM511 immersed collagen sheet (Combination group), only LM511 immersed collagen sheet (LM group), only ONO1301 immersed collagen sheet (ONO group), and PBS immersed collagen sheet (control) to rat acute infarction model. Four weeks later, qPCR analysis and histological analysis revealed that the expression of cytokines related to cell migration or angiogenesis were significantly higher in the combination group as compared to the other groups. The number of mesenchymal stem cell (PDGFRα and CD90 double positive cells) tended to be higher in the combination group compared to the other groups (combination: 388 ± 7 cells/mm 2 , LM: 292 ± 34 cells/mm 2 , ONO: 216 ± 30 cells/mm 2 , control: 160 ± 34 cells/mm 2 ). In addition, the number of matured arterioles which have both endothelial cells and smooth muscle cells was markedly higher in the combination group compared to the control group (combination: 616 ± 44 cells/mm 2 , control: 226 ± 60cells/mm 2 ; p < 0.05). In addition, infarct size was remarkably reduced in the combination group than the other groups (combination: 11.5 ± 0.1%, LM: 14.8 ± 0.8%, ONO: 23.6 ± 2.9%, control: 29.2 ± 2.0%). Ultrasonographically, ejection fraction significantly improved in the combination group compared to the other groups (combination: 55.0 ± 0.9%, LM: 51.6 ± 1.4%, ONO: 46.9 ± 1.4%, control: 43.5 ± 2.9%). Conclusion: The combined administration of LM511 and ONO1301 promotes arteriogenesis by enhanced endogenous repair with declined infarct size and improved cardiac function in rat acute myocardial infarction model, proposing new therapeutic strategy for ischemic cardiomyopathy.

Functional engineered heart tissue cultured in a rotating wall vessel bioreactor improve cardiac function in the distressed rat heart

Abstract Introduction How to construct massive cardiac tissue and culture it with functional improvement may be crucial as cardiomyogenesis in failed heart. We previously presented that dynamic culture in a rotating wall vessel (RWV) bioreactor could provide a better culture environment for maintenance of the engineered 3D cardiac tissue. However, it is unknown about the effect of the tissue cultured in a RWV bioreactor on engraftment and improvement of function in the distressed rat heart. Hypothesis We hypothesized that the engineered 3D cardiac tissue cultured in a RWV bioreactor could improve its engraftment and lead recovery of cardiac function in rat infarction model. Methods We made engineered cardiac tissue by seeding 2.0 × 106 human induced pluripotent stem cell derived cardiomyocytes on the PLGA fiber sheet. It was cultured in the RWV bioreactor for seven days (RWV group). For the control, static culture has been done. After in vitro assessment, these tissues were transplanted to myocardial infarction model nude rats (sham, control, and RWV group, n=10, respectively) and cardiac performance was evaluated by ultrasonography. Four weeks after transplantation, we evaluated their hearts by histological analysis. Results The RWV group demonstrated maturation of cardiomyocytes evidenced by significantly higher expression of Troponin T (TnT), sarcomeric α actinin (SAA), connexin 43 (Cx43) and myosin heavy chain 7 (MYH7) than the control by Western blots (TnT; 2.7±1.0 vs. 1.0±0.4, p<0.01, SAA; 2.1±0.7 vs. 1.0±0.2, p<0.01, Cx 43; 2.0±0.6 vs. 1.0±0.1, p<0.05, MYH7; 10.9±2.7 vs. 1.0±0.1, p<0.01). In the culture supernatant, the concentration of cytokines related to angiogenesis was significantly higher in the RWV group than in the control (VEGF; 29.6±7.4 vs. 12.2±4.3pg/ml, p<0.01, HGF; 72.7±9.9 vs. 42.6±5.9pg/ml, p<0.01). Four weeks after transplantation, the left ventricular ejection fraction was significantly improved in the RWV group than in the control (RWV vs. control; 47±4.9 vs. 38±6.9%, p<0.01). On histological analysis, more engineered cardiac tissue survived in the RWV group than in the control (RWV vs. control; 7/10 vs. 3/10, p=0.18). A vascular-like structure double-stained with isolectin B4 and smooth muscle actin was partially observed in the transplanted tissue. LV remodeling exhibiting extracellular collagen deposition (fibrotic area, RWV vs. control; 17±4.3 vs. 24±5.2%, p<0.05) and cardiomyocyte hypertrophy (RWV vs. control; 16±1.7 vs. 18±2.1μm, p<0.05) was significantly attenuated in RWV group than in the control. Neovascularization was significantly noted in the RWV group compared with the control (capillary density, RWV vs. control; 545±113 vs. 356±92, p<0.01). Conclusion Functional engineered 3D cardiac tissue cultured in a RWV bioreactor could induce angiogenesis and improved its engraftment, leading significant improvement of cardiac function in rat infarction model. Dynamic culture in a RWV bioreactor Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science

