ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium.

[Figure: see text].

PDE1 Inhibition Modulates Cav1.2 Channel to Stimulate Cardiomyocyte Contraction.

[Figure: see text].

Cardiac magnetic resonance for the early prediction of reverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: To evaluate the changes in cardiac magnetic resonance (CMR) characteristics and investigate the predictors of reverse left ventricular remodeling (r-LVR) in ST-segment elevation myocardial infarction (STEMI) patients. MATERIALS AND METHODS: Eighty-six STEMI patients (median 56 years) were retrospectively studied. The patients were divided into r-LVR and without r-LVR groups. CMR analysis included LV volume, infarct characteristics, and global and regional myocardial function. The strain and displacement were assessed by CMR-feature tracking. The predictors of r-LVR were analyzed by the logistic regression method. RESULTS: There were 37 patients in the r-LVR group and 49 patients in the without r-LVR group. At initial CMR, there was no difference in LV volume and global cardiac function between the two groups. However, the infarct zone radial and longitudinal displacements were higher in the r-LVR group (p < 0.05, respectively). At the second CMR, the r-LVR group showed higher LVEF, lower LV volume, and total enhanced mass (all p < 0.05). The infarct zone radial and circumferential strains and radial displacement were higher in the r-LVR group (all p < 0.05). The r-LVR group had better recovery of myocardial injury and function. Of note, microvascular obstruction (MVO) mass (odds ratio: 0.779 (0.613-0.989), p = 0.041) and infarct zone peak longitudinal displacement (PLD) (odds ratio: 1.448 (1.044-2.008), p = 0.026) were independent predictors of r-LVR. CONCLUSIONS: At initial CMR, there were no differences in global cardiac function between the two groups, but infarct zone displacements were higher in the r-LVR group. The r-LVR group had better recovery of cardiac function. In addition, MVO mass and infarct zone PLD were independent predictors of r-LVR. CLINICAL RELEVANCE STATEMENT: Our study assessed changes in cardiac structure, function, and tissue characteristics after STEMI by CMR, investigated the best predictors of r-LVR in STEMI patients, and laid the foundation for the development of new parameter-guided treatment strategies for STEMI patients. KEY POINTS: • At initial CMR, the reverse left ventricular remodeling (r-LVR) group had less myocardial damage and higher infarct zone displacement, but there were no differences in global function between the two groups. • Both groups showed recovery of myocardial injury and cardiac function over time, but the r-LVR group had less enhanced mass and better cardiac function compared to the without r-LVR group at the second CMR. • Microvascular obstruction mass and infarct zone peak longitudinal displacement by cardiac magnetic resonance feature-tracking were significant predictors of r-LVR in STEMI patients.

Hesperetin ameliorates ischemia/hypoxia-induced myocardium injury via inhibition of oxidative stress, apoptosis, and regulation of Ca2+ homeostasis.

Ischemia/hypoxia (I/H)-induced myocardial injury has a large burden worldwide. Hesperetin (HSP) has a cardioprotective effect, but the molecular mechanism underlying this is not clearly established. Here, we focused on the protective mechanisms of HSP against I/H-induced myocardium injury. H9c2 cardiomyocytes were challenged with CoCl2 for 22 h to imitate hypoxia after treatment groups received HSP for 4 h. The viability of H9c2 cardiomyocytes was evaluated, and cardiac function indices, reactive oxygen species, apoptosis, mitochondrial membrane potential (MMP), and intracellular Ca2+ concentration ([Ca2+ ]i ) were measured. L-type Ca2+ current (ICa-L ), myocardial contraction, and Ca2+ transients in isolated ventricular myocytes were also recorded. We found that HSP significantly increased the cell viability, and MMP while significantly decreasing cardiac impairment, oxidative stress, apoptosis, and [Ca2+ ]i caused by CoCl2 . Furthermore, HSP markedly attenuated ICa-L , myocardial contraction, and Ca2+ transients in a concentration-dependent manner. Our findings suggest a protective mechanism of HSP on I/H-induced myocardium injury by restoring oxidative balance, inhibiting apoptosis, improving mitochondrial function, and reducing Ca2+ influx via L-type Ca2+ channels (LTCCs). These data provide a new direction for HSP applied research as a LTCC inhibitor against I/H-induced myocardium injury.

Echocardiographic assessment of cardiovascular function and clinical outcomes in liver transplant recipients.

