Stretching single titin molecules from failing human hearts reveals titin's role in blunting cardiac kinetic reserve.

Aims: Heart failure (HF) patients commonly experience symptoms primarily during elevated heart rates, as a result of physical activities or stress. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with HF, with unresolved involvement regarding its role at different heart rates. To determine whether titin is playing a role in the heart rate (frequency-) dependent acceleration of relaxation (FDAR).

Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure.

Two common genetic polymorphisms in the beta-1 adrenergic receptor (ADRB1 Ser49Gly [rs1801252] and Arg389Gly [rs1801253]) significantly affect receptor function in vitro. The objective of this study was to determine whether ADRB1 Ser49Gly and Arg389Gly are associated with recovery of left ventricular ejection fraction (LVEF) in patients with heart failure. Patients with heart failure and baseline LVEF ≤ 40% were genotyped (n = 98), and retrospective chart review assessed the primary outcome of LVEF recovery to ≥ 40%.

Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts.

We tested the hypothesis that induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) are less able to adhere to the extracellular matrix (ECM) derived from failing human hearts with dilated cardiomyopathy compared to nonfailing human heart ECM. We also hypothesized that morphological development, cell beating rates, and mRNA levels of Nkx2.5 and cardiac troponin T would be altered after culturing the iPSC-CPCs on the failing heart ECM under cardiomyocyte differentiation conditions.

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium.

In this study, we investigated the quantitative and qualitative role of the sarcoplasmic reticulum (SR) in the regulation of the force-frequency relationship (FFR). We blocked the function of SR with cyclopiazonic acid (CPA) and ryanodine and measured twitch kinetics and developed force at various stimulation frequencies in nonfailing and failing intact human right ventricular trabeculae. We found that developed forces are only slightly reduced upon SR blockade, while the positive FFR in nonfailing trabeculae and negative FFR in failing trabeculae were both preserved.

NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth.

Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium.

Background: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium.

Methods And Results: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis.

Human Myocardium Has a Robust α1A-Subtype Adrenergic Receptor Inotropic Response.

Recent studies report that a single subtype of α1-adrenergic receptor (α1-AR), the α1A-subtype, mediates robust cardioprotective effects in multiple experimental models of heart failure, suggesting that the α1A-subtype is a potential therapeutic target for an agonist to treat heart failure. Moreover, we recently found that the α1A-subtype is present in human heart. The goal of this study was to assess the inotropic response mediated by the α1A-subtype in human myocardium, and to determine whether the response is downregulated in myocardium from failing human heart.

Increased cross-bridge recruitment contributes to transient increase in force generation beyond maximal capacity in human myocardium.

Unlabelled: Cross-bridge attachment allows force generation to occur, and rate of tension redevelopment (k) is a commonly used index of cross-bridge cycling rate. Tension overshoots have been observed briefly after a slack-restretch k maneuver in various species of animal models and humans. In this study, we set out to determine the properties of these overshoots and their possible underlying mechanism.

In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice.

Rationale: Duchenne muscular dystrophy is a severe inherited form of muscular dystrophy caused by mutations in the reading frame of the dystrophin gene disrupting its protein expression. Dystrophic cardiomyopathy is a leading cause of death in Duchenne muscular dystrophy patients, and currently no effective treatment exists to halt its progression. Recent advancement in genome editing technologies offers a promising therapeutic approach in restoring dystrophin protein expression.

Effects of zacopride, a moderate I channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium.

Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate I channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats.

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts.

Insights into length-dependent regulation of cardiac cross-bridge cycling kinetics in human myocardium.

Cross-bridge cycling kinetics play an essential role in the heart's ability to contract and relax. The rate of tension redevelopment (ktr) slows down as a muscle length is increased in intact human myocardium. We set out to determine the effect of rapid length step changes and protein kinase A (PKA) and protein kinase C-βII (PKC-βII) inhibitors on the ktr in ultra-thin non-failing and failing human right ventricular trabeculae.

Effect of exercise training and myocardial infarction on force development and contractile kinetics in isolated canine myocardium.

