Cardiac Workload Research Articles

Right Ventricular Assessment in Critically Ill COVID-19 Patients and its Prognostic Importance

Background; Cardiac injury is a prevalent complication and is associated with worse prognosis in COVID-19 patients. The increased cardiac workload resulting from respiratory failure and hypoxemia is a common mechanism of cardiac injury and the right ventricle may bear the brunt of its impact. The aim of the present study was to determine the incidence and prognostic value of RV dysfunction in COVID-19 patients admitted to ICU using conventional echocardiography parameters.Patients were subjected to full history taking, and clinical examination, Computed Tomography of chest was done for all patients to assess severity of lung infiltration, all patients received standard treatment according to Ministry of Health and Population COVID19 treatment protocol recommendations. Echocardiographic assessment was done to all patients.The mean age of the patients was 61.10±9.64years (range 42-80years).There were 36 (60%) male and 24 (40%) female. The non-survivor group consisted of 28 patients (46.7%) and survivors consisted of 32 patients (53.3%). There was statistically significant association between mortality and RV function regarding TAPSE, FAC%, RV basal diameter and EPAP. We concluded that in COVID-19 patients, RV function must be assessed and its prognostic importance recognized. RV dysfunction is not only a symptom of high pulmonary pressures, but it also contributes to cardiac insufficiency.

Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure

Mitochondrial calcium (mCa2+) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive mCa2+ uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the involvement of mCa2+ signaling in cardiac adaptations to chronic stress remains poorly defined. Changes in NCLX expression are reported in heart failure (HF) patients and models of cardiac hypertrophy. Therefore, we hypothesized that altered mCa2+ homeostasis contributes to the hypertrophic remodeling of the myocardium that occurs upon a sustained increase in cardiac workload. The impact of mCa2+ flux on cardiac function and remodeling was examined by subjecting mice with cardiomyocyte-specific overexpression (OE) of the mitochondrial Na+/Ca2+ exchanger (NCLX), the primary mediator of mCa2+ efflux, to several well-established models of hypertrophic and non-ischemic HF. Cardiomyocyte NCLX-OE preserved contractile function, prevented hypertrophy and fibrosis, and attenuated maladaptive gene programs in mice subjected to chronic pressure overload. Hypertrophy was attenuated in NCLX-OE mice, prior to any decline in cardiac contractility. NCLX-OE similarly attenuated deleterious cardiac remodeling in mice subjected to chronic neurohormonal stimulation. However, cardiomyocyte NCLX-OE unexpectedly reduced overall survival in mice subjected to severe neurohormonal stress with angiotensin II + phenylephrine. Adenoviral NCLX expression limited mCa2+ accumulation, oxidative metabolism, and de novo protein synthesis during hypertrophic stimulation of cardiomyocytes in vitro. Our findings provide genetic evidence for the contribution of mCa2+ to early pathological remodeling in non-ischemic heart disease, but also highlight a deleterious consequence of increasing mCa2+ efflux when the heart is subjected to extreme, sustained neurohormonal stress.

Cardiovascular events after liver transplantation: MACE hurts.

The curative therapy for patients with end-stage liver disease is liver transplantation. However, liver transplantation challenges the cardiovascular system, and is associated with major adverse cardiovascular events (MACE). Immediately after implantation of the liver graft, changes in cardiac preload and afterload increase the cardiac workload. Longer-term postoperatively, a more sedentary lifestyle and enhanced appetite increase obesity and body mass index. Immunosuppressants may also affect the cardiovascular system. All these factors that liver recipients encounter impact the function of the cardiovascular system. Cardiac events are the third-leading cause of death in liver recipients. This review describes the pertinent factors that predispose to development of MACE after liver transplantation, and how to predict these cardiovascular events in the post-transplant period. We review the roles of metabolic syndrome, renal dysfunction, non-alcoholic fatty liver disease, diagnostic tests such as imaging and biomarkers, and parameters such as systolic and diastolic dysfunction, and QT interval prolongation in cardiovascular events. We summarize the current literature on scoring systems to predict cardiovascular events.

