Geoffrey D. Mills

Ca2+ Influx–Induced Sarcoplasmic Reticulum Ca2+ Overload Causes Mitochondrial-Dependent Apoptosis in Ventricular Myocytes

Increases in Ca2+ influx through the L-type Ca2+ channel (LTCC, Cav1.2) augment sarcoplasmic reticulum (SR) Ca2+ loading and the amplitude of the cytosolic Ca2+ transient to enhance cardiac myocyte contractility. Our hypothesis is that persistent increases in Ca2+ influx through the LTCC cause apoptosis if the excessive influx results in SR Ca2+ overload. Feline ventricular myocytes (VMs) in primary culture were infected with either an adenovirus (Ad) containing a rat Cav1.2 &bgr;2a subunit-green fluorescent protein (GFP) fusion gene (Ad&bgr;2a) to increase Ca2+ influx or with AdGFP as a control. Significantly fewer &bgr;2a-VMs (21.4±5.6%) than GFP-VMs (99.6±1.7%) were viable at 96 hours. A fraction of &bgr;2a-VMs (20.8±1.8%) contracted spontaneously (SC-&bgr;2a-VMs), and viability was significantly correlated with the percentage of SC-&bgr;2a-VMs. Higher percentages of apoptotic nuclei, DNA laddering, and cytochrome C release were detected in &bgr;2a-VMs. This apoptosis was prevented with pancaspase or caspase-3 or caspase-9 inhibitors. L-type calcium current (ICa-L) density was greater in &bgr;2a-VMs (23.4±2.8 pA/pF) than in GFP-VMs (7.6±1.6 pA/pF). SC-&bgr;2a-VMs had higher diastolic intracellular Ca2+ (Indo-1 ratio: 1.1±0.1 versus 0.7±0.03, P<0.05) and systolic Ca2+ transients (1.89±0.27 versus 0.80±0.08) than GFP-VMs. Inhibitors of Ca2+ influx, SR Ca2+ uptake and release, mitochondrial Ca2+ uptake, mitochondrial permeation transition pore, calpain, and Bcl-2-associated X protein protected &bgr;2a-VMs from apoptosis. These results show that persistent increases in Ca2+ influx through the ICa-L enhance contractility but lead to apoptosis through a mitochondrial death pathway if SR Ca2+ overload is induced.

Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release

Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca2+ transient. Synchronization of Ca2+ release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca2+ transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca2+ release slows the rise of the cytosolic Ca2+ transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca2+ transients were measured in ventricular myocytes using confocal line scan imaging. Ca2+ transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca2+ release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca2+ currents (ICa) were maximal resynchronized SR Ca2+ release. Correspondingly, decreases in the amplitude of ICa desynchronized SR Ca2+ release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller ICa density, which should both reduce Ca2+ influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca2+ release was desynchronized. SR Ca2+ release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca2+ influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart.

Aspirin for Cardioprotection and Strategies to Improve Patient Adherence

Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in North America. Aspirin therapy has proven clinical effectiveness in the prevention and treatment of CVD and is one of the most widely used drugs nationwide. However, despite the medications popularity and utility, adherence to a proper aspirin regimen is suboptimal, resulting in adverse health outcomes and increased health care costs. Our review outlines current knowledge on aspirin therapy adherence, causes of nonadherence, and strategies available to increase adherence to aspirin and medications in general. We demonstrate that, indeed, aspirin adherence rates are suboptimal, ranging from 72% to 92%, and that a combination of patient– and medication–related factors contribute to nonadherence. A multidimensional approach involving patient education and medication innovations to reduce aspirin side effects is imperative to improving rates of aspirin therapy adherence.

Effective Strategies to Improve the Management of Heart Failure

The purpose of this article is to provide resources for primary care physicians to manage heart failure as a chronic disease. We review evidence-based interventions that can be adopted in primary care practices to improve adherence to available guidelines for medication use, promotion of self-care behaviors, transitions of care in acute decompensated heart failure, and end of life care. This information will be valuable to primary care providers who care for patients with heart failure in all care settings but is focused on the management of heart failure in the outpatient setting.

