Cardiac Workload Research Articles

Cirrhotic cardiomyopathy: Implications for liver transplantation.

The majority of patients on a waiting list for liver transplantation have end-stage liver disease. Because of the marked peripheral vasodilatation of end-stage cirrhosis that masks a latent myocardial dysfunction, cardiac abnormalities in the resting state are usually subclinical and escape the attention of physicians. However, when challenged, the systolic and diastolic contractile responses are attenuated. In addition to these contractile abnormalities, morphological changes, such as enlargement or hypertrophy of cardiac chambers, and electrophysiological repolarization changes, including a prolonged QT interval, can be observed. The constellation of these cardiac abnormalities is termed cirrhotic cardiomyopathy. Liver transplantation induces significant cardiovascular stress. Clamping of the inferior vena cava and portal vein, hemorrhage and blood/volume infusion, and ischemia/reperfusion all cause hemodynamic fluctuation. The changing cardiac preload and afterload status increases the cardiac workload, and thus, the previously subclinical ventricular dysfunction may manifest as overt heart failure during the operative and perioperative periods. Cardiac dysfunction contributes to morbidity and mortality associated with liver transplantation. Cardiovascular events are the third leading cause of death in liver recipients. However, because liver transplantation is the only definitive treatment for end-stage liver failure and also appears to reverse cardiac abnormalities, it is important to understand the challenges of the heart in liver transplantation. This review focuses on cardiac status before, during, and after liver transplantation. Liver Transplantation 23 826-835 2017 AASLD.

EMPA-REG OUTCOME: The Cardiologist's Point of View

Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardiovascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in this report.

The mechano-sensitivity of cardiac ATP-sensitive potassium channels is mediated by intrinsic MgATPase activity

Cardiac ATP-sensitive K+ (KATP) channel activity plays an important cardio-protective role in regulating excitability in response to metabolic stress. Evidence suggests that these channels are also mechano-sensitive and therefore may couple KATP channel activity to increased cardiac workloads. However, the molecular mechanism that couples membrane stretch to channel activity is not currently known. We hypothesized that membrane stretch may alter the intrinsic MgATPase activity of the cardiac KATP channel resulting in increased channel activation. The inside-out patch-clamp technique was used to record single-channel and macroscopic recombinant KATP channel activity in response to membrane stretch elicited by negative pipette pressure. We found that stretch activation requires the presence of the SUR subunit and that inhibition of MgATPase activity with either the non-hydrolysable ATP analog AMP-PNP or the ATPase inhibitor BeFx significantly reduced the stimulatory effect of stretch. We employed a point mutagenic approach to determine that a single residue (K1337) in the hairpin loop proximal to the major MgATPase catalytic site in the SUR2A subunit is responsible for the difference in mechano-sensitivity between SUR2A and SUR1 containing KATP channels. Moreover, using a double cysteine mutant substitution in the hairpin loop region revealed the importance of a key residue-residue interaction in this region that transduces membrane mechanical forces into KATP channel stimulation via increases in channel MgATPase activity. With respect to KATP channel pharmacology, glibenclamide, but not glicalizide or repaglinide, was able to completely inhibit KATP channel mechano-sensitivity. In summary, our results provide a highly plausible molecular mechanism by which mechanical membrane forces are rapidly converted in changes in KATP channel activity that have implications for our understanding of cardiac KATP channels in physiological or pathophysiological settings that involve increased workload.

Energy dynamics of the intraventricular vortex after mitral valve surgery.

Mitral valve morphology after mitral valve surgery affects postoperative intraventricular flow patterns and long-term cardiac performance. We visualized ventricular flow by echocardiography vector flow mapping (VFM) to reveal the impact of different mitral valve procedures. Eleven cases of mechanical mitral valve replacement (nine in the anti-anatomical and two in the anatomical position), three bioprosthetic mitral valve replacements, and four mitral valve repairs were evaluated. The mean age at the procedure was 57.4 ± 17.8year, and the echocardiography VFM in the apical long-axis view was performed 119.9 ± 126.7months later. Flow energy loss (EL), kinetic pressure (KP), and the flow energy efficiency ratio (EL/KP) were measured. The cases with MVR in the anatomical position and with valve repair had normal vortex directionality ("Clockwise"; N = 6), whereas those with MVR in the anti-anatomical position and with a bioprosthetic mitral valve had the vortex in the opposite direction ("Counterclockwise"; N = 12). During diastole, vortex direction had no effect on EL ("Clockwise": 0.080 ± 0.025W/m; "Counterclockwise": 0.083 ± 0.048W/m; P = 0.31) or KP ("Clockwise": 0.117 ± 0.021N; "Counterclockwise": 0.099 ± 0.057N; P = 0.023). However, during systole, the EL/KP ratio was significantly higher in the "Counterclockwise" vortex than that in the "Clockwise" vortex (1.056 ± 0.463 vs. 0.617 ± 0.158; P = 0.009). MVP and MVR with a mechanical valve in the anatomical position preserve the physiological vortex, whereas MVR with a mechanical valve in the anti-anatomical position and a bioprosthetic mitral valve generate inefficient vortex flow patterns, resulting in a potential increase in excessive cardiac workload.