BACKGROUND & AIMS: Cardiovascular disease contributes to a high rate of morbidity and mortality after liver transplantation (LT). However, the progression of cardiac function and cardiac remodeling in LT recipients remains poorly understood. This study sought to evaluate the progression of cardiac function and structure in LT recipients and identify independent predictors of prognosis using echocardiography. METHODS: From 2009 to 2019, 178 adult LT recipients at a tertiary academic transplant center were retrospectively studied. Transthoracic echocardiograms 1-year pre- and post-LT were assessed. Primary outcomes were progression of systolic and diastolic function. Secondary outcomes included left ventricular remodeling, all-cause mortality, and heart failure readmission post-LT. Subgroup analyzes were performed for etiology of native liver disease. A multivariable model was constructed to examine independent predictors of outcomes. RESULTS: Systolic function significantly worsened, with reduction in stroke volume (45-37 ml/m2 , p < .001), left ventricular ejection fraction (LVEF) (65%-62%, p < .001) and cardiac index (3.00-2.60 L/min/m2 , p < .001). Conversely, there were significant improvements in diastolic indices, including tricuspid regurgitation Vmax (228-215 cm/s, p = .017), left atrial volume index (LAVI) (32-26 ml/m2 , p < .001) and right ventricular systolic pressure (RVSP) (31-28 mmHg, p = .001). Additionally, patients had increased relative wall thickness (RWT) (p < .001) and decreased left ventricular end-diastolic dimension/body surface area (p < .001) post-LT. The independent predictors for all-cause mortality and heart failure were increased pre-LT mitral annular early diastolic velocity (HR 1.11, CI 1.02-1.22, p = .018), LAVI (HR 1.06, CI 1.02-1.11, p = .007) and decreased LVEF (HR .89, CI .82-.97, p = .006). The effect of non-alcoholic steatohepatitis on cardiovascular outcomes post-LT was largely comparable to that of Hepatitis B. CONCLUSION: This study showed reduced systolic and improved diastolic function in LT recipients and highlighted the utility of pre-LT echocardiogram in the prognostication and risk stratification of LT candidates.

Knockout of MYOM1 in human cardiomyocytes leads to myocardial atrophy via impairing calcium homeostasis.

Myomesin-1 (encoded by MYOM1 gene) is expressed in almost all cross-striated muscles, whose family (together with myomesin-2 and myomesin-3) helps to cross-link adjacent myosin to form the M-line in myofibrils. However, little is known about its biological function, causal relationship and mechanisms underlying the MYOM1-related myopathies (especially in the heart). Regrettably, there is no MYMO1 knockout model for its study so far. A better and further understanding of MYOM1 biology is urgently needed. Here, we used CRISPR/Cas9 gene-editing technology to establish an MYOM1 knockout human embryonic stem cell line (MYOM1-/- hESC), which was then differentiated into myomesin-1 deficient cardiomyocytes (MYOM1-/- hESC-CMs) in vitro. We found that myomesin-1 plays an important role in sarcomere assembly, contractility regulation and cardiomyocytes development. Moreover, myomesin-1-deficient hESC-CMs can recapitulate myocardial atrophy phenotype in vitro. Based on this model, not only the biological function of MYOM1, but also the aetiology, pathogenesis, and potential treatments of myocardial atrophy caused by myomesin-1 deficiency can be studied.

Advancing physiological maturation in human induced pluripotent stem cell-derived cardiac muscle by gene editing an inducible adult troponin isoform switch.

Advancing maturation of stem cell-derived cardiac muscle represents a major barrier to progress in cardiac regenerative medicine. Cardiac muscle maturation involves a myriad of gene, protein, and cell-based transitions, spanning across all aspects of cardiac muscle form and function. We focused here on a key developmentally controlled transition in the cardiac sarcomere, the functional unit of the heart. Using a gene-editing platform, human induced pluripotent stem cell (hiPSCs) were engineered with a drug-inducible expression cassette driving the adult cardiac troponin I (cTnI) regulatory isoform, a transition shown to be a rate-limiting step in advancing sarcomeric maturation of hiPSC cardiac muscle (hiPSC-CM) toward the adult state. Findings show that induction of the adult cTnI isoform resulted in the physiological acquisition of adult-like cardiac contractile function in hiPSC-CMs in vitro. Specifically, cTnI induction accelerated relaxation kinetics at baseline conditions, a result independent of alterations in the kinetics of the intracellular Ca2+ transient. In comparison, isogenic unedited hiPSC-CMs had no cTnI induction and no change in relaxation function. Temporal control of adult cTnI isoform induction did not alter other developmentally regulated sarcomere transitions, including myosin heavy chain isoform expression, nor did it affect expression of SERCA2a or phospholamban. Taken together, precision genetic targeting of sarcomere maturation via inducible TnI isoform switching enables physiologically relevant adult myocardium-like contractile adaptations that are essential for beat-to-beat modulation of adult human heart performance. These findings have relevance to hiPSC-CM structure-function and drug-discovery studies in vitro, as well as for potential future clinical applications of physiologically optimized hiPSC-CM in cardiac regeneration/repair.

Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.

RATIONALE: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. OBJECTIVE: To investigate the role of SRSF3 in cardiac function. METHODS AND RESULTS: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. CONCLUSIONS: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing: A Scientific Statement From the American Heart Association.

It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell-derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell-derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.

[Cardiac contractility modulation]. / Kardiale Kontraktilitätsmodulation.

Heart failure (HF) will be one of the biggest medical challenges in the coming years, with increasing prevalence in an aging society. It is associated with a poor prognosis and impaired quality of life-despite steadily improving medical therapy which has resulted in a steady decrease in mortality and an increase in quality of life. In medically refractory patients with impaired left ventricular (LV) function, left bundle branch block and wide QRS complex (≥130 ms) cardiac resynchronization therapy (CRT) in addition to medical therapy has become the gold standard. Additionally, other therapeutic modalities such as vagal stimulation are being clinically tested but as yet have no general therapeutic recommendation. Overall, CRT patients represent only one-third of all HF patients and about 25% are "non-responders" who do not benefit from CRT.In HF patients with an LVEF between 25 and 45% and a QRS duration <130 ms who are not suitable for CRT, cardiac contractility modulation (CCM) is currently a therapeutic option that has been shown in several randomized trials to be efficacious and safe. It reduces the frequency of HF hospitalizations and improves HF symptoms, functional capacity, and quality of life. The goal of this article is to present mechanisms of action, major clinical studies, current indications, and recent developments of CCM for the treatment of patients with chronic HF.

[Prognostic implications of stone heart syndrome in cardiac arrest]. / Stellenwert des "Stone-heart"-Phänomens bei Herz-Kreislauf-Stillstand.

The stone heart syndrome is defined as an ischemic systolic contracture of the heart and also termed contractile cardiac arrest. It was first described in 1972 by the American cardiac surgeon Denton Cooley, who observed this phenomenon during bypass surgery. It is mostly the result of prolonged cardiac arrest where myocardial cells suffer hypoxia or anoxia. Insufficient forward blood flow and a decreased pressure gradient in the central aorta lead to reduced coronary perfusion. The resulting anaerobic metabolism causes an ischemic contracture as described in the stone heart syndrome. This article presents three cases of patients with traumatic cardiac arrest (TCA) and myocardial contracture in postmortem computed tomography (PMCT) and discuss the origins of the stone heart syndrome as well as its implications in cardiopulmonary resuscitation.

Deleting Full Length Titin Versus the Titin M-Band Region Leads to Differential Mechanosignaling and Cardiac Phenotypes.

BACKGROUND: Titin is a giant elastic protein that spans the half-sarcomere from Z-disk to M-band. It acts as a molecular spring and mechanosensor and has been linked to striated muscle disease. The pathways that govern titin-dependent cardiac growth and contribute to disease are diverse and difficult to dissect. METHODS: To study titin deficiency versus dysfunction, the authors generated and compared striated muscle specific knockouts (KOs) with progressive postnatal loss of the complete titin protein by removing exon 2 (E2-KO) or an M-band truncation that eliminates proper sarcomeric integration, but retains all other functional domains (M-band exon 1/2 [M1/2]-KO). The authors evaluated cardiac function, cardiomyocyte mechanics, and the molecular basis of the phenotype. RESULTS: Skeletal muscle atrophy with reduced strength, severe sarcomere disassembly, and lethality from 2 weeks of age were shared between the models. Cardiac phenotypes differed considerably: loss of titin leads to dilated cardiomyopathy with combined systolic and diastolic dysfunction-the absence of M-band titin to cardiac atrophy and preserved function. The elastic properties of M1/2-KO cardiomyocytes are maintained, while passive stiffness is reduced in the E2-KO. In both KOs, we find an increased stress response and increased expression of proteins linked to titin-based mechanotransduction (CryAB, ANKRD1, muscle LIM protein, FHLs, p42, Camk2d, p62, and Nbr1). Among them, FHL2 and the M-band signaling proteins p62 and Nbr1 are exclusively upregulated in the E2-KO, suggesting a role in the differential pathology of titin truncation versus deficiency of the full-length protein. The differential stress response is consistent with truncated titin contributing to the mechanical properties in M1/2-KOs, while low titin levels in E2-KOs lead to reduced titin-based stiffness and increased strain on the remaining titin molecules. CONCLUSIONS: Progressive depletion of titin leads to sarcomere disassembly and atrophy in striated muscle. In the complete knockout, remaining titin molecules experience increased strain, resulting in mechanically induced trophic signaling and eventually dilated cardiomyopathy. The truncated titin in M1/2-KO helps maintain the passive properties and thus reduces mechanically induced signaling. Together, these findings contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications for genotype-phenotype relations that support a personalized medicine approach to the diverse titinopathies.