Pre-Operative Modeling of Transcatheter Mitral Valve Replacement in a Surgical Heart Valve Bioprosthesis

Obstruction of the left ventricular outflow tract (LVOT) is a common complication of transcatheter mitral valve replacement (TMVR). This procedure can determine an elongation of an LVOT (namely, the neo-LVOT), ultimately portending hemodynamic impairment and patient death. This study aimed to understand the biomechanical implications of LVOT obstruction in a patient who underwent TMVR using a transcatheter heart valve (THV) to repair a failed bioprosthetic heart valve. We first reconstructed the heart anatomy and the bioprosthetic heart valve to virtually implant a computer-aided-design (CAD) model of THV and evaluate the neo-LVOT area. A numerical simulation of THV deployment was then developed to assess the anchorage of the THV to the bioprosthetic heart valve as well as the resulting Von Mises stress at the mitral annulus and the contract pressure among implanted bioprostheses. Quantification of neo-LVOT and THV deployment may facilitate more accurate predictions of the LVOT obstruction in TMVR and help clinicians in the optimal choice of the THV size.

Effects of the left ventricular viscosity on a failed heart: An in-silico analysis

Effects of the left ventricular viscosity on a failed heart: An in-silico analysis

Differential microRNA-21 and microRNA-221 Upregulation in the Biventricular Failing Heart Reveals Distinct Stress Responses of Right Versus Left Ventricular Fibroblasts.

The failing right ventricle (RV) does not respond like the left ventricle (LV) to guideline-directed medical therapy of heart failure, perhaps due to interventricular differences in their molecular pathophysiology. Using the canine tachypacing-induced biventricular heart failure (HF) model, we tested the hypothesis that interventricular differences in microRNAs (miRs) expression distinguish failing RV from failing LV. Severe RV dysfunction was indicated by elevated end-diastolic pressure (11.3±2.5 versus 5.7±2.0 mm Hg; P<0.0001) and diminished fractional area change (24.9±7.1 versus 48.0±3.6%; P<0.0001) relative to prepacing baselines. Microarray analysis of ventricular tissue revealed that miR-21 and miR-221, 2 activators of profibrotic and proliferative processes, increased the most, at 4- and 2-fold, respectively, in RV-HF versus RV-Control. Neither miR-21 or miR-221 was statistically significantly different in LV-HF versus LV-Control. These changes were accompanied by more extensive fibrosis in RV-HF than LV-HF. To test whether miR-21 and miR-221 upregulation is specific to RV cellular response to mechanical and hormonal stimuli associated with HF, we subjected fibroblasts and cardiomyocytes isolated from normal canine RV and LV to cyclic overstretch and aldosterone. These 2 stressors markedly upregulated miR-21 and miR-221 in RV fibroblasts but not in LV fibroblasts nor cardiomyocytes of either ventricle. Furthermore, miR-21/221 knockdown significantly attenuated RV but not LV fibroblast proliferation. We identified a novel, biological difference between RV and LV fibroblasts that might underlie distinctions in pathological remodeling of the RV in biventricular HF.

Advanced Failing Hearts Have a Wide Range of Fibrosis Including Overlap with Nonfailing Hearts

Advanced Failing Hearts Have a Wide Range of Fibrosis Including Overlap with Nonfailing Hearts

Markery włóknienia w niewydolności serca

Cardiovascular diseases, especially heart failure (HF) are the major cause of death worldwide. HF is a leading Health problem with an increasingly incidence and prevalence of the disease, despite advances in medical therapy and interventional cardiology. The treatment of heart failure represents a signifi cant fi nancial burden for healthcare system. For many years there has been an intense research conducted to fi nd the biological markers that aid in diagnosis, treatment and prognosis, and assessing the effectiveness of therapeutic intervention. They may provide valuable information for risk stratifi cation. Biomarkers refl ect different pathogenic processes in failed heart and correlate with changes in myocardial structure or function. Fibrosis plays an important role in cardiac remodelling that occurs in heart failure. Plasma biomarkers of fi brosis can be evaluated as prognostic indicators of myocardial accumulation of fi brous tissue. They correlated with the extent of cardiac fi brosis. Circulating biomarkers may be a useful tools to monitor the disease severity and therapeutic response. In our review we aim to analyze the role of well-known and novel biomarkers in the development of heart failure and their potential clinical utility in diagnostics of HF.