It is well known that moderate exercise training elicits a small increase in ventricular mass (i.e., a physiological hypertrophy) that has many beneficial effects on overall cardiac health.

The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium.

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts.

Is It Feasible to Use Electronic Health Records for Quality Measurement of Adolescent Care?

Objective: To determine the extent to which it is feasible to implement quality measures on electronic health records (EHRs) as currently implemented in pediatric health centers.

Methods: A survey of information technology professionals at 10 institutions that provide primary care services to adolescents. The survey asked whether data about care was being captured electronically across the nine domains relevant to adolescent well care: Screening, Health Risks, Sexual Health, Diagnosis and History, Laboratory Results, Prescriptions, Referrals, Forms Management, and Patient Demographics.

Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1.

Claudin-5 is transcriptionally downregulated resulting in dramatically reduced protein levels in human heart failure. Studies in mice have demonstrated that reduced claudin-5 levels occur prior to cardiac damage and far before reduced whole heart function. Therefore, claudin-5 may be a useful early therapeutic target for human heart failure.

Variations in measurement of sexual activity based on EHR definitions.

Objective: The goal of this study was to compare the performance of 4 operational definitions of sexual activity by using data electronically abstracted from electronic health records (EHRs) and examine how documentation of Chlamydia screening and positivity vary according to definition of sexual activity.

Methods: Extracts were created from EHRs of adolescent females 12 to 19 years old who had ≥1 visit to a primary care practice during 2011 at 4 US pediatric health care organizations. We created 4 definitions of sexual activity derived from electronically abstracted indicator variables.

Using computer-extracted data from electronic health records to measure the quality of adolescent well-care.

Objective: To determine whether quality measures based on computer-extracted EHR data can reproduce findings based on data manually extracted by reviewers.

Data Sources: We studied 12 measures of care indicated for adolescent well-care visits for 597 patients in three pediatric health systems.

Study Design: Observational study.

The force-temperature relationship in healthy and dystrophic mouse diaphragm; implications for translational study design.

In the field of muscular dystrophy, striated muscle function is often assessed in vitro in dystrophin-deficient mdx mice in order to test the impact of a potential treatment strategy. Although many past studies have assessed diaphragm contractile function at or near room temperature, the diaphragm performs in vivo at 37°C. To improve translation of bench-top results to possible clinical application, we studied temperature-dependence of contractile performance in wild-type (C57BL/10) and mdx muscle strips at temperatures from 25°C to 37°C.

Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model.

Identification of new molecular targets in heart failure could ultimately have a substantial positive impact on both the health and financial aspects of treating the large heart failure population. We originally identified reduced levels of the cell junction protein claudin-5 specifically in heart in the dystrophin/utrophin-deficient (Dmd(mdx);Utrn(-/-)) mouse model of muscular dystrophy and cardiomyopathy, which demonstrates physiological hallmarks of heart failure. We then showed that at least 60% of cardiac explant samples from patients with heart failure resulting from diverse etiologies also have reduced claudin-5 levels.

IKKα and alternative NF-κB regulate PGC-1β to promote oxidative muscle metabolism.

Although the physiological basis of canonical or classical IκB kinase β (IKKβ)-nuclear factor κB (NF-κB) signaling pathway is well established, how alternative NF-κB signaling functions beyond its role in lymphoid development remains unclear. In particular, alternative NF-κB signaling has been linked with cellular metabolism, but this relationship is poorly understood. In this study, we show that mice deleted for the alternative NF-κB components IKKα or RelB have reduced mitochondrial content and function.

mdx(⁵cv) mice manifest more severe muscle dysfunction and diaphragm force deficits than do mdx Mice.

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle dysfunction leading to premature death by the third decade of life. The mdx mouse, the most widely used animal model of DMD, has been extremely useful to study disease mechanisms and to screen new therapeutics. However, unlike patients with DMD, mdx mice have a very mild motor function deficit, posing significant limitations for its use as a platform to assess the impact of treatments on motor function.

Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice.

Background: Nearly universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. Because DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with antifibrotic effect may be beneficial.

Methods And Results: Three groups of 10 utrn(+/-);mdx, or "het" mice, deficient for dystrophin and haploinsufficient for utrophin with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied.