Science of left ventricular unloading.

The concept of left ventricular unloading has its foundation in heart physiology. In fact, the left ventricular mechanics and energetics represent the cornerstone of this approach. The novel sophisticated therapies for acute heart failure, particularly mechanical circulatory supports, strongly impact on the mechanical functioning and energy consuption of the heart, ultimately affecting left ventricle loading. Notably, extracorporeal circulatory life support which is implemented for life-threatening conditions, may even overload the left heart, requiring additional unloading strategies. As a consequence, the understanding of ventricular overload, and the associated potential unloading strategies, founds its utility in several aspects of day-by-day clinical practice. Emerging clinical and pre-clinical research on left ventricular unloading and its benefits in heart failure and recovery has been conducted, providing meaningful insights for therapeutical interventions. Here, we review the current knowledge on left ventricular unloading, from physiology and molecular biology to its application in heart failure and recovery.

The Role of Speckle Tracking Echocardiography in the Evaluation of Advanced-Heart-Failure Patients.

Health care is currently showing a fall in heart failure (HF) incidence and prevalence, particularly in developed countries, but with only a subset receiving appropriate therapy to protect the heart against maladaptive processes such as fibrosis and hypertrophy. Appropriate markers of advanced HF remain unidentified, which would help in choosing the most suitable therapy and avoid major compliance problems. Speckle tracking echocardiography (STE) is a good choice, being a non-invasive imaging technique which is able to assess cardiac deformation in a variety of conditions. Several multicenter studies and meta-analyses have demonstrated the clinical application and accuracy of STE in early and late stages of HF, as well as its association with both left ventricular (LV) filling pressures and myocardial oxygen consumption. Furthermore, STE assists in assessing right ventricular free-wall longitudinal strain (RVFWLS), which is a solid predictor of right ventricle failure (RVF) following LV assist device (LVAD) implantation. However, STE is known for its limitations; despite these, it has been shown to explain symptoms and signs and also to be an accurate prognosticator. The aim of this review is to examine the advantages of STE in the early evaluation of myocardial dysfunction and its correlation with right heart catheterization (RHC) parameters, which should have significant clinical relevance in the management of HF patients.

Changes in rate-pressure product associated with pregnancy.

BACKGROUND: In nonpregnant individuals, the rate-pressure product, the product of heart rate and systolic blood pressure, is used as a noninvasive surrogate of myocardial O2 consumption during cardiac stress testing. Pregnancy is considered a physiological cardiovascular stress test. Evidence describing the impact of pregnancy on myocardial O2 demand, as assessed by the rate-pressure product, is limited. OBJECTIVE: This study aimed to describe changes in the rate-pressure product for each pregnancy trimester, during labor and delivery, and the postpartum period among low-risk pregnancies. STUDY DESIGN: This was a retrospective cohort study that assessed uncomplicated pregnancies delivered vaginally at term. We collected rate-pressure product (heart rate × systolic blood pressure) values preconception, during pregnancy for each trimester (at ≤13 weeks + 6/7 days, at 14 weeks + 0/7 days through 27 weeks + 6/7 days, and at ≥28 weeks + 0/7 days), during the labor and delivery encounter (hospital admission until complete cervical dilation, complete cervical dilation until placental delivery, and after placental delivery until hospital discharge), and during the outpatient postpartum visit at 2 to 6 weeks after delivery. We calculated the percentage change at each time point from the preconception rate-pressure product (delta rate-pressure product). We used a mixed-linear model to analyze differences in the mean delta rate-pressure product over time and the influence of prepregnancy age, prepregnancy body mass index, and neuraxial anesthesia status during labor and delivery on these estimates. RESULTS: Our cohort comprised 316 patients. The mean rate-pressure product increased significantly from preconception starting at the third trimester of pregnancy and during labor and delivery (P≤.05). The mean delta rate-pressure product peaked at 12% and 38% in the third trimester and during labor and delivery, respectively. Prepregnancy body mass index was inversely correlated with the mean delta rate-pressure product changes (estimate, -0.308; 95% confidence interval, -0.536 to -0.80; P=.008). In contrast, neither the prepregnancy age, nor neuraxial anesthesia status during labor had a significant influence on this parameter. CONCLUSION: This study validates the transient but significant increase in the rate-pressure product, a clinical estimate of myocardial O2 demand, during uncomplicated pregnancies delivered vaginally at term. Pregnant individuals with lower prepregnancy body mass index experienced a sharper increase in this parameter. Patients who receive neuraxial anesthesia during labor and delivery experience similar changes in the rate-pressure product as those who did not.