Associations between hip bone mineral density, aortic calcification and cardiac workload in community-dwelling older Australians.

To determine whether there is an association between lower bone mineral density (BMD) and increased cardiac workload in older adults, and if this association was independent of abdominal aortic calcification (AAC). Three hundred thirty-seven participants [mean±SD age=70±5years and BMI=28±5kg/m2, 61% females] had BMD determined by dual-energy X-ray absorptiometry and AAC determined by radiography. Aortic calcification score (ACS) was determined visually in the L1-L4 vertebrae (range 0-24). Systolic blood pressure (BP) and heart rate (HR) were measured. The rate pressure product (RPP), a measure of cardiac workload, was determined by multiplying BP and HR. AAC was present in 205 (61%) participants. Mean±SD RPP was 9120±1823; range was 5424-18,537. In all participants, ACS was positively associated with log-transformed RPP [LnRPP] (β=0.011, p<0.001), and severe calcification was positively associated with LnRPP (β=0.083, p=0.004 relative to no calcification). In sex-stratified analyses, these associations were significant only in females. Lower odds of any AAC were observed per 1g/cm2 increment in femoral neck BMD (OR=0.08, 95% CI 0.01-0.95). A similar trend was evident in women separately (OR=0.05, 95% CI 0-1.17) but not men. In all participants, femoral neck (β=-0.20, p=0.04) and total hip BMD (β=-0.17, p=0.04) were inversely associated with LnRPP after multivariate adjustment. Adjusting additionally for AAC reduced the strength of the association in femoral neck (β=-0.19, p=0.05) but not total hip BMD (β=-0.17, p=0.04). Lower BMD was marginally, but significantly with increased LnRPP, and this relationship was partially mediated by AAC suggesting that older adults, particularly females, with osteoporosis may have an increased cardiovascular risk.

Platitudes and Attitudes.

Platitudes and Attitudes.

Science Signaling Podcast for 28 February 2017: Balancing autophagy in the stressed heart.

This Podcast features an interview with Saumya Das, senior author of a Research Article that appears in the 28 February 2017 issue of Science Signaling, about a protein that inhibits pathological cardiac hypertrophy in mice. Temporary increases in cardiac workload, such as those caused by exercise or pregnancy, induce physiological cardiac hypertrophy, a beneficial type of heart enlargement that is adaptive. However, a sustained increase in workload due to metabolic stress or uncontrolled high blood pressure induces pathological cardiac hypertrophy, which can contribute to heart failure. Simonson et al found that expression of DNA-damage-inducible transcript 4-like (DDiT4L) increased during pathological hypertrophy, but not during physiological hypertrophy, in mice. DDiT4L promoted stress-induced autophagy in cardiomyocytes by inhibiting signaling through the mechanistic target of rapamycin complex 1 (mTORC1) and stimulating signaling through mTORC2. These findings suggest that targeting autophagy, which is important for cellular homeostasis but can be detrimental in excess, may be useful for treating some cardiovascular diseases.Listen to Podcast.