Posture-Related Differences in Cardiovascular Function Between Young Men and Women: Study of Noninvasive Hemodynamics in Rural Malawi.

BackgroundCardiovascular risk is higher in men than in women, but little information exists about sex‐related differences in cardiovascular function from low‐income countries. We compared hemodynamics between sexes in rural Malawi in a cohort followed up since their birth.Methods and ResultsSupine, seated, and standing hemodynamics were recorded from 251 women and 168 men (mean age, 21 years; body mass index, 21 kg/m2) using oscillometric brachial waveform analyses (Mobil‐O‐Graph). The results were adjusted for estimated glomerular filtration rate, and plasma potassium, lipids, and glucose. Men had higher brachial and aortic systolic blood pressure and stroke index regardless of posture (P<0.001), and higher upright but similar supine diastolic blood pressure than women. Regardless of posture, heart rate was lower in men (P<0.001), whereas cardiac index did not differ between sexes. Women presented with lower supine and standing systemic vascular resistance index (P<0.001), whereas supine‐to‐standing increase in vascular resistance (P=0.012) and decrease in cardiac index (P=0.010) were higher in women. Supine left cardiac work index was similar in both sexes, whereas standing and seated left cardiac work index was higher in men than in women (P<0.001).ConclusionsIn young Malawian adults, men had higher systolic blood pressure, systemic vascular resistance, and upright cardiac workload, whereas women presented with higher posture‐related changes in systemic vascular resistance and cardiac output. These findings show systematic sex‐related differences in cardiovascular function in a cohort from a low‐income country with high exposure to prenatal and postnatal malnutrition and infectious diseases.

Transcatheter Mitral Intervention Relieves Dynamic Outflow Obstruction and Reduces Cardiac Workload in Hypertrophic Cardiomyopathy.

Transcatheter Mitral Intervention Relieves Dynamic Outflow Obstruction and Reduces Cardiac Workload in Hypertrophic Cardiomyopathy.

IP3 receptor orchestrates maladaptive vascular responses in heart failure.

Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC–/– mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC–/– mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC–/– mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC–/– mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.

Preoperative Left Ventricular Energy Loss in the Operating Theater Reflects Subjective Symptoms in Chronic Aortic Regurgitation.

BackgroundThere is currently no subjective, definitive evaluation method for therapeutic indication other than symptoms in aortic regurgitation. Energy loss, a novel parameter of cardiac workload, can be visualized and quantified using echocardiography vector flow mapping. The purpose of the present study was to evaluate whether energy loss in patients with chronic aortic regurgitation can quantify their subjective symptoms more clearly than other conventional metrics.MethodsWe studied 15 patients undergoing elective aortic valve surgery for aortic regurgitation. We divided the patients into symptomatic and asymptomatic groups using their admission records. We analyzed the mean energy loss in one cardiac cycle using transesophageal echocardiography during the preoperative period. The relationships between symptoms, energy loss, and other conventional metrics were statistically analyzed.ResultsThere were seven and eight patients in the symptomatic and asymptomatic groups, respectively. The mean energy loss of one cardiac cycle was higher in the symptomatic group (121 mW/m [96–184]) than in the asymptomatic group (87 mW/m [80–103]) (p = 0.040), whereas the diastolic diameter was higher in the asymptomatic group (65 mm [59–78]) than in the symptomatic group (57 mm [51–57]) (p = 0.040). There was no significant difference between the symptomatic and asymptomatic groups in terms of other conventional metrics.ConclusionsAn energy loss can quantify patients' subjective symptoms more clearly than other conventional metrics. The small sample size is the primary limitation of our study, further studies assessing larger cohort of patients are warranted to validate our findings.

Piezo1 and TRPM4 work in tandem to initiate cardiac hypertrophic signalling in response to pressure overload

Pathological left ventricular hypertrophy (LVH) occurs in response to an increased cardiac workload or injury and remains the single most important clinical predictor of cardiac mortality. Two very common clinical conditions, essential hypertension, and aortic valve stenosis leading to LVH are currently treated by medications that lower blood pressure or replacement of the stenotic aortic valve, respectively. Nonetheless, they do not completely reverse the pathological effects on the myocardium once LVH is established.

