Cardiac Work Research Articles

The utility of impedance cardiography in hemodynamic monitoring of patients with sepsis

BackgroundCommonly used biochemical indicators and hemodynamic and physiologic parameters of sepsis vary with regard to their sensitivity and specificity to the diagnosis. The aim of this preliminary study was to...

674PD - Perioperative FLOT + anti-PD-L1 avelumab (FLOT-A) chemo-immunotherapy in resectable oesophagogastric adenocarcinoma (OGA): Safety and biomarker data from the ICONIC trial safety run-in

BackgroundICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. MethodsEligible pts were enrolled into the 3+3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. ResultsAt data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1pt), thrombotic event (1pt) and cardiac chest pain (1pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. ConclusionsThis is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification2016-003306-13. Legal entity responsible for the studyRoyal Marsden Hospitals NHS Foundation Trust. FundingRoyal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. DisclosureM. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Abnormal aortic flow conduction is associated with increased viscous energy loss in patients with repaired tetralogy of Fallot.

Aortopathy in tetralogy of Fallot (TOF) is characterized by increased aortic stiffness, dilation and reduced left ventricular (LV) function. Repair in infancy normalizes aortic dimensions in early childhood. Our prior work demonstrated that early TOF repair does not normalize aortic compliance and that abnormal ascending aortic flow patterns are prevalent. The objectives of this study were to: (i) determine whether proximal aortic flow-mediated viscous energy loss (EL') is elevated in patients with early TOF repair compared with healthy controls, and (ii) determine whether the degree of EL' is associated with LV function. Forty-one patients post TOF repair with normalized aortic size and 15 healthy controls underwent 4-dimenisonal-flow magnetic resonance imaging flow analysis and EL' assessment. Correlations between EL', aortic size, and LV function were assessed. The TOF group had increased peak systolic thoracic aorta EL' (3.8 vs 1.5 mW, P = 0.004) and increased averaged EL' throughout the cardiac cycle (1.2 vs 0.5 mW, P = 0.003). Peak and mean systolic EL' in the ascending aorta was increased 2-fold in the TOF group compared with control (peak: 2.0 vs 0.9 mW, P = 0.007). Peak EL' measured along the entire thoracic aortic length correlated with LV ejection fraction (R = -0.45, P = 0.009), indexed LV end-systolic volume (R = -0.40, P = 0.010), and right ventricular end-systolic volume (R = -0.37, P = 0.034). Patients with repaired TOF exhibit abnormal aortic flow associated with increased EL' in the thoracic aorta. The magnitude of EL' is associated with LV function and volumes. Increased aortic EL' in TOF is likely due to inherently abnormal LV outflow geometry and or right ventricular interaction. Reduced aortic flow efficiency in TOF increases cardiac work and may be an important factor in long-term cardiac performance.

Abstract P2062: Vitamin D Supplementation Improves Vascular Function in Adolescents Suffering from Orthostatic Intolerance

Background: In previous work we identified a group of adolescents whose diagnostic workup for chronic unexplained nausea revealed underlying cardiovascular instability manifesting as orthostatic intolerance (OI) and syncope. These patients exhibited impairment in autonomic and vascular function and excessive release of catecholamines upon head up tilt compared to pre tilt. They also had low vitamin D level that correlated with the severity of symptoms on tilt. In this pilot study we hypothesized that vitamin D supplementation to normal levels will improve the vascular function in these participants. Methods: A cohort of ten Adolescents (mean age= 16.3 years) who are vitamin D deficient had a head up tilt at baseline and after two months of vitamin D supplementation (2000-5000 IU daily based on baseline level). Heart rate, blood pressure, cardiac work index, arterial compliance and pulse wave velocity (PWV) were measured in supine position. Results: As shown in the table. Compared to baseline, vitamin D supplementation improved vitamin D level, arterial compliance and reduced cardiac work index under stress challenge and baseline PWV. Conclusions: Vitamin D supplementation for two months restored vitamin D to normal levels and was associated with improvement in the vascular function. These data provides evidence of potential therapeutic benefit of vitamin D supplementation for patients suffering from orthostatic intolerance and syncope who are vitamin D deficient.