Índice de eficiencia miocárdica en cardiópatas posterior a un programa de rehabilitación cardiaca / Myocardial efficiency index in patients with heart disease after a cardiac rehabilitation program

Resumen Objetivo: El índice de eficiencia miocárdica (IEM) correlaciona el consumo miocárdico de oxígeno (MVO2) con el consumo máximo de oxígeno, el cual proporciona información sobre la eficiencia cardiovascular (EfCV). En deportistas, el IEM mejora posterior a un microciclo de entrenamiento, en el paciente con enfermedad cardiovascular sometido a un programa de rehabilitación cardiaca y prevención secundaria PRHCyPS, el comportamiento del IEM podría resultar un estimador relacionado con mejoría derivado de un periodo de entrenamiento. El objetivo del estudio fue determinar el comportamiento del IEM posterior a un PRCyPS en pacientes con cardiopatías y riesgo cardiovascular alto (RCVA). Métodos: Estudio de cohorte ambilectivo, descriptivo, analítico, no aleatorizado. Se seleccionaron pacientes con cardiopatías de etiología mixta con RCVA ingresados a un PRCyPS durante 4-6 semanas. A todos los pacientes se les realizó una prueba de ejercicio máximo en banda antes y después del PRCyPS. Se determinaron umbrales de consumo de oxígeno (VO2) pico, equivalentes metabólicos-carga, doble producto e IEM. Se estableció un punto de corte del IEM mediante una curva ROC con un valor de 7.37 con un área bajo la curva de 0.68 (IC 95%: 0.61-0.76; p < 0.001), sensibilidad 0.60 y 1-especificidad de 0.35. Resultados: Se incluyeron 193 pacientes con una media de edad de 62.3 años, en su mayoría del sexo masculino (66.2%). Se observaron porcentajes de cambio en el IEM -27.1% (p < 0.001), MET 43.1% (p < 0.001), doble producto 5.7% (p < 0.01) y MVO2: 8.3% (p < 0.01) al término del PRCyPS. Conclusiones: Se observó un cambio significativo en el IEM posterior a un PRCyPS, lo cual se asoció a una mejoría en la EfCV, sugiriendo que este pueda considerarse como un parámetro clínico que evaluar en los programas de rehabilitación cardiaca.

Abstract Objective: The myocardial efficiency index (MEI) correlates the Myocardial Oxygen Consumption (MVO2) with the Maximum Oxygen Consumption (VO2max), this index provides information about the cardiovascular efficiency (CVEf). In athletes, the MEI improves after a micro-cycle training, however in patients with cardiovascular disease undergoing Cardiac Rehabilitation Program (CRP), IEM behavior could be a good estimator related to the improvement training period. The objective of this study was to determine the myocardial efficiency index behavior in patients with heart disease and high cardiovascular risk (HCVR) after a CRP. Methods: Ambilective, descriptive, analytical, non-randomized cohort study was conducted. Patients with heart disease of mixed etiology and HCVR admitted to a CRP for 4-6 weeks were selected. All patients performed a maximal exercise test in band before and after the CPR. Thresholds of VO2 peak, METs-load, Double product (DP) and MEI were determined. A cut-off point for the MEI was established using a ROC curve with a value of 7.37, area under the curve: 0.68 (95% CI 0.61 - 0.76, p < 0.001), sensitivity 0.60 and 1-specificity 0.35. Results: 193 patients with a mean age of 62.3 years were included, predominantly men (66.2%). Percentages changes in the MEI-27.1% (p < 0.001),METs-43.1% (p < 0.001),DP 5.7% (p < 0.01), and MVO2: 8.3% (p < 0.01) were observed at the end of CRP. Conclusions: Significant change in the MEI were observed after CRP associated to CVEf improvement, suggesting that this parameter could be considered as a good clinical tool in the CRP care programs.