Hemodynamic Parameters for Cardiovascular System in 4D Flow MRI: Mathematical Definition and Clinical Applications.

Blood flow imaging becomes an emerging trend in cardiology with the recent progress in computer technology. It not only visualizes colorful flow velocity streamlines but also quantifies the mechanical stress on cardiovascular structures; thus, it can provide the detailed inspections of the pathophysiology of diseases and predict the prognosis of cardiovascular functions. Clinical applications include the comprehensive assessment of hemodynamics and cardiac functions in echocardiography vector flow mapping (VFM), 4D flow MRI, and surgical planning as a simulation medicine in computational fluid dynamics (CFD).For evaluation of the hemodynamics, novel mathematically derived parameters obtained using measured velocity distributions are essential. Among them, the traditional and typical parameters are wall shear stress (WSS) and its related parameters. These parameters indicate the mechanical damages to endothelial cells, resulting in degenerative intimal change in vascular diseases. Apart from WSS, there are abundant parameters that describe the strength of the vortical and/or helical flow patterns. For instance, vorticity, enstrophy, and circulation indicate the rotating flow strength or power of 2D vortical flows. In addition, helicity, which is defined as the cross-linking number of the vortex filaments, indicates the 3D helical flow strength and adequately describes the turbulent flow in the aortic root in cases with complicated anatomies. For the description of turbulence caused by the diseased flow, there exist two types of parameters based on completely different concepts, namely: energy loss (EL) and turbulent kinetic energy (TKE). EL is the dissipated energy with blood viscosity and evaluates the cardiac workload related to the prognosis of heart failure. TKE describes the fluctuation in kinetic energy during turbulence, which describes the severity of the diseases that cause jet flow. These parameters are based on intuitive and clear physiological concepts, and are suitable for in vivo flow measurements using inner velocity profiles.

The hypotensive effect of the aqueous calyx extract of Hibiscus sabdariffa may occur through the attenuation of Autonomic nervous system activity.

This study tested the hypothesis that the hypotensive effect of the aqueous calyx extract of Hibiscus sabdariffa (HS) occurs through autonomic mechanisms that may be associated with a reduction in the double product (DP) of the heart. Experiments were performed in accordance with the Principles of the Declaration of Helsinki. Following ethical approval and informed consent, the Harvard step test (HST) was performed in healthy subjects (n=14) to activate the autonomic nervous system before and after the oral administration of 15mg/kg HS. The blood pressure (BP) and heart rate (HR) responses were measured and DPs and the mean arterial pressure (MAP) were calculated. Results were expressed as mean ±SEM. Paired t-test and one way ANOVA with a posthoc Bonferoni test were used for statistical analyses. P<0.05 was considered significant. HST without HS resulted in a significant rise in MAP, HR and DP (112.6±2.7mmHg, 97.7±2.5/min and 12630.0±642 mmHg.bpm) from the basal values (98.5±2.3mmHg, 76.5±2.0/min and 8730.7±354.9 mmHg.bpm, P<0.001, P<0.01 and P<0.001 respectively). In the presence of HS, HST-induced changes (∆MAP=7.8±1.6mmHg; ∆HR=8.1±1.6/min; ∆DP= 1113.6±103.4 mmHg.bpm) were significantly dampened compared to its absence (∆MAP= 13.3±2.6mmHg; ∆HR=17.0±3.7/min; ∆DP= 3899.3±287.2 mmHg.bpm; P<0.001, P<0.01 and P<0.0001 respectively). The HST-induced increase in BP, HR and DP suggest sympathetic nervous system (SNS) activation and parasympathetic nervous system (PNS) withdrawal associated with an increased cardiac O2 consumption and workload. These were dampened by HS suggesting that its hypotensive effect occurs through the inhibition of SNS activation, PNS withdrawal and an associated reduction in cardiac O2 demand and workload.