Cardiopulmonary Exercise Testing, Impedance Cardiography, and Reclassification of Risk in Patients Referred for Heart Failure Evaluation

An impaired cardiac output response to exercise is a hallmark of chronic heart failure (HF). We determined the extent to which impedance cardiography (ICG) during exercise in combination with cardiopulmonary exercise test (CPX) responses reclassified risk for adverse events in patients with HF. CPX and ICG were performed in 1236 consecutive patients (48±15 years) evaluated for HF. Clinical, ICG and CPX variables were acquired at baseline and subjects were followed for the composite outcome of cardiac-related death, hospitalization for worsening HF, cardiac transplantation, and left ventricular assist device implantation. Cox proportional hazards analyses including clinical, noninvasive hemodynamic, and CPX variables were performed to determine their association with the composite endpoint. Net reclassification improvement (NRI) was calculated to quantify the impact of adding hemodynamic responses to a model including established CPX risk markers on reclassifying risk. There were 422 events. Among CPX variables, peak VO2 and indices of ventilatory inefficiency (VE/VCO2 slope, oxygen uptake efficiency slope) were significant predictors of risk for adverse events. Among hemodynamic variables, change in cardiac index, peak cardiac time interval, and peak left cardiac work index were the strongest predictors of risk. Having 5 impaired CPX and ICG responses to exercise yielded a sevenfold higher risk for adverse events compared with having no abnormal responses. Combining ICG responses to CPX resulted in NRIs ranging between 0.34 and 0.89, attributable to better reclassification of events. Cardiac hemodynamics determined by ICG complement established CPX measures in reclassifying risk among patients with HF.

Indicators of the left ventricular-arterial coupling interaction in chronic forms of ischemic heart disease: relationships of the protradenomedullin and N-terminal probrain natriuretic peptide

Analyze the parameters of the interaction between the left ventricle and the arterial system in patients with chronic forms of coronary heart disease and to identify relationships with levels of proadrenomedullin (MR‑proADM) and N‑terminal precursor of the brain natriuretic peptide B (NT‑proBNP). 240 patients with chronic forms of coronary heart disease (median - 55,9 [43; 63] years) and Q‑forming myocardial infarction in the past were examined. Of these, 110 patients with myocardial infarction and preserved lef ventricular ejection fraction and 130 patients with ischemic cardiomyopathy. All patients were calculated parameters of lef ventricular‑arterial interaction and the determination in blood serum levels of MR‑proADM and NT‑proBNP. In patients with ischemic cardiomyopathy, an increase in the lef ventricular‑arterial interaction index was detected (2,51 [1,18; 5,00]), which reflects a decrease in the functional abilities and efficiency of the heart. In patients with myocardial infarction and a preserved left ventricular ejection fraction, this indicator was in the range of normal values (0,78 [0,55; 1,07]), which indicates an effective cardiac work. A study of MR‑proADM and NT‑proBNP levels demonstrated an increase in both groups (1,72 [1,56; 1,98] nmol/l and 779,3 [473; 2193] pg/ml in the group of patients with ischemic cardiomyopathy; 0,89 [0,51; 1,35] nmol/l and 246 [118; 430] pg/ml in the group of patients with myocardial infarction and preserved left ventricular ejection fraction), and the correlation analysis with left ventricular‑arterial coupling interaction parameters allowed identify statistically significant connections (in the group of patients with ischemic cardiomyopathy: with the level of MR‑proADM ‑ r=0,67, p=0,006, with the level of NT‑proBNP ‑ r=0,78, p<0,001; in the group of patients with myocardial infarction and preserved left ventricular ejection fraction: with MR‑proADM level ‑ r=‑0,52, p=0,024, with NT‑proBNP level ‑ r =‑0,38, p=0,037). The findings suggest a pathogenetic association between the biomarkers under study and the parameters of left ventricular‑arterial coupling interaction.

Acute Soy Supplementation Improves 20-km Time Trial Performance, Power, and Speed.