A Theoretical Study on the Roles of Ca2+ in the Energy Metabolite Stability during Cardiac Workload Transition

The heart is a continuously working pump that is energetically driven by hydrolysis of ATP. Since the amount of ATP in the heart is small, ATP synthesis must increase so as to adapt to a rise in cardiac ATP demand. Therefore, the cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant during physiological cardiac workload transition. Ca2+ has been implicated to be one of the regulators of the constancy, though its detailed roles are not yet clarified. Here, we constructed and analyzed a detailed mathematical model of cardiac mitochondria which includes oxidative phosphorylation, substrate metabolism and ion/substrate transporters, based on experimental literatures, for the purpose of elucidating the roles of Ca2+-dependent regulation mechanisms in the metabolite constancy.The model well reproduced the experimental data on Ca2+- and inorganic phosphate (Pi)-dependencies of oxygen consumption, NADH level, and mitochondrial membrane potential, under the in vitro condition of isolated mitochondria with malate/glutamate used as substrates. When the model was incorporated into a simple cardiac cell model and malate/glutamate were used as substrates, the metabolite constancy could not be maintained at higher workload with cytosolic Ca2+ below physiological range ( ∼ 0.1 μM). Pi and NADH levels became stable during workload transition with higher cytosolic Ca2+. Interestingly, the Ca2+ dependency of NADH was influenced by the composition of cytosolic mitochondrial substrates. That is, the Ca2+-dependency of NADH almost disappeared and energy metabolites became more stable during workload transition under the in vivo condition that malate, glutamate, pyruvate, citrate and 2-oxoglutarate were used as substrates. It was revealed that composition of mitochondrial substrates is important for metabolite constancy during cardiac workload transition, and Ca2+ has only a minor role under physiological conditions. These results help us understanding the regulation mechanisms of cardiac energy metabolism under the physiological conditions.

Acute effect of intermittent and continuous aerobic exercise on release of cardiac troponin T in sedentary men

BackgroundStudies have shown that acute exercise can increase serum concentrations of cardiac biomarkers, including cardiac troponin T (cTnT). We investigated the acute effects of intermittent (IE) and continuous (CE) exercise at the same cardiac workload on myocardial necrosis biomarkers in sedentary men. MethodsEleven sedentary healthy men aged 22.3±1.9years completed the study. The subjects were divided into two groups and performed, in random order, IE (intensity alternating between 50% (2min) and 80% (1min) HRreserve) or CE (60% HRreserve). The study was designed as a single-blinded randomised crossover trial performed on two distinct experimental days separated by a 1-week washout period. Each session consisted of 40min of aerobic exercise, either IE or CE, on a treadmill. Blood samples were taken before (PRE), immediately after (POST) and 1h after (POST-1) each exercise session. Resultshs-cTnT significantly increased immediately after exercise in both protocols and remained elevated at POST-1 (P<0.05). There was no significant difference between POST and POST-1 values(P>0.05). Neither CE nor IE caused any significant change in CK-MB (P>0.05). The results also showed that HR and RPP increased significantly following both exercise protocols (P=0.001). ConclusionsIn summary, both CE and IE results in increased serum concentrations of hs-cTnT in sedentary men. However, this increase does not seem to be caused by the irreversible death of cardiomyocytes. CE resulted in a greater hs-cTnT concentration than IE.

Renal transplantation in a patient with alport syndrome and cardiac dysfunction: Role of levosimendan

Anesthetic management in patients with end-stage renal disease and cardiac dysfunction coming for renal transplant is very challenging since the maintenance of adequate cardiac output is essential for good graft function. Levosimendan is an inodilator that increases cardiac output without increasing cardiac workload. Hence, it is the drug of choice in patients with ischemic heart disease and congestive cardiac failure. We present successful perioperative management of a renal transplant recipient with left ventricular dysfunction using levosimendan for maintenance of stable hemodynamics. Levosimendan, an inodilator, can be safely used in patients with cardiac dysfunction coming for renal transplantation.

PENGUKURAN BEBAN KERJA KARYAWAN DALAM MENGANGKAT TBS DENGAN PENDEKATAN ERGONOMI DI PT INCASI RAYA MUARA SAKAI

PT Incasi Raya is one of the companies engaged in industry palm oil. The production of palm oil is mostly exported to all over the world market. The number of requests from the world market, then the company should be able to optimize the available manpower to meet demand.This study aims to determine the percentage of employees' workload of the heart's workload seen in the lifting of fresh fruit bunches using CVL method, analyze the position of the employee in the lift FFB whether in accordance with ergonomic approach. Data were analyzed quantitatively using the method of CVL (Cardiovascular load) by analyzing the positions of employees in lifting the fresh fruit bunches.Based on the results of the research, the percentage of employees receiving workload CVL biggest heart in block A with an average of 39.804% and the percentage of employees receiving CVL smallest cardiac workload on the block E with an average of 25.976% and the employee's position in the lifting of fresh fruit bunches into the dump the truck is not ergonomic. Keywords: Palm Oil, Workload, Ergonomics, Cardiovascular Load.