The hypotensive effect of the aqueous calyx extract of Hibiscus sabdariffa may occur through the attenuation of Autonomic nervous system activity

This study tested the hypothesis that the hypotensive effect of the aqueous calyx extract of Hibiscus sabdariffa (HS) occurs through autonomic mechanisms that may be associated with a reduction in the double product (DP) of the heart. Experiments were performed in accordance with the Principles of the Declaration of Helsinki. Following ethical approval and informed consent, the Harvard step test (HST) was performed in healthy subjects (n=14) to activate the autonomic nervous system before and after the oral administration of 15mg/kg HS. The blood pressure (BP) and heart rate (HR) responses were measured and DPs and the mean arterial pressure (MAP) were calculated. Results were expressed as mean ±SEM. Paired t-test and one way ANOVA with a posthoc Bonferoni test were used for statistical analyses. P&lt;0.05 was considered significant. HST without HS resulted in a significant rise in MAP, HR and DP (112.6±2.7mmHg, 97.7±2.5/min and 12630.0±642 mmHg.bpm) from the basal values (98.5±2.3mmHg, 76.5±2.0/min and 8730.7±354.9 mmHg.bpm, P&lt;0.001, P&lt;0.01 and P&lt;0.001 respectively). In the presence of HS, HST-induced changes (∆MAP=7.8±1.6mmHg; ∆HR=8.1±1.6/min; ∆DP= 1113.6±103.4 mmHg.bpm) were significantly dampened compared to its absence (∆MAP= 13.3±2.6mmHg; ∆HR=17.0±3.7/min; ∆DP= 3899.3±287.2 mmHg.bpm; P&lt;0.001, P&lt;0.01 and P&lt;0.0001 respectively). The HST-induced increase in BP, HR and DP suggest sympathetic nervous system (SNS) activation and parasympathetic nervous system (PNS) withdrawal associated with an increased cardiac O2 consumption and workload. These were dampened by HS suggesting that its hypotensive effect occurs through the inhibition of SNS activation, PNS withdrawal and an associated reduction in cardiac O2 demand and workload.

Biventricular Compared to Left Ventricular Impella and Norepinephrine Support in a Porcine Model of Severe Cardiogenic Shock.

Contemporary management of cardiogenic shock (CS) with vasopressors is associated with increased cardiac workload and despite the use of unloading devices such as the Impella pump, concomitant vasopressors are often necessary. Therefore, we compared if cardiac workload could be reduced and end-organ perfusion preserved with biventricular support (Bipella) compared to ImpellaCP and norepinephrine in pigs with left ventricular (LV) CS caused by left main coronary microembolization. Cardiac workload was calculated from heart rate × ventricular pressure-volume area obtained from conductance catheters placed in the LV and right ventricle (RV), whereas organ perfusion was measured from venous oxygen saturation in the pulmonary artery (SvO 2 ) and the kidney- and the cerebral vein. A cross-over design was used to access the difference after 30 minutes of ImpellaCP and norepinephrine 0.1 µg/kg/min versus Bipella for 60 minutes. Bipella treatment reduced LV workload ( p = 0.0078) without significant difference in RV workload from ImpellaCP and norepinephrine, however a decrease in SvO 2 (49[44-58] vs . 66[63-73]%, p = 0.01) and cerebral venous oxygen saturations (62[48-66] vs . 71[63-77]%, p = 0.016) was observed during Bipella compared to ImpellaCP and norepinephrine. We conclude that Bipella reduced LV workload but did not preserve end-organ perfusion compared to ImpellaCP and norepinephrine in short-term LV CS.

Exercise in Water Provides Better Cardiac Energy Efficiency Than on Land.