Isoflavones, a chemical class of phytoestrogens found in soybeans and soy products, may have biological functions similar to estradiol. After binding with ERβ or perhaps independently of estrogen receptors, isoflavones may augment vascular endothelial relaxation, contributing to improved limb blood flow. To determine if acute fermented soy extract supplementation influences 20-km time trial cycling performance and cardiac hemodynamics compared with a placebo. Subjects included 25 cyclists and triathletes (31 ± 8 yr, V˙O2peak: 55.1 ± 8.4 mL·kg·min). Each subject completed a V˙O2peak assessment, familiarization, and two 20-km time trials in randomized order after ingestion of a fermented soy extract supplement or placebo. The fermented soy extract consisted of 30 g powdered supplement in 16 fl. ounces of water. The placebo contained the same quantities of organic cocoa powder and water. Each trial consisted of 60 min of rest, 30 min at 55% Wpeak, and a self-paced 20-km time trial. Soy supplementation elicited a faster time to 20-km completion (-0.22 ± 0.51 min; -13 s), lower average HR (-5 ± 7 bpm), and significantly greater power (7 ± 3 W) and speed (0.42 ± 0.16 km·h) during the last 5 km of the time trial compared with placebo. Analysis of the results by relative fitness level (<57 vs ≥ 57 mL⋅kg⋅min) indicated that those with a higher level of fitness reaped the largest performance improvement alongside a reduced HR (-5 ± 7 bpm). Ingestion of a fermented soy extract supplement improved sprint-distance performance through improvements in both power and speed. For those with great aerobic fitness, soy supplementation may help to decrease cardiac demand alongside performance improvement.

Descriptions and outcomes of cardiac evaluations in pediatric patients hospitalized for asthma

Objective: Patients hospitalized for asthma can exhibit concurrent cardiac symptoms and undergo cardiac work up. We identify patients admitted for asthma that underwent cardiac workup and describe outcomes to evaluate the utility of cardiac testing in this population.Methods: Patients aged 4 to 17 years admitted for status asthmaticus from 2012 - 2016 were screened for EKG, ECHO, or cardiac enzyme obtainment.Results: Out of 1296 patients, 77 (6%) received cardiac testing. The most common reasons for testing were chest pain (25, 32%), blood pressure abnormalities (11, 14%), tachycardia (8, 10%), arrhythmia (6, 8%), and syncope (6, 8%). Sinus tachycardia (43, 66%) was the most common EKG finding. 4 out of 27 patients who underwent ECHOs had abnormalities: 2 with hypertrophic cardiomyopathy (HCM), 1 with vascular ring, and 1 with evidence of pulmonary hypertension. All patients who underwent an EKG to evaluate tachycardia had normalization of heart rate at discharge. Cardiac ischemia was not evident in any patients who underwent workup with cardiac enzymes to evaluate chest pain. All cases of arrhythmias resolved on discharge. Diastolic hypotension (DhTN) was found in 10 out of the 11 blood pressure abnormalities. There was mixed efficacy of fluid bolus in correcting DhTN. All DhTN resolved on discharge. One patient with syncope had a new diagnosis of HCM.Conclusions: While cardiac complications are seen in patients admitted for status asthmaticus, the etiology rarely stems from underlying cardiac disease. EKGs, ECHOs, and cardiac enzymes should have a minimal role in the management of the hospitalized asthmatic patient.

Near-Newtonian Blood Behavior - Is It Good to Be a Camel?

From a certain level of exercise-intensity onward, hematocrit increases in horses, which brings more oxygen carriers into the bloodstream. Camels, however, when used in competitive racing could be even in need of iron supplementation and blood transfusions due to a severe reduction of their available hematocrit compared to their resting hematocrit. Since the extrinsic and intrinsic mechanical properties of camel erythrocytes (RBC) are so different compared to RBCs of other mammals, the question arises whether this observation might be a response to endurance exercise aiming at keeping the RBC count low. Rheometry indicated dromedary camel blood to behave almost Newtonian, which is unique amongst mammals. Shear thinning did increase with the hematocrit, but remained marginal compared to horses. As a result, camel whole blood viscosity (WBV) exceeded horse WBV at high shear rates, an effect, which was significantly augmented when the packed cell volume (PCV) was increased. Therefore, in camels any infusion of RBCs into the bloodstream can increase the cardiac work and the energy input into the endothelium more effectively, which should generate vascular remodeling in the long term. Yielding, however, was completely absent in camel blood, confirming low cohesion between its components at quasi-static flow. Camel blood remained a viscous liquid without a threshold even at unphysiologically high PCVs. This can help to washout lactate when camels start to dehydrate and might contribute to the sustained working ability of these animals. The subtle pseudoplastic behavior and the high viscosity contrast across the RBC membrane point to weak coupling between blood flow and red cell behavior. We predict that RBCs flow as separate entities and can show various types of motion, which can lead to friction instead of being collectively aligned to the flow direction. In comparison to horses, this behavior will become relevant at higher RBC counts in front of flow obstacles and possibly cause vascular remodeling if the PCV rises during strenuous exercise, a matter that should be avoided.

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging

Changes in the myocardial energetics associated with aging—reductions in creatine phosphate/ATP ratio, total creatine, and ATP—mirror changes observed in failing hearts compared to healthy controls. Similarly, both aging and heart failure are associated with significant reductions in cardiac performance and maximal left ventricular cardiac power output compared with young healthy individuals. Based on these observations, we hypothesize that reductions in the concentrations of cytoplasmic adenine nucleotide, creatine, and phosphate pools that occur with aging impair the myocardial capacity to synthesize ATP at physiological free energy levels and that the resulting changes to myocardial energetic status impair the mechanical pumping ability of the heart. The purpose of this study is to test these hypotheses using an age-structured population model for myocardial metabolism in the adult female population and to determine the potential impact of reductions in key myocardial metabolite pools in causing metabolic/energetic and cardiac mechanical dysfunction associated with aging. To test these hypotheses, we developed a population model for myocardial energetics to predict myocardial ATP, ADP, creatine phosphate, creatine, and inorganic phosphate concentrations as functions of cardiac work and age in the adult female population. Model predictions support our hypotheses and are consistent with previous experimental observations. The major findings provide a novel, to our knowledge, theoretical and computational framework for further probing complex relationships between the energetics and performance of the heart with aging.

TARGET TREATMENT OF PRIMARY ALDOSTERONISM AFFECTS CARDIAC WORK AND BIOENERGETICS

Objective: We hypothesized that hyperaldosteronism along with renin suppression can induce an energetically inefficient cardiac mechanical work in humans. Design and method: To test this hypothesis we investigated the LV mechanical efficiency by measuring myocardial mechano-energetic efficiency (MEE) and its modification after target treatment in patients with PA and essential hypertension (EH) with normal LV ejection fraction, in comparison with age-matched healthy control subjects (HS). Left ventricular (LV) dimension and systolic function, stroke volume (SV), stroke work (SW), and cardiac output (CO) were also estimated at baseline, and after adrenalectomy or medical treatment. MEE was estimated by echocardiographic SV (z-derived)/(heart rate x 0.6) and normalized for LV mass (MEEi ml/s x g). Results: We recruited 178 PA patients (age 51 ± 11 years), 78 EH patients (age 55 ± 14 years) and 60 HS (age 54 ± 11 years). At baseline, both PA and EH patients showed similarly increased LV dimension, LV mass, SV, SW and similarly reduced MEEi (PA 0.86 ± 0.2, EH 0.91 ± 0.2) compared with HS (1.07 ± 0.2, p < 0.0001). Among PA patients, those with eccentric LVH showed higher MEEi (1.06 ± 0.2 vs 0.78 ± 0.2, p < 0.0001), SV (96 ± 22 vs 81 ± 14, p < 0.0001), and CO (6.6 ± 0.1 vs 5.4 ± 0.1, p = 0.002) than those with concentric LVH. By regression analysis plasma aldosterone concentration, systolic blood pressure (BP) and body mass index (BMI) were identified as predictors of MEEi. At follow up surgically treated PA and EH showed a significant reduction of BP, LV mass and rate of LVH (PA 48% vs 69% at baseline, p = 0.001; EH 54% vs 65% at baseline, p < 0.05) and SW, and increase of arterial compliance and (not significant) of MEEi. Surgically treated PA showed also a reduction of SV (75 ± 19 vs 82 ± 16 at baseline, p < 0.0001) and CO (5.1 ± 1.4 vs 5.6 ± 1.3 at baseline, p = 0.001), not observed in medically treated PA patients. Conclusions: The lower myocardial mechano-energetic efficiency of PA patients with concentric than with eccentric LVH suggests a more detrimental effect of the former type of LV remodeling. Importantly, at follow-up LV mechano-energetic efficiency improved more in surgically-treated than in medically treated PA patients despite similar BP reductions.

Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency

BackgroundImpaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. ObjectivesTo determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. MethodsC57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. ResultsIn contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. ConclusionsThese results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.

Stable coronary artery disease: are there therapeutic benefits of heart rate lowering?

