The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac ...pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field.
Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice.
Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
The impact of stress and depression on outcomes in patient with cardiovascular disease, including heart failure, is now well recognized and provides clear evidence for the importance of the mind-body ...connection. Ongoing research has identified physiologic pathways that govern these interactions that accordingly constitute targets for preventive therapies. A variety of non-pharmacologic practices and interventions that affect the mind-body axis have been preliminarily tested in patients with heart failure. Further development of these interventions may provide new cost-effective approaches to augment current guideline directed therapy and further enhance the prevention of adverse clinical events in patients with heart failure.
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. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.
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.
The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the β-adrenergic response to isoproterenol was depressed in both pathologies.
Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.
Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K(+) channels have been ...well characterized in the heart, much less is known about regulation and/or targeting of two-pore K(+) channel (K(2P)) family members, despite their potential importance in modulation of heart function.
Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K(2P) channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that β(IV)-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing β(IV)-spectrin lacking TREK-1 binding (qv(4J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal β(IV)-spectrin levels in human heart failure.
These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for β(IV)-spectrin in organizing functional membrane domains critical for normal heart function.
Traditional needs assessments often rely on self-reported skill levels. To gather more objective and growth-focused data, we developed a behavior-based inventory to measure perceived faculty ...competence and desired areas for growth in four common domains of academic medicine: clinical, administrative/leadership, research, and education (CARE).
Competencies in teaching, research, and professional development and leadership noted in the literature were used as the foundation of our instrument. Clinical service topics were added, and questions were vetted with the executive committee of our faculty development center. A behavior-based inventory was developed to enhance self-reporting of competency. The instrument was piloted with faculty at an external institution and revisions made prior to data collection.
In May 2016, the CARE Inventory was sent to all full-time faculty members in the Ohio State University College of Medicine (
= ∼1,800). We received 350 responses (20% response rate). Individual reports were generated and sent to the faculty member and his/her identified mentor for individual professional development. Summary data were used in aggregate for professional development program planning.
Anchoring measurement to current and desired future behavior allows for more self-reflective and growth-oriented assessment for individuals, and results can inform tactical faculty development by both individual and program. We believe this is a scalable and generalizable instrument other academic medical and health sciences programs could use both as a needs assessment tool for program planning and for individualized development plans with faculty and their mentors.
β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of ...β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis.
Psychological depression has been linked to heart failure, both an antecedent to and as a risk factor for poor outcomes among patients with existing heart failure. Elevated levels of proinflammatory ...cytokines have been proposed as a possible physiological link between the 2 conditions. The objective of this study was to examine the proinflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNFα) in heart failure patients with and without elevated symptoms of depression.
Thirty-two heart failure patients were recruited from an outpatient heart failure clinic. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and a patient was classified as having elevated symptoms of depression if he/she scored ≥10. The cognitive-affective subscale score of the BDI, which measures depressed mood independent of physical symptoms, was also examined.
In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL-6 (
P = .7612) or IL-1β (
P = .8261). However, there was a statistically significant positive relation between BDI score and TNFα (
P = .0374). There was also a significant relation between an elevated cognitive-affective score and TNFα (
P = .0322) but no association with IL-6 (
P = .8593) or IL-1β (
P = .3737).
The association between TNFα and the cognitive-affective subscale, which eliminates the physical signs and symptoms that are shared by depression and heart failure, demonstrates a depression-specific activation of proinflammatory cytokines that may promote disease progression and mortality in patients with heart failure.
PDF