Although water-based exercise is one of the most recommended forms of physical activity, little information is available regarding its influence on cardiac workload and myocardial oxygen supply-to-demand. To address this question, we compared subendocardial viability ratio (SEVR, the ratio of myocardial oxygen supply-to-demand), cardiac inotropy (via the maximum rate of aortic pressure rise [dP/dTmax]), and stroke volume (SV, via a Modelflow method) responses between water- and land-based exercise. Eleven healthy men aged 24 ± 1 years underwent mild- to moderate-intensity cycling exercise in water (WC) and on land (LC) consecutively on separate days. In WC, cardiorespiratory variables were monitored during leg cycling exercise (30, 45, and 60 rpm of cadence for 5 min each) using an immersible stationary bicycle. In LC, each participant performed a cycling exercise at the oxygen consumption (VO2) matched to the WC. SEVR and dP/dTmax were obtained by using the pulse wave analysis from peripheral arterial pressure waveforms. With increasing exercise intensity, SEVR exhibited similar progressive reductions in WC (from 211 ± 44 to 75 ± 11%) and LC (from 215 ± 34 to 78 ± 9%) (intensity effect: P < 0.001) without their conditional differences. WC showed higher SV at rest and a smaller increase in SV than LC (environment-intensity interaction: P = 0.009). The main effect of environment on SV was significant (P = 0.002), but that of dP/dTmax was not (P = 0.155). SV was correlated with dP/dTmax (r = 0.717, P < 0.001). When analysis of covariance (ANCOVA) was performed with dP/dTmax as a covariate, the environment effect on SV was still significant (P < 0.001), although environment-intensity interaction was abolished (P = 0.543). These results suggest that water-based exercise does not elicit unfavorable myocardial oxygen supply-to-demand balance at mild-to-moderate intensity compared with land-based exercise. Rather, water-based exercise may achieve higher SV and better myocardial energy efficiency than land-based exercise, even at the same inotropic force.

Sex differences in the coronary vascular response to combined chemoreflex and metaboreflex stimulation in healthy humans.

What is the central question of this study? Coronary blood flow in healthy humans is controlled by both local metabolic signalling and adrenergic activity: does the integration of these signals during acute hypoxia and adrenergic activation differ between sexes? What are the main findings and its importance? Both males and females exhibit an increase in coronary blood velocity in response to acute hypoxia, a response that is constrained by adrenergic stimulation in males but not females. These findings suggest that coronary blood flow control differs between males and females. Coronary hyperaemia is mediated through multiple signalling pathways, including local metabolic messengers and adrenergic stimulation. This study aimed to determine whether the coronary vascular response to adrenergic stressors is different between sexes in normoxia and hypoxia. Young, healthy participants (n=32; 16F) underwent three randomized trials of isometric handgrip exercise followed by post-exercise circulatory occlusion (PECO) to activate the muscle metaboreflex. End-tidal was controlled at (1) normoxic levels throughout the trial, (2) 50mmHg for the duration of the trial (hypoxia trial), or (3) 50mmHg only during PECO (mixed trial). Mean left anterior descending coronary artery velocity (LADVmean ; transthoracic Doppler echocardiography), heart rate and blood pressure were assessed at baseline and during PECO. In normoxia, there was no change in LADVmean or cardiac workload induced by PECO in males and females. Acute hypoxia increased baseline LADVmean to a greater extent in males compared with females (P<0.05), despite a similar increase in cardiac workload. The change in LADVmean induced by PECO was similar between sexes in normoxia (P=0.31), greater in males during the mixed trial (male: 12.8 (7.7) cm/s vs. female: 8.1 (6.3) cm/s; P=0.02) and reduced in males but not females in acute hypoxia (male: -4.8 (4.5) cm/s vs. female: 0.8 (6.2) cm/s; P=0.006). In summary, sex differences in the coronary vasodilatory response to hypoxia were observed, and metaboreflex activation during hypoxia caused a paradoxical reduction in coronary blood velocity in males but not females.