: A physiologically lower heart rate, such as that seen in athletes, has been associated with better survival in epidemiological studies. In patients with coronary artery disease, heart rate is considered an independent risk factor for adverse outcomes. Higher heart rate increases cardiac work load and oxygen demand and reduces coronary perfusion by decreasing the amount of time spent in diastole, which in patients with obstructive coronary artery disease can trigger angina and myocardial infarction. Whether pharmacological reduction in heart rate by using a beta-blocker or ivabradine improves prognosis has been debated. In this review, we explore the effect of pharmacological heart rate lowering with a beta-blocker or ivabradine on cardiovascular outcomes in patients with cardiovascular disease and address the question as to whether pharmacological heart rate reduction is ready for prime time in the management of patients with coronary artery disease. Although physiologically lower heart rates are associated with improved survival, the effect of pharmacological heart rate reduction with beta-blockers (in patients without heart failure or postmyocardial infarction) or ivabradine on improvement in survival is weak at best.

Revascularisation and mechanical circulatory support in patients with ischaemic cardiogenic shock

### Learning objectives Cardiogenic shock (CGS) complicates 5 – 10% of cases of acute myocardial infarction (AMI) and the most common cause of CGS is AMI (80% of cases).1 When...

Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM.

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by ventricular hypertrophy, myofibrillar disarray, and fibrosis, and is primarily caused by mutations in sarcomeric genes. With no definitive cure for HCM, there is an urgent need for the development of novel preventive and reparative therapies. This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at Ser15-RLC phosphorylation site (S15D-RLC) into the hearts of humanized HCM-D166V mice. Improvement of heart function was monitored by echocardiography, invasive hemodynamics (PV-loops) and muscle contractile mechanics. A significant increase in cardiac output and stroke work and a decrease in relaxation constant, Tau, shown to be prolonged in HCM mice, were observed in AAV- vs. PBS-injected HCM mice. Strain analysis showed enhanced myocardial longitudinal shortening in AAV-treated vs. control mice. In addition, increased maximal contractile force was observed in skinned papillary muscles from AAV-injected HCM hearts. Our data suggest that myosin RLC phosphorylation may have important translational implications for the treatment of RLCmutations-induced HCM and possibly play a role in other disease settings accompanied by depressed Ser15-RLC phosphorylation. KEY MESSAGES: HCM-D166V mice show decreased RLC phosphorylation and decompensated function. AAV9-S15D-RLC gene therapy in HCM-D166V mice, but not in WT-RLC, results in improved heart performance. Global longitudinal strain analysis shows enhanced contractility in AAV vs controls. Increased systolic and diastolic function is paralleled by higher contractile force. Phosphomimic S15D-RLC has a therapeutic potential for HCM.

Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization.

The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300mg PO) 24h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60min coronary occlusion followed by 2h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.

The Role of Kv1.2 Channels in Coronary Metabolic Dilation

The coupling between metabolism and flow in the heart is critical for normal cardiac function, because the myocardium depends on a continuous supply of oxygenated blood for aerobic metabolism and energy production. If this coupling is altered, the imbalance could lead coronary insufficiency causing areas of hypoxia and ischemia in the heart. Recently we proposed that one component of this coupling is mediated by mitochondrial production of hydrogen peroxide (H2O2), which activates Kv1.5 channels in coronary smooth muscle. Our present goal was to ascertain if Kv1.2 channels, that are known to be redox sensitive, serve as a metabolic sensor in the heart to engender coupling of flow to metabolism. To accomplish this goal, we used Kv1.2+/− mice (Kv1.2−/− is lethal) to evaluate coronary metabolic dilation, i.e., the relationship between myocardial blood flow and cardiac work. Myocardial blood flow was measured using contrast echocardiography. Graded doses of norepinephrine (NE) were used to increase cardiac work (CW) and myocardial blood flow was measured during these incremental changes in work. Cardiac work was calculated as a triple product of mean arterial pressure × heart rate × stroke volume. We also isolated coronary arterioles and tested their vasodilatory responses to endothelium-dependent and –independent agonists. As shown in panel A, vasodilation to hydrogen peroxide was significantly lower in arterioles isolated from Kv1.2+/− mice compared to wild-type mice (WT). Vasodilation was lower at any given concentration of H2O2. Although not shown, the responses between the two groups were similar for acetylcholine and sodium nitroprusside. Panel B shows the relationship between myocardial blood flow and cardiac work. In Kv1.2+/− mice myocardial blood flow at baseline was similar to WT mice. However, when CW was increased via NE infusion, for any incremental increase in work, myocardial blood flow was less in Kv1.2+/− compared to WT mice (P<0.05). For example, at the highest dose of NE, myocardial blood flow in the Kv1.2+/− and WT were 23±3 vs 34±2 ml/min/g, respectively (P<0.05). Taken together, our results indicate that Kv1.2 channels, a redox sensitive channel in the Kv1 family, are involved in the coupling of myocardial blood flow to cardiac work. Support or Funding Information AHA10POST4360030; R01 HL135024; RO1HL135110 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A short chain fatty acid produced by the gut microbiota plays a role in blood pressure regulation and cardiac contractility