Increased cardiac workload in the upright posture in male subjects: non-invasive hemodynamics in men versus women

Increased cardiac workload in the upright posture in male subjects: non-invasive hemodynamics in men versus women

Abstract 13015: Inhibition of Mitochondrial Calcium Uptake in the Heart Does Not Compromise Cardiac Energetics or Function Due to a Preferential Increase in Fatty Acid Oxidation During Increased Cardiac Work

The mitochondrial calcium (Ca 2+ ) uniporter (MCU) is primarily responsible for relaying cytosolic Ca 2+ transients to the mitochondria. Increasing cardiac workload by positive inotropes results in increased mitochondrial Ca 2+ , increasing glucose oxidation in comparison to fatty acid oxidation. This has been attributed to Ca 2+ stimulation of pyruvate dehydrogenase, the rate-limiting enzyme in glucose oxidation. We examined what effect increasing workload has on cardiac energetics and cardiac function if mitochondrial Ca 2+ levels are decreased in hearts from inducible cardio-specific deleted MCU (MCU -/- ) mice. Hearts from MCU -/- and MCU fl/fl control mice were isolated and perfused as working hearts with 5 mM glucose, 0.8 mM palmitate, 3% albumin, ± insulin (100 μU/ml) and isoproterenol (10 nM). Surprisingly, MCU -/- hearts showed increased cardiac work (p&lt;0.05 vs. MCU fl/fl ). MCU -/- hearts were also not energy-starved, displaying basal rates of glucose and fatty acid oxidation comparable to controls, and even higher glucose oxidation in response to insulin (3027±213 vs. 2268±166 nmol . g dry wt -1. min -1 in MCU fl/fl , p &lt;0.05). In response to isoproterenol treatment, MCU -/- hearts showed a similar increase in glucose oxidation, compared to controls. However, palmitate oxidation increased to a larger extent in MCU -/- hearts compared to controls (793±60 vs. 558±55 nmol . g dry wt -1. min -1 , p &lt;0.05, respectively), resulting in a greater reliance on fatty acid oxidation for ATP production (40.1±1.9 % vs. 32.7±2.1% in MCU fl/fl , p &lt;0.05). This high fatty acid oxidation supported the higher energy demand at increased workload and provided a higher energy reserve as evident by higher acetyl-CoA/ CoA ratios (0.36±0.03 vs. 0.26±0.02 in MCU fl/fl , p&lt;0.05). The rise in fatty acid oxidation correlated with lower levels of malonyl CoA, an endogenous fatty acid oxidation inhibitor, (4.50±0.29 vs. 8.66±0.98 nmol . g dry wt -1 in MCU fl/fl , p&lt; 0.05), and to an increase in acetylation of the fatty acid oxidation enzyme 3-hydroxyacyl CoA dehydrogenase (which stimulates activity). These results suggest that low mitochondrial Ca 2+ does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation.

Abstract 13520: Empagliflozin Reduces Markers of Arterial Stiffness, Vascular Resistance and Cardiac Workload in EMPA-REG OUTCOME

Introduction: In EMPA-REG OUTCOME ® , empagliflozin added to standard of care in patients with type 2 diabetes and established vascular disease, significantly reduced the primary composite outcome of CV death, non-fatal myocardial infarction or non-fatal stroke, a result driven mainly by a 38% reduction in CV death. We aimed to assess the vascular effects of empagliflozin in the trial, beyond its recognized effects in reducing systolic blood pressure (SBP) and diastolic BP (DBP). Hypothesis: We hypothesized that empagliflozin reduced 1) pulse pressure (PP), a vascular marker of arterial stiffness determined by the cardiac output, the stiffness of elastic central arteries and wave reflection (PP = SBP - DBP), 2) mean arterial pressure (MAP), a measure reflecting the cardiac cycle determined by the cardiac output, systemic vascular resistance, and central venous pressure (MAP = ([2 x diastolic BP]+ systolic BP)/3), and 3) the double product (DP), a marker of cardiac workload and an indirect measure of myocardial oxygen demand (DP = heart rate x SBP). Methods: Patients with type 2 diabetes and high CV risk were randomised to receive placebo, empagliflozin 10 mg, or empagliflozin 25 mg in addition to standard of care. We analysed changes from baseline to week 164 for SBP, DBP, HR, PP, MAP and DP, between treatment and placebo groups using a mixed model repeated measures analysis. Results: In total, 2333, 2345 and 2342 patients received placebo, empagliflozin 10 mg and empagliflozin 25 mg, respectively and followed for a median period of 3.1 years. There were nominal significantly greater reductions in PP, MAP and DP with empagliflozin treatment as compared with placebo (Table), without increases in mean HR (Table). Conclusions: Empagliflozin had favorable effects on BP, arterial stiffness, vascular resistance and on the indirect measure of cardiac workload. Further analyses are needed to determine the potential contribution of these changes to the reduction in CV mortality.