Cardiorespiratory fitness bolsters cerebrovascular health in adults at risk for Alzheimer’s disease

AbstractBackgroundCerebral blood flow (CBF) alterations and brain microvascular deficits contribute to progression of Alzheimer’s disease (AD). The aim of this series of studies was to evaluate whether cardiorespiratory fitness (CRF) supports cerebrovascular health among individuals at risk for AD.MethodsFour studies were conducted among participants from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center. Both cohorts are enriched for AD risk due to parental history and/or the APOE e4 allele. Study 1 assessed resting cardiac workload via rate pressure product (RPP=systolic blood pressure*heart rate). Study 2 used 4D flow MRI to quantify pulsatility index [PI=(flowmax–flowmin)/flowmean] in cerebral large vessels. Study 3 deployed 3D arterial spin labeling imaging to measure CBF. Study 4 assessed white matter hyperintensity (WMH) lesion volume using 3D MRI scans. In these studies, CRF was assessed via gold‐standard graded maximal exercise test or estimated using a validated formula; physical activity (PA) was measured using accelerometry; amyloid and tau were measured from cerebrospinal fluid. Multiple linear regression was used to assess associations among the variables of interest in each study.ResultsStudy 1 established a positive association between RPP and p‐tau and t‐tau, but not Ab42. This effect was exacerbated in old age. Study 2 revealed that higher CRF was associated with lower PI in the internal carotid and basilar arteries and that traditional cardiovascular risk factors partly mediate those associations. Study 3 revealed that CRF, but not PA, was positively associated with CBF in brain regions vulnerable to hypoperfusion in aging and AD. This effect was stronger among females. Study 4 revealed that increasing age was associated with WMH lesion volume and that this relationship is attenuated by CRF.ConclusionThese studies support that deleterious cardio‐ and cerebrovascular characteristics associated with AD risk may be ameliorated by CRF, and that age and sex are important modifiers deserving of greater attention in future studies. Notably, CRF appears to exert a stronger effect than PA per se. In sum, CRF is a modifiable physiological characteristic that may reduce cerebrovascular risk in individuals with familial or genetic predisposition to AD.

Metabolic adaptation to the chronic loss of Ca2+ signaling induced by KO of IP3 receptors or the mitochondrial Ca2+ uniporter

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP3R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely because of adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.

Abstract 10484: Cardiac Adaptation to Acute Haemodynamic Stress in Patients with Type 2 Diabetes

Background: Due to varying cardiac workloads, efficient demand-supply matching is crucial for maintaining normal cardiac function. Cardiac metabolism is profoundly affected by changes in cardiac workload. There is scarcity of non-invasive studies evaluating how the heart adapts to hemodynamic stress in type 2 diabetes (T2D) patients. Objectives: Using cardiovascular magnetic resonance (CMR) and 31 Phosphorus MR spectroscopy ( 31 P-MRS) we assessed changes in cardiac energetics, perfusion, strain, systolic and diastolic function in response to increases in cardiac workload with dobutamine stress in T2D patients and healthy volunteers (HV). Methods: 24 T2D patients and 18 matched HV were recruited. Participants with ischemic heart disease were excluded. Results: Table-1 shows clinical and CMR/ 31 P-MRS data. Compared to HV, T2D patients showed reductions in left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at rest, and a blunted increase in LVEF and GLS during stress. Diastolic function was impaired in T2D with lower mitral in-flow E/A ratio compared to HV at rest, which was further reduced during stress in both groups. Stress myocardial blood flow was lower in T2D patients.Compared to HV, rest phosphocreatinine (PCr)/ATP ratio was 17% lower in T2D patients, with a further 8% reduction during stress. However, there was a more pronounced reduction in the PCr/ATP with stress in HV (33% relative reduction), although stress PCr/ATP remained numerically higher in HV compared to T2D patients. Conclusions: T2D is associated with blunted ability of the myocardium to significantly increase contractile function from rest to stress. Moreover, T2D patients show exacerbated reductions in myocardial energetics and diastolic function during stress. Although reductions in myocardial energetics and diastolic function in response to acute stress were also detected in HV, these assessments remained higher in HV at stress compared to T2D patients.