Recent studies by our laboratory and others have highlighted the important role played by short chain fatty acids (SCFA) produced by the gut microbiota and their effect on host physiology. Acetate, the most abundant SCFA present in the blood, has been shown to modulate blood pressure control through at least two mechanisms; renin release in the juxtaglomerular apparatus, and changes in vascular tone in peripheral resistance beds (Pluznick, Protzko et al. 2013). Prior studies by our laboratory have shown that intravenous administration of SCFAs causes acute hypotension in anesthetized mice (Pluznick, Protzko et al. 2013). These prior studies suggested that acetate was acting purely on the peripheral vasculature to cause a vasodilatory effect, as treating vessels with acetate ex‐vivo resulted in relaxation (Natarajan, Hori et al. 2016). To expand upon these findings, here we performed IP injections of acetate in mice that were implanted with DSI telemetry transmitters to monitor blood pressure and heart rate (HR) in real time. Sodium acetate was delivered at a 1g/kg dose via IP, a dose which we have previously found to elevate plasma acetate by 3–4 fold over baseline. This resulted in a rapid and reproducible drop in mean arterial pressure (MAP) (−54.32 +/− 14.20 mmHg maximum drop, n=4, p&lt;0.05) when compared to an IP injection of the same volume of saline. The duration, but not the magnitude of the blood pressure drop was dose dependent based on IP injections of sodium acetate at 0.625 g/kg (27.08 +/− 4.80 minutes to ½ recovery vs 15.57 +/− 7.24 minutes, n=4, p&lt;0.05). Surprisingly, in addition to a significant depression of blood pressure, mice injected with acetate also showed a significant depression in heart rate (−233.50 +/− 101.20 bpm maximum drop, n=4, p&lt;0.05). Preliminary data using combinatory injections of acetate and the vasoconstrictor phenylephrine show a potential attenuation of the blood pressure drop caused by acetate, suggesting a strong vascular component to the physiological effects of acetate. However, had acetate purely been acting on the vasculature, we would have expected heart rate to increase. Lower doses of acetate (0.625g/kg) also yielded a drop in heart rate not significantly different from the 1g/kg dose. To further probe the effects of exogenous acetate administration on specific cardiac functions, pressure volume loops were performed in rats and acetate was administered intravenously at a continuous infusion to provide a steady, measurable effect. Rats treated with acetate showed a significant decrease in cardiac stroke work, developed pressure, and dP/dtmax, and a significant increase in dP/dtmin (n=4, p&lt;0.05), indicating a potential effect on contractility. We hypothesize that acetate acts both on the peripheral vasculature and the cardiac muscle, with both components contributing to the blood pressure and heart rate effects seen in whole animals. Together these data hint at a previously unknown and potentially detrimental effect of short chain fatty acids on cardiac function, and efforts are underway to further what role these effects play in whole organism physiology.Support or Funding InformationFunding: F31HL144061, R01HL128512, R01DK107726This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Function of the KCNQ1 Potassium Ion Channel in the Human Heart