Blood pressure reduction after gastric bypass surgery is explained by a decrease in cardiac output.

The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients.

A simulation study on the constancy of cardiac energy metabolites during workload transition

The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant during physiological cardiac workload transition. How this is accomplished is not yet clarified, though Ca2+ has been suggested to be one of the possible mechanisms. We constructed a detailed mathematical model of cardiac mitochondria based on experimental data and studied whether known Ca2+ -dependent regulation mechanisms play roles in the metabolite constancy. Model simulations revealed that the Ca2+ -dependent regulation mechanisms have important roles under the in vitro condition of isolated mitochondria where malate and glutamate were mitochondrial substrates, while they have only a minor role and the composition of substrates has marked influence on the metabolite constancy during workload transition under the simulated in vivo condition where many substrates exist. These results help us understand the regulation mechanisms of cardiac energy metabolism during physiological cardiac workload transition. The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant over a wide range of cardiac workload, though the mechanisms are not yet clarified. One possible regulator of mitochondrial metabolism is Ca2+ , because it activates several mitochondrial enzymes and transporters. Here we constructed a mathematical model of cardiac mitochondria, including oxidative phosphorylation, substrate metabolism and ion/substrate transporters, based on experimental data, and studied whether the Ca2+ -dependent activation mechanisms play roles in metabolite constancy. Under the in vitro condition of isolated mitochondria, where malate and glutamate were used as mitochondrial substrates, the model well reproduced the Ca2+ and inorganic phosphate (Pi ) dependences of oxygen consumption, NADH level and mitochondrial membrane potential. The Ca2+ -dependent activations of the aspartate/glutamate carrier and the F1 Fo -ATPase, and the Pi -dependent activation of Complex III were key factors in reproducing the experimental data. When the mitochondrial model was implemented in a simple cardiac cell model, simulation of workload transition revealed that cytoplasmic Ca2+ concentration ([Ca2+ ]cyt ) within the physiological range markedly increased NADH level. However, the addition of pyruvate or citrate attenuated the Ca2+ dependence of NADH during the workload transition. Under the simulated in vivo condition where malate, glutamate, pyruvate, citrate and 2-oxoglutarate were used as mitochondrial substrates, the energy metabolites were more stable during the workload transition and NADH level was almost insensitive to [Ca2+ ]cyt . It was revealed that mitochondrial substrates have a significant influence on metabolite constancy during cardiac workload transition, and Ca2+ has only a minor role under physiological conditions.

Design, synthesis, and negative inotropic evaluation of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties.

In this study, four novel series of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties were designed, synthesized, and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations. Almost all of the compounds showed an ability to moderate the cardiac workload by decreasing the heart rate and contractility. Among them, 7h was found to be the most potent with a change in stroke volume of -48.22±0.36% at a concentration of 3×10-5 mol/L (metoprolol: -9.74±0.14%). The cytotoxicity of these compounds was evaluated using the human cervical cancer cell line HeLa, the liver cancer cell line Hep3B, and the human normal hepatic cell line LO2. A preliminary study of the mechanism of action for the compound 7h on the regulation of atrial dynamics with ATP-sensitive K+ channel and L-type Ca2+ channel blockers glibenclamide and nifedipine was performed in the isolated perfused beating rabbit atria.

Hypoglycemia and Cardiovascular Risk: Is There a Major Link?