Significance of integrated in silico transmural ventricular wedge preparation models of human non-failing and failing hearts for safety evaluation of drug candidates

IntroductionTo evaluate the usefulness of in silico assay in predicting drug-induced QTc prolongation and ventricular proarrhythmia, we describe in this study 2-dimensional transmural ventricular wedge preparation model (2D model) of non-failing (non-FH) and failing hearts (FH) based on O'Hara-Rudy dynamic model of human ventricular myocytes. MethodsUsing the prepared 2D model, we simulated ventricular action potential and recorded electrocardiogram for the non-FH and FH. The FH model was constructed based on differences in mRNA, protein, and/or current levels of ion channels between non-diseased heart and failing heart. To simulate the effects of selected drugs, we incorporated changes in ion channel conductance depending on the IC50 value and Hill coefficient at unbound drug blood concentrations. ResultsDofetilide concentration-dependently induced QTc prolongation at therapeutic concentration in the 2D model of both non-FH and FH. The QTc prolongation in FH was longer than that in non-FH. These findings are consistent with previously reported clinical data. At supratherapeutic concentration 20nM, dofetilide induced Torsade de Pointes-like arrhythmia in the 2D non-FH model. In contrast, the single ventricular myocyte model did not quantitatively reproduce experimental data due to lack of electrotonic interaction. The simulated QTc change induced by six drugs examined in the IQ-CSRC prospective study was almost equivalent to that recorded in drug-treated healthy volunteers. DiscussionOur 2D model with or without heart failure faithfully reproduced drug-induced QT prolongation and ventricular arrhythmias, suggesting that the in silico approach is a powerful tool for predicting cardiac safety of drug candidates at preclinical stage.

Alginate for cardiac regeneration: From seaweed to clinical trials.

Heart failure is a growing endemic in the aging Western population with a prevalence of over 20 million people worldwide1. Existing heart failure therapies are unable to reverse heart failure and do not address its fundamental cause, the loss of cardiomyocytes2. In order to induce myocardial regeneration for the myocardium and the heart valve, facilitate self-repair, improve tissue salvage, reduce or reverse the adverse-remodeling and ultimately achieve long-term functional stabilization and improvement in the heart function, novel strategies for therapeutic regeneration are being developed which are aiming to compensate for the insufficient and low intrinsic regenerative ability of the adult heart3. Similarly, valve replacement with mechanical or biological substitutes meets numerous hurdles. New approaches using multicellular approaches and new material are extensively studied. Most of those strategies depend on biomaterials that help to achieve functional integrated vasculogenesis and myogenesis in the heart/tissue. Especially for failed heart valve function a number of therapeutic approaches are common from corrective intervention to complete replacement4. However the complexity of the heart valve tissue and its high physical exposure has led to a variety of approaches, however therapeutic regeneration needs to be established. Beside other approaches alginate has been identified as one building block to achieve therapeutic regeneration.Alginate is a versatile and adaptable biomaterial that has found numerous biomedical applications which include wound healing, drug delivery and tissue engineering. Due to its biologically favorable properties including the ease of gelation and its biocompatibility, alginate-based hydrogels have been considered a particularly attractive material for the application in cardiac regeneration and valve replacement techniques. Here, we review current applications of alginate in cardiac regeneration as well as perspectives for the alginate-dependent, cardiac regeneration strategies.

Interplay between the effects of a Protein Kinase C phosphomimic (T204E) and a dilated cardiomyopathy mutation (K211Δ or R206W) in rat cardiac troponin T blunts the magnitude of muscle length-mediated crossbridge recruitment against the β-myosin heavy chain background

Failing hearts of dilated cardiomyopathy (DCM)-patients reveal systolic dysfunction and upregulation of several Protein Kinase C (PKC) isoforms. Recently, we demonstrated that the functional effects of T204E, a PKC phosphomimic of cardiac troponin T (TnT), were differently modulated by α- and β-myosin heavy chain (MHC) isoforms. Therefore, we hypothesized that the interplay between the effects of T204E and a DCM-linked mutation (K211Δ or R206W) in TnT wouldmodulate contractile parameters linked-to systolic function in an MHC-dependent manner. To test our hypothesis, five TnT variants (wildtype, K211Δ, K211Δ+T204E, R206W, and R206W+T204E) were generated and individually reconstituted into demembranated cardiac muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rats. Steady-state and mechano-dynamic measurements were performed on reconstituted fibers. Myofilament Ca(2+) sensitivity (pCa50) was decreased by both K211Δ and R206W to a greater extent in α-MHC fibers (~0.15pCa units) than in β-MHC fibers (~0.06pCa units). However, T204E exacerbated the attenuating influence of both mutants on pCa50 only in β-MHC fibers. Moreover, the magnitude of muscle length (ML)-mediated crossbridge (XB) recruitment was decreased by K211Δ+T204E (~47%), R206W (~34%), and R206W+T204E (~36%) only in β-MHC fibers. In relevance to human hearts, which predominantly express β-MHC, our data suggest that the interplay between the effects of DCM mutations, PKC phosphomimic in TnT, and β-MHC lead to systolic dysfunction by attenuating pCa50 and the magnitude of ML-mediated XB recruitment.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries