Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle

BACKGROUND: The index of myocardial performance has prognostic power in patients with cardiomyopathy and following myocardial infarction. As the index of myocardial performance has been shown to be preload and afterload dependent, the effect of altering contractility on IMP and its components with left ventricular dysfunction has been incompletely delineated. METHODS: Chronic left ventricular dysfunction was induced in 10 canines using coronary microsphere embolization. Each dog was instrumented and imaged with 2D echo and Doppler. At the same atrially paced rate, contractility was increased with a dobutamine infusion and then following 4 weeks of oral digoxin. RESULTS: With chronic left ventricular dysfunction, a reduced left ventricular ejection fraction (42 ± 3%, p < 0.001) and increased index of myocardial performance (0.58 ± 0.17, p < 0.01) due to isovolumic contraction time lengthening and shortened left ventricular ejection time were noted. Dobutamine increased ejection fraction (p < 0.001), reduced left ventricular end diastolic pressure (p < 0.01), and reduced the index of myocardial performance (0.33 ± 0.17, p < 0.001) due to isovolumic contraction time, isovolumic relaxation time, and left ventricular ejection time shortening. Digoxin increased ejection fraction (p < 0.05), reduced left ventricular end diastolic pressure (p < 0.05), and reduced the index of myocardial performance (0.42 ± 0.13, p < 0.01) due to isovolumic contraction time shortening (p < 0.001). Both dobutamine and digoxin lengthened the diastolic filling period (p < 0.01). CONCLUSION: Increased inotropy with digoxin and dobutamine reduced the index of myocardial performance in dogs with left ventricular dysfunction. Shortened isovolumic contraction time, increased diastolic filling period, and reduced left ventricular end diastolic pressure with digoxin may provide insight into its efficacy in heart failure

The effect of glycemic control on left ventricular function in clinical and experimental diabetes

BACKGROUND: Glycemic control in diabetes mellitus (DM) has not improved cardiovascular outcomes with normal left ventricular (LV) function. We assessed the effect on LV dysfunction using a canine model of LV dysfunction and DM, and in patients with DM and LV dysfunction. METHODS: Chronic LV dysfunction was produced by coronary microsphere embolization in 34 canines (15-25 kg). Following 8 weeks of stabilization, DM was induced in 24 canines and randomized to good or poor glycemic control for 3 months. Ten canines without DM were controls. Hemodynamic and Doppler echocardiographic data were obtained prior to and following pressure loading. We reviewed the Doppler-echocardiography at baseline and follow-up in 207 patients with DM with reduced ejection fraction (EF; median follow-up = 612 days) and 60 age- and sex-matched non-DM patients with normal EF. Laboratory results, medications, and incident adverse events from medical records were obtained RESULTS: EF = 43.8% ± 11.2% for all canines at 8 weeks. Canines with CONCLUSIONS: Poor glycemic control had an adverse effect on preexisting LV dysfunction experimentally and in patients with type 2 diabetes

Comparison of the effect of pressure loading on left ventricular size, systolic and diastolic function in canines with left ventricular dysfunction with preserved and reduced ejection fraction

Abstract Background Decompensated heart failure may present with severe hypertension in patients with preserved (PreEF) or reduced left ventricular (LV) ejection fraction (RedEF) and is clinically indistinguishable. Previously, we demonstrated that arterial pressure elevation increases LV filling pressures in a canine model of chronic LV dysfunction with PreEF or RedEF. It is not clear whether any differences in hemodynamics, LV volume or performance, or diastolic function can be demonstrated between canines with PreEF or RedEF in response to arterial pressure elevation. We hypothesized that the LV systolic, diastolic, and hemodynamic response to pressure loading would be similar in RedEF or PreEF. Methods We studied 25 dogs with chronic LV dysfunction due to coronary microsphere embolization with RedEF (35 ± 4%) and 20 dogs with PreEF (50 ± 3%). Arterial pressure was increased with methoxamine infusion and hemodynamics and echo-Doppler parameters of LV size, function, transaortic and transmitral pulsed Doppler prior to and with methoxamine infusion was obtained. Results Though LV filling pressures were similar at baseline, LV size was larger (p \u3c 0.01) and ejection fraction lower in dogs with RedEF (p \u3c 0.001). With methoxamine, there were similar increases in LV size, LV pressures, and index of myocardial performance with the ejection fraction reduced similarly. Diastolic parameters demonstrated similar tau increases, E/A reduction, and diastolic filling shortening in RedEF and PreEF dogs. A similar extent of isovolumic contraction and relaxation times and index of myocardial performance prolongation occurred with pressure loading. Conclusion Pressure loading in a canine model of LV dysfunction with PreEF and RedEF resulted in similar degrees of LV dilatation, increased filling pressures, and increased index of myocardial performance

Bilinear Programming and Protein Structure Alignment

Proteins are a primary functional component of organic life, and understanding their function is integral to many areas of research in biochemistry. The three-dimensional structure of a protein largely determines this function. Protein structure alignment compares the structure of a protein with known function to that of a protein with unknown function. A protein’s three-dimensional structure can be transformed through a smooth piecewise-linear sigmoid function to a real symmetric contact matrix that represents the functional significance of certain parts of the protein. We address the protein alignment problem as a minimization of the 2-norm difference of two proteins’ contact matrices. The minimization is presented as a bilinear program, and spectral bounds for best- and worst-case alignments are provided, which are continuous with respect to small changes in the protein’s structure. Further conditions for a perfect alignment and heuristics for finding quality solutions are given

Basophils balance healing after myocardial infarction via IL-4/IL-13

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels

Feasibility of interleukin-6 receptor blockade in cardiac antibody-mediated rejection

BACKGROUND: Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. METHODS: This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. RESULTS: All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. CONCLUSIONS: These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies

Repetitive myocardial ischemia promotes coronary growth in the adult mammalian heart

BACKGROUND: Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown. METHODS AND RESULTS: To date, no mouse models of coronary arterial growth have been described. Using a closed‐chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels. CONCLUSIONS: These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth

Access and Continuity: A Multidisciplinary Education Workshop to Teach Patient-Centered Medical Home (PCMH) Principles

Introduction: As more practices move to patient-centered medical home (PCMH) models, future health care professionals must train to work in collaborative settings. We implemented a 3-hour workshop for multidisciplinary trainees on the PCMH principles of access and continuity based on the EFECT framework (eliciting a patient-centered narrative, facilitating an interprofessional team discussion, evaluating the clinical evidence, creating a shared care plan, and tracking outcomes). Methods: Participants included internal medicine residents and medical, physician assistant (PA), and clinical psychology students. The workshop incorporated reflective activities identifying patient and provider health care delivery priorities, plus a PCMH presentation and group activities focusing on access and continuity. Evaluations were analyzed qualitatively and quantitatively. Results: The workshop had 39 participants (seven physicians, one PA, one educator, one psychologist, three staff, nine residents, one PA student, one psychology extern, and 15 medical students). On a 0-10 Likert scale (0 = don\u27t agree at all, 10 = completely agree), learners reported higher knowledge of PCMH principles (M = 8.8), feeling better prepared for PCMH work (M = 8.6), and having obtained real-world skills (M = 8.3). Open-ended responses describing the workshop\u27s take-home message included the role of patient-centeredness in clinical redesign, the value of the multidisciplinary team in optimizing access and continuity, and how to use a quality improvement approach for access and continuity. Discussion: This workshop increased PCMH-related knowledge and encouraged discussion of professional roles within the team. Learners recognized the benefits of team-based rather than provider-centric approaches to access and continuity