Severe hypoglycemia is recognized to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in patients with type 2 diabetes. However, it is uncertain whether a direct pathophysiological link exists or whether hypoglycemia is primarily a marker of vulnerability to these events. Large clinical trials have reported an increased hazard ratio for all-cause mortality and cardiovascular events in patients with type 2 diabetes and severe hypoglycemia, but such an association has not been demonstrated in prospective trials of people with type 1 diabetes. Several cardiovascular effects occur during hypoglycemia either as a result of low blood glucose levels per se or through activation of the sympathoadrenal response: hemodynamic changes with an increase in cardiac work load and potential attenuation of myocardial perfusion, electrophysiological changes that may be arrhythmogenic, induction of a prothrombotic state, and release of inflammatory markers. Although the potential for a causal relationship has been demonstrated in mechanistic studies, the evidence from large prospective studies that hypoglycemia is a major causal contributor to cardiovascular events is limited to date. Other preexisting cardiovascular risk factors in addition to hypoglycemia may be the major link to the final cardiovascular event, but a low blood glucose level can trigger these events in patients with a high cardiovascular risk.

Low Relative Lean Mass is Associated with Increased Likelihood of Abdominal Aortic Calcification in Community-Dwelling Older Australians.

Age-related loss of skeletal muscle is associated with increased risk of functional limitation and cardiovascular (CV) mortality. In the elderly abdominal aortic calcification (AAC) can increase CV risk by altering aortic properties which may raise blood pressure and increase cardiac workload. This study investigated the association between low muscle mass and AAC in community-dwelling older Australians. Data for this cross-sectional analysis were drawn from a 2010 sub-study of the Melbourne Collaborative Cohort Study in the setting of community-dwelling older adults. Three hundred and twenty-seven participants [mean age=71±6years; mean BMI=28±5kg/m(2); females n=199 (62%)] had body composition determined by dual-energy x-ray absorptiometry (DXA) and AAC determined by radiography. Participants were stratified into tertiles of sex-specific BMI-normalised appendicular lean mass (ALM). Those in the lowest tertile were considered to have low relative muscle mass. Aortic calcification score (ACS) was determined visually as the extent of calcification on the aortic walls between L1 and L4 vertebrae (range: 0-24). Severe AAC was defined as ACS≥6. Prevalence of any AAC was highest in participants with low relative muscle mass (74%) compared to the middle (65%) and upper (53%) tertiles (p trend=0.006). The lower ALM/BMI tertile had increased odds (Odds ratio=2.3; 95% confidence interval: 1.1-4.6; p=0.021) of having any AAC; and having more severe AAC (2.2; 1.2-4.0; p=0.009) independent of CV risk factors, serum calcium and physical activity. AAC is more prevalent and severe in community-dwelling older adults with low relative muscle mass. Maintaining muscle mass could form part of a broader primary prevention strategy in reducing AAC.

DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling.

Mitogen-activated protein kinase (MAPK) signaling regulates the growth response of the adult myocardium in response to increased cardiac workload or pathological insults. The dual-specificity phosphatases (DUSPs) are critical effectors, which dephosphorylate the MAPKs to control the basal tone, amplitude, and duration of MAPK signaling. To examine DUSP8 as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiac myocyte growth dynamics. Dusp8 gene-deleted mice and transgenic mice with inducible expression of DUSP8 in the heart were used here to investigate how this MAPK-phosphatase might regulate intracellular signaling and cardiac growth dynamics in vivo. Dusp8 gene-deleted mice were mildly hypercontractile at baseline with a cardiac phenotype of concentric ventricular remodeling, which protected them from progressing towards heart failure in 2 surgery-induced disease models. Cardiac-specific overexpression of DUSP8 produced spontaneous eccentric remodeling and ventricular dilation with heart failure. At the cellular level, adult cardiac myocytes from Dusp8 gene-deleted mice were thicker and shorter, whereas DUSP8 overexpression promoted cardiac myocyte lengthening with a loss of thickness. Mechanistically, activation of extracellular signal-regulated kinases 1/2 were selectively increased in Dusp8 gene-deleted hearts at baseline and following acute pathological stress stimulation, whereas p38 MAPK and c-Jun N-terminal kinases were mostly unaffected. These results indicate that DUSP8 controls basal and acute stress-induced extracellular signal-regulated kinases 1/2 signaling in adult cardiac myocytes that then alters the length-width growth dynamics of individual cardiac myocytes, which further alters contractility, ventricular remodeling, and disease susceptibility.