Pharmacological Effects of ATI22-107 [2-(2-{2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic Acid Dimethyl Ester)], a Novel Dual Pharmacophore, on Myocyte Calcium Cycling and Contractility

Historically, inhibitors of type III phosphodiesterases (PDE-III) have been effective inotropes in mammalian myocardium, but their clinical utility has been limited by adverse events, including arrhythmias that are considered to be due to Ca2+ overload. ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel, dual pharmacophore compound, was designed to simultaneously inhibit the cardiac phosphodiesterase (PDE-III) and produce inotropic effects, whereas inhibiting the L-type calcium channel (LTCC) was designed to minimize increases in diastolic Ca2+. We compared the effects of ATI22-107 and enoximone, a pure PDE-III inhibitor, on the Fluo-3 calcium transient in normal feline ventricular myocytes and trabeculae. Enoximone-induced dose-dependent increases in peak [Ca2+]i, diastolic [Ca2+]i, T50, and T75. ATI22-107 demonstrated similar dose-dependent increases in peak [Ca2+]i at 300 nM and 1.0 μM doses, with no further increases at higher doses. Throughout the dosing range, ATI22-107 induced much smaller, if any, increases in diastolic [Ca2+]i, T25, and T75. Current measurement of LTCC via patch-clamp techniques revealed dose-dependent decreases in LTCC current with an increasing dose of ATI22-107, thereby validating the dual functionality of the drug that has been proposed in this study. Studies in isolated trabeculae demonstrated that enoximone-induced a dose-dependent augmentation of the entire force-frequency relation in normal myocardium, whereas augmentation of contractility was only observed at lower stimulation frequencies with ATI22-107. These results demonstrate the effects of the LTCC-antagonizing moiety of ATI22-107 and suggest that the novel simultaneous combination of PDE-III and LTCC inhibition by one molecule may produce a favorable profile of limited inotropy without detrimental effects of increased diastolic [Ca2+]i.

Concept Mapping as a Method to Engage Patients in Clinical Quality Improvement

Patient engagement has become a primary care research and practice priority. Little guidance exists, however, on how best to engage patients in primary care practice improvement, or how to measure the impact of their engagement. We present an overview of group concept mapping as a method for engaging patients in primary care practice improvement. We detail the group concept mapping process as a tool for use in primary care practice improvement, research, and evaluation, and we present resources to enable researchers and practice leaders to use this tool in practice improvement. To illustrate the method, we present a practice-based quality improvement project conducted with patients and staff at a large urban academic primary care practice.

Pharmacological Effects of ATI22-107, a Novel Dual-Pharmacophore, on Myocyte Calcium Cycling and Contractility

Historically, inhibitors of type III phosphodiesterases (PDE-III) have been effective inotropes in mammalian myocardium, but their clinical utility has been limited by adverse events, including arrhythmias that are considered to be due to Ca2+ overload. ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel, dual pharmacophore compound, was designed to simultaneously inhibit the cardiac phosphodiesterase (PDE-III) and produce inotropic effects, whereas inhibiting the L-type calcium channel (LTCC) was designed to minimize increases in diastolic Ca2+. We compared the effects of ATI22-107 and enoximone, a pure PDE-III inhibitor, on the Fluo-3 calcium transient in normal feline ventricular myocytes and trabeculae. Enoximone-induced dose-dependent increases in peak [Ca2+]i, diastolic [Ca2+]i, T50, and T75. ATI22-107 demonstrated similar dose-dependent increases in peak [Ca2+]i at 300 nM and 1.0 μM doses, with no further increases at higher doses. Throughout the dosing range, ATI22-107 induced much smaller, if any, increases in diastolic [Ca2+]i, T25, and T75. Current measurement of LTCC via patch-clamp techniques revealed dose-dependent decreases in LTCC current with an increasing dose of ATI22-107, thereby validating the dual functionality of the drug that has been proposed in this study. Studies in isolated trabeculae demonstrated that enoximone-induced a dose-dependent augmentation of the entire force-frequency relation in normal myocardium, whereas augmentation of contractility was only observed at lower stimulation frequencies with ATI22-107. These results demonstrate the effects of the LTCC-antagonizing moiety of ATI22-107 and suggest that the novel simultaneous combination of PDE-III and LTCC inhibition by one molecule may produce a favorable profile of limited inotropy without detrimental effects of increased diastolic [Ca2+]i.