Abstract 9321: Cardiac Work and End-Organ Perfusion During Biventricular Compared to Left Ventricular Impella and Norepinephrine Support in a Porcine Model of Severe Cardiogenic Shock

Background: Vasopressors are often combined with left ventricular (LV) mechanical support in severe cardiogenic shock to increase end-organ perfusion. Biventricular mechanical support might improve end-organ perfusion at lower cardiac workload compared to LV mechanical support and vasopressor infusion in severe cardiogenic shock. Aim: To compare LV and right ventricular (RV) total cardiac work (pressure-volume area x heart rate x 10 3 ) and organ-specific venous oxygen saturations from the pulmonary artery (SvO 2 ), kidney- and cerebral- veins in pigs with cardiogenic shock treated with biventricular (Bipella) versus ImpellaCP + norepinephrine 0.10 μg/kg/min (Imp+NE). Methods: Cardiogenic shock was induced by injections of microspheres into the left main coronary artery in eight pigs (approx. 70 kg). From conductance catheters in both ventricles, cardiac workload was calculated, and oxygen saturations were attained from the pulmonary artery, internal jugular- and kidney vein. Pigs were allocated in a crossover model to Bipella for 60 minutes (n=4) or Imp+NE for 30 minutes (n=4) and after completion shifted to the opposite treatment. Results are presented as median(Q1;Q3). Results: Bipella effectively unloaded the LV with reduction in LV work compared to Imp+NE (569[410-685] vs 357[206-509] 10 3 ml x mmHg/min, p=0.0078) while RV work was comparable (p=0.74). A significant increase in SvO 2 (66[63-73] vs 49[44-58]%, p=0.01) and cerebral venous oxygen saturations (71[63-77] vs 62[48-66]%, p=0.016) was observed during Imp+NE compared to Bipella, whereas no difference in kidney oxygen saturations was demonstrated (p=0.31). Conclusion: In this porcine study of cardiogenic shock due to left main coronary ischemia, Bipella decreased LV workload, but systemic oxygen delivery was not optimal (Figure). Imp+NE provided a higher LV workload balanced by an improvement in cerebral- and mixed venous oxygen saturation.

Post-Transfusion Takotsubo Cardiomyopathy

In three recent cases an initial transfusion-related adverse event (TRAE) occurred that had a significant respiratory component, and other features suggesting a severe allergic reaction. All were treated as such. Shortly after treatment the nature of the event changed to something resembling transfusion-associated circulatory overload (TACO).These cases suggest the possibility that a severe TRAE that is not TACO may precipitate TACO. In other words, some transfusions, sometimes, may deliver a ‘double whammy’. A possible mechanism might be through the development of Takotsubo, or stress, cardiomyopathy - a cause of acute, reversible, heart failure. Takotsubo cardiomyopathy typically presents with chest pain or shortness of breath. Ventricular wall dysfunction occurs, and characteristic echocardiographic abnormalities are seen. ECG and biochemical features suggest cardiac ischaemia. It is commoner in post-menopausal women. A range of ‘stressors’ - hypotension, asthma attacks, accidents, medical procedures, pain, bad news, etc. - may precipitate it. 1 Catecholamines such as adrenaline are believed to play a central role. They cause direct toxicity to the myocardium, and also coronary artery spasm, and increased cardiac workload. 2 One other such case is reported. There, a 48 years old post-menopausal woman developed acute reversible heart failure with the features of Takotsubo cardiomyopathy, following urticaria and pruritus, whilst having a platelet transfusion. No adrenaline was given, but the authors postulate that adrenergic and histaminergic elements may have combined to produce the effect on the heart. 3 Thus, in some patients the ‘perfect storm’ compounded of 1.borderline cardiac function,2.catecholamine release (secondary to the stress of the underlying disorder, the transfusion, and the TRAE),3.histamine release (in allergic TRAE),4.the treatment of the allergic reaction with adrenaline5.recent or ongoing volume overloadmay be sufficient to precipitate or exacerbate TACO. Careful consideration of cases with similar features is needed. Potential precipitating factors are modifiable or preventable.

Role of Cardiac AMP-Activated Protein Kinase in a Non-pathological Setting: Evidence From Cardiomyocyte-Specific, Inducible AMP-Activated Protein Kinase α1α2-Knockout Mice.

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.