Cardiovascular magnetic resonance-derived myocardial strain in asymptomatic heart transplanted patients and its correlation with late gadolinium enhancement.

OBJECTIVES: To investigate whether cardiovascular magnetic resonance (CMR)-derived myocardial strains were abnormal in asymptomatic heart transplant (HT) patients with normal left ventricular ejection fraction (LVEF) and to detect the relationship between CMR-derived myocardial strain parameters and late gadolinium enhancement (LGE) in asymptomatic HT patients. METHODS: A total of 72 HT patients and 35 healthy volunteers underwent 1.5-T MR scanning. The examination protocol included basic cine imaging and LGE. The deformation registration algorithm (DRA) and feature tracking (FT) software were used for the strain analyses. Myocardial strain measurements included left ventricular global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS), LV global radial strain (LVGRS) and right ventricular longitudinal strain (RVLS). RESULTS: Compared with healthy volunteers, HT patients had significantly decreased DRA- and FT- derived myocardial strain measurements (all p < 0.05). There was a significant correlation and high reproducibility between the DRA- and FT-derived strain parameters. Both CMR-derived LVGLS and LVGRS were significantly related to the presence of LGE, and multivariate logistic regression analyses showed that the LVGLS measurement obtained from both techniques was independently associated with the presence of LGE. The odds ratios (ORs) for DRA- and FT-LVGLS were 1.340 and 1.342, respectively. CONCLUSIONS: Asymptomatic HT patients with preserved LVEF exhibited reduced myocardial strain parameters. The CMR-derived LVGLS was independently related to the presence of LGE in HT patients. KEY POINTS: • Reduced myocardial strain parameters were found in asymptomatic heart transplanted (HT) patients with normal left ventricular ejection fraction (LVEF). • The deformation registration algorithm (DRA) and feature tracking (FT)-derived strains in asymptomatic HT patients had high reproducibility. • DRA- and FT-derived LVGLS had an independent relationship with late gadolinium enhancement (LGE) in asymptomatic HT patients.

Influence of contrast agent and spatial resolution on myocardial strain results using feature tracking MRI.

OBJECTIVES: Feature tracking for assessing myocardial strain from cardiac magnetic resonance (CMR) cine images detects myocardial deformation abnormalities with prognostic implication, e.g., in myocardial infarction and cardiomyopathy. Standards for image acquisition and processing are not yet available. Study aim was analyzing the influence of spatial resolution and contrast agent on myocardial strain results. METHODS: Seventy-five patients underwent CMR for analyzing peak systolic circumferential, longitudinal, and radial strain. Group A included n = 50 with normal left ventricular ejection fraction, no wall motion abnormality, and no fibrosis on late enhancement imaging. Group B included n = 25 with chronic myocardial infarct. For feature tracking, steady-state free precession cine images were acquired repeatedly. (1) Native standard cine (spatial resolution 1.4 × 1.4 × 8 mm3). (2) Native cine with lower spatial resolution (2.0 × 2.0 × 8 mm3). (3) Cine equal to variant 1 acquired after administration of gadoteracid. RESULTS: Lower spatial resolution was associated with elevated longitudinal strain (- 21.7% vs. - 19.8%; p < 0.001) in viable myocardium in group A, and with elevated longitudinal (- 17.0% vs. - 14.3%; p = 0.001), circumferential (- 18.6% vs. - 14.6%; p = 0.002), and radial strain (36.8% vs. 31.0%; p = 0.013) in infarcted myocardium in group B. Gadolinium administration was associated with reduced circumferential (- 21.4% vs. - 22.3%; p = 0.001) and radial strain (44.4% vs. 46.9%; p = 0.016) in group A, whereas strain results of the infarcted tissue in group B did not change after contrast agent administration. CONCLUSIONS: Variations in spatial resolution and the administration of contrast agent may influence myocardial strain results in viable and partly in infarcted myocardium. Standardized image acquisition seems important for CMR feature tracking. KEY POINTS: • Feature tracking is used for calculating myocardial strain from cardiac magnetic resonance (CMR) cine images. • This prospective study demonstrated that CMR strain results may be influenced by spatial resolution and by the administration of gadolinium-based contrast agent. • The results underline the need for standardized image acquisition for CMR strain analysis, with constant imaging parameters and without contrast agent.