Implementation of Technology-based Patient Engagement Strategies within Practice-based Research Networks

Background: Technology-based patient engagement strategies (such as patient portals) are increasingly available, yet little is known about current use and barriers within practice-based research networks (PBRNs). PBRN directors have unique opportunities to inform the implementation of patient-facing technology and to translate these findings into practice. Methods: PBRN directors were queried regarding technology-based patient engagement strategies as part of the 2015 CAFM Educational Research Alliance (CERA) survey of PBRN directors. A total of 102 PBRN directors were identified via the Agency for Healthcare Research and Qualitys registry; 54 of 96 eligible PBRN directors completed the survey, for a response rate of 56%. Results: Use of technology-based patient engagement strategies within PBRNs was limited, with less than half of respondents reporting experience with the most frequently named tools (risk assessments/decision aids). Information technology (IT) support was the top barrier, followed by low rates of portal enrollment. For engaging participant practices, workload and practice leadership were cited as most important, with fewer respondents noting concerns about patient privacy. Discussion: Given limited use of patient-facing technologies, PBRNs have an opportunity to clarify the optimal use of these strategies. Providing IT support and addressing clinician concerns regarding workload may facilitate the inclusion of innovative technologies in PBRNs.

The Effect of Living in the United States on Body Mass Index in Refugee Patients

Background. We describe body mass index (BMI) trajectories over 20 months in newly settled refugees in the United States. Methods. Growth curves were modeled in in hierarchical linear modeling for cohorts from Southeast Asia, Africa, and the Middle East. Results. For refugees from Southeast Asia and Africa, coefficients suggest an increase of greater than 1.0 kg/m2 per three-month time period, though the best fit function differed between the two groups. A non-linear model was the best fit for refugees from the Middle East, with an average increase of just under 1.0 kg/m2 over the study period. Discussion. A significant increase in BMI was observed for all refugees but of a different form, predicted by the refugee’s region of origin. This may be related to food insecurity, acculturation, environmental factors, and cultural influences prior to and after arrival in the United States, though further study is needed to develop causal relationships.

The effect of diabetes self-management education on HbA1c and quality of life in African-Americans: a systematic review and meta-analysis

BackgroundType 2 diabetes presents a major morbidity and mortality burden in the United States. Diabetes self-management education (DSME) is an intervention associated with improved hemoglobin A1c(HbA1c) and quality of life(QOL), and is recommended for all individuals with type 2 diabetes. African-Americans have disproportionate type 2 diabetes morbidity and mortality, yet no prior meta-analyses have examined DSME outcomes exclusively in this population. This systematic review and meta-analysis examined the impact of DSME on HbA1c and QOL in African-Americans compared to usual care.MethodsRandomized controlled trials, cluster-randomized trials, and quasi-experimental interventions were included. 352 citations were retrieved; 279 abstracts were reviewed, and 44 full-text articles were reviewed. Fourteen studies were eligible for systematic review and 8 for HbA1c meta-analysis; QOL measures were too heterogeneous to pool. Heterogeneity of HbA1c findings was assessed with Cochran’s Q and I2.ResultsHbA1c weighted mean difference between intervention and usual care participants was not significant: − 0.08%[− 0.40–0.23];χ2 = 84.79 (p < .001), I2 = 92%, (n = 1630). Four of five studies measuring QOL reported significant improvements for intervention participants.ConclusionsMeta-analysis results showed non-significant effect of DSME on HbA1c in African-Americans. QOL did show improvement and is an important DSME outcome to measure in future trials. Further research is needed to understand effectiveness of DSME on HbA1c in this population.Trial registrationPROSPERO registration: CRD42017057282.