KCNQ1 is a homotetrameric voltage‐gated potassium ion channel subunit protein. KCNQ1 is the alpha‐subunit of the ion channel and forms heteromultimers with protein members of the KCNE family (“beta subunits”) to create a pore in the membrane of a cell. Two of these beta subunits are KCNE1 and KCNE3. Under physiological conditions, four KCNQ1 alpha subunits combine with two or four beta subunits to form the potassium ion channel. The alpha subunits form the structure of the channel whereas the beta subunit binds onto the channel and regulates its activity. KCNQ1 is embedded in the membranes of numerous types of cells, including cardiac myocytes, epithelial cells, and cells in the human inner ear. In human cardiac myocytes, KCNQ1 and KCNE1 work to regulate the rhythm of the heart by controlling the repolarization phase of the cardiac action potential. Almost three hundred mutations have been identified in the KCNQ1 gene, which is located on chromosome 11. The majority of these are missense mutations and alter the protein's structure to the extent that the flow of potassium ions out of the cardiac cells is disrupted. The most common condition resulting from a mutation in KCNQ1 in hereditary Long QT Syndrome (LQTS), which is characterized by a delay in the ventricular repolarization component of a heart beat. Symptoms associated with LQTS include dizziness, fainting, and potentially seizures and sudden death. In rare cases, a mutation in KCNQ1 can also cause further complications, which include atrial fibrillation, Short QT syndrome, and Jervell and Romano‐Ward syndrome. Treatments are available for LQTS, such as making lifestyle changes, taking beta blockers, and implanting a defibrillator. Current research in medication for LQTS is centered around compounds such as hexachlorophene that can target the individual subunits in the ion channel as opposed to the entire channel. Pairing compounds with this ability may provide enough correction to the subunits that LQTS can be effectively “cured.” The Walton High School SMART Team has designed a 3D model of the KCNQ1 ion channel using JMOL to investigate the relationship between structure and function.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Alterations in Myocardial Oxygen Balance, Anaerobic Metabolism and Diastolic Dysfunction in Exercising Swine with Multiple Comorbidities

IntroductionMultiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) are associated with diastolic dysfunction. These risk factors also cause coronary microvascular dysfunction leading to impaired myocardial perfusion and ischemia with non‐obstructive coronary artery disease (INOCA). Recently a link has been proposed between INOCA and HFpEF. We investigated the detrimental effects of DM, CKD and high fat diet (HFD) on myocardial function and perfusion.HypothesisProlonged exposure to multiple comorbidities in swine leads to diastolic dysfunction, associated with impaired myocardial perfusion and anaerobic metabolism.MethodsDM (streptozotocin 3×50mg/kg i.v.) and CKD (renal embolization) were induced in 7 female swine fed a high fat diet (DM+HFD+CKD), while 10 female healthy swine on normal diet served as controls (CON). After 6 months, myocardial perfusion and oxygen balance were studied at rest and during treadmill exercise. At sacrifice PV‐loop measurements and histology were performed.ResultsDM+HFD+CKD animals showed hyperglycemia (glucose: 19.2±1.5 vs 7.5±0.6 mmol/L), renal dysfunction (glomerular filtration rate: 132±14 vs 197±10 ml/min) and hypercholesterolemia (total cholesterol: 8.28±0.86 vs 1.65±0.06 mmol/l, all P&lt;0.05). DM+HFD+CKD had an increased EDPVR (0.14±0.02 vs 0.09±0.01 mmHg/mL) with preserved ejection fraction, a lower cardiac index compared to CON at similar levels of exercise (fig A). Left ventricular myocardial capillary density was decreased (1229±59 vs 1502±86 #/mm2) and collagen content was increased (9.6±1.9 vs 5.0±0.6 %). Their myocardium required more oxygen for similar levels of cardiac work, suggesting cardiac inefficiency (fig B). Furthermore, they showed a lower myocardial oxygen delivery (fig C), forcing the myocardium to increase its oxygen extraction (fig D) leading to lower coronary venous oxygen saturation (fig E) both at rest and during exercise. This was accompanied by a decrease in myocardial lactate consumption at the same lactate supply as in CON (fig F), suggestive of anaerobic metabolism. Importantly, DM+HFD+CKD showed no coronary atherosclerosis.ConclusionMultiple co‐morbidities in swine result in severe perturbations in myocardial oxygen balance and anaerobic metabolism in the absence of significant atherosclerosis, indicating severe coronary microvascular dysfunction co‐occurring with diastolic dysfunction.Support or Funding InformationThis study was supported by grants from the European Commission FP7‐Health‐2010 grant MEDIA‐261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2012‐08 (PHAEDRA), CVON2014‐11 (RECONNECT)]. Cardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p&lt;0.05 DM+HFD+CKD versus CONimageCardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p&lt;0.05 DM+HFD+CKD versus CONThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.