Myocardial Contraction Fraction Predicts Cardiovascular Events in Patients With Hypertrophic Cardiomyopathy and Normal Ejection Fraction.

BACKGROUND: Myocardial contraction fraction (MCF), the ratio of left ventricular stroke volume to myocardial volume, is a novel parameter that can distinguish between pathologic and physiologic hypertrophy. However, its prognostic value in hypertrophic cardiomyopathy (HCM) has never been examined. The objective was to determine if MCF is associated with functional capacity and predicts adverse cardiovascular outcomes in patients with HCM and normal left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We conducted a prospective cohort study of 137 patients with HCM and LVEF ≥55%. Patients were followed for 2.7 ± 2.5 years. We examined association of MCF with New York Heart Association (NYHA) functional class and a composite outcome of embolic stroke, heart transplantation, and cardiac death. We performed time-to-event analysis with the use of Cox proportional hazards modeling and stepwise elimination. The average age was 52 ± 18 years. The average MCF was 26 ± 11%. MCF was inversely correlated with NYHA functional class (P = .001). A total of 20 subjects experienced an outcome event with an event rate of 5.6% per patient-year. MCF independently predicted the outcome (adjusted hazard ratio 0.50 per 10% increase, 95% confidence interval 0.28-0.90, adjusted P = .02). CONCLUSIONS: In patients with HCM and normal LVEF, MCF is associated with functional capacity and independently predicts adverse cardiovascular outcomes.

Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction.

RATIONALE: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown. OBJECTIVE: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction. METHODS AND RESULTS: Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal ß-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated ß-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction. CONCLUSIONS: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity.

RATIONALE: Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. OBJECTIVE: The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. METHODS AND RESULTS: Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ≈4-fold compared with non-hMSC-supplemented controls during physiological 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential proarrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium-handling genes (eg, SERCA2a, L-type calcium channel). CONCLUSIONS: Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.

Clinical usefulness of right ventricular 3D area strain in the assessment of treatment effects of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: comparison with 2D feature-tracking MRI.

OBJECTIVES: To evaluate the usefulness of right ventricular (RV) area strain analysis via cardiac MRI (CMRI) as a tool for assessing the treatment effects of balloon pulmonary angioplasty (BPA) in inoperable chronic thromboembolic pulmonary hypertension (CTEPH), RV area strain was compared to two-dimensional (2D) strain with feature-tracking MRI (FTMRI) before and after BPA. METHODS: We retrospectively analyzed 21 CTEPH patients who underwent BPA. End-systolic global area strain (GAS), longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were measured before and after BPA. Changes in GAS and RV ejection fraction (RVEF) values after BPA were defined as ΔGAS and ΔRVEF. Receiver operating characteristic (ROC) analyses were performed to determine the optimal cutoff of the strain at after BPA for detection of improved patients with decreased mean pulmonary artery pressure (mPAP) less than 30 mmHg and increased RVEF more than 50%. RESULTS: ROC analysis revealed the optimal cutoffs of strains (GAS, LS, CS, and RS) for identifying improved patients with mPAP < 30 mmHg (cutoff (%) = - 41.2, - 13.8, - 16.7, and 14.4: area under the curve, 0.75, 0.56, 0.65, and 0.75) and patients with RVEF > 50% (cutoff (%) = - 37.2, - 29.5, - 2.9, and 14.4: area under the curve, 0.81, 0.60, 0.56, and 0.56). CONCLUSIONS: Area strain analysis via CMRI may be a more useful tool for assessing the treatment effects of BPA in patients with CTEPH than 2D strains with FTMRI. KEY POINTS: • Area strain values can detect improvement of right ventricular (RV) pressure and function after balloon pulmonary angioplasty (BPA) equally or more accurately than two-dimensional strains. • Area strain analysis is a useful analytical method that reflects improvements in complex RV myocardial deformation by BPA. • Area strain analysis is a robust method with reproducibility equivalent to that of 2D strain analysis.