Myocardial efficiency index in patients with heart disease after a cardiac rehabilitation program.

OBJECTIVE: The myocardial efficiency index (MEI) correlates the Myocardial Oxygen Consumption (MVO2) with the Maximum Oxygen Consumption (VO2max), this index provides information about the cardiovascular efficiency (CVEf). In athletes, the MEI improves after a micro-cycle training, however in patients with cardiovascular disease undergoing Cardiac Rehabilitation Program (CRP), IEM behavior could be a good estimator related to the improvement training period. The objective of this study was to determine the myocardial efficiency index behavior in patients with heart disease and high cardiovascular risk (HCVR) after a CRP. METHODS: Ambilective, descriptive, analytical, non-randomized cohort study was conducted. Patients with heart disease of mixed etiology and HCVR admitted to a CRP for 4-6 weeks were selected. All patients performed a maximal exercise test in band before and after the CPR. Thresholds of VO2 peak, METs-load, Double product (DP) and MEI were determined. A cut-off point for the MEI was established using a ROC curve with a value of 7.37, area under the curve: 0.68 (95% CI 0.61 - 0.76, p < 0.001), sensitivity 0.60 and 1-specificity 0.35. RESULTS: 193 patients with a mean age of 62.3 years were included, predominantly men (66.2%). Percentages changes in the MEI-27.1% (p < 0.001),METs-43.1% (p < 0.001),DP 5.7% (p < 0.01), and MVO2: 8.3% (p < 0.01) were observed at the end of CRP. CONCLUSIONS: Significant change in the MEI were observed after CRP associated to CVEf improvement, suggesting that this parameter could be considered as a good clinical tool in the CRP care programs.

OBJETIVO: El índice de eficiencia miocárdica (IEM) correlaciona el consumo miocárdico de oxígeno (MVO2) con el consumo máximo de oxígeno, el cual proporciona información sobre la eficiencia cardiovascular (EfCV). En deportistas, el IEM mejora posterior a un microciclo de entrenamiento, en el paciente con enfermedad cardiovascular sometido a un programa de rehabilitación cardiaca y prevención secundaria PRHCyPS, el comportamiento del IEM podría resultar un estimador relacionado con mejoría derivado de un periodo de entrenamiento. El objetivo del estudio fue determinar el comportamiento del IEM posterior a un PRCyPS en pacientes con cardiopatías y riesgo cardiovascular alto (RCVA). MÉTODOS: Estudio de cohorte ambilectivo, descriptivo, analítico, no aleatorizado. Se seleccionaron pacientes con cardiopatías de etiología mixta con RCVA ingresados a un PRCyPS durante 4-6 semanas. A todos los pacientes se les realizó una prueba de ejercicio máximo en banda antes y después del PRCyPS. Se determinaron umbrales de consumo de oxígeno (VO2) pico, equivalentes metabólicos-carga, doble producto e IEM. Se estableció un punto de corte del IEM mediante una curva ROC con un valor de 7.37 con un área bajo la curva de 0.68 (IC 95%: 0.61-0.76; p < 0.001), sensibilidad 0.60 y 1-especificidad de 0.35. RESULTADOS: Se incluyeron 193 pacientes con una media de edad de 62.3 años, en su mayoría del sexo masculino (66.2%). Se observaron porcentajes de cambio en el IEM ­27.1% (p < 0.001), MET 43.1% (p < 0.001), doble producto 5.7% (p < 0.01) y MVO2: 8.3% (p < 0.01) al término del PRCyPS. CONCLUSIONES: Se observó un cambio significativo en el IEM posterior a un PRCyPS, lo cual se asoció a una mejoría en la EfCV, sugiriendo que este pueda considerarse como un parámetro clínico que evaluar en los programas de rehabilitación cardiaca.

SGLT2 inhibition reduces myocardial oxygen consumption.

Aims/hypothesis: SGLT2 inhibition is associated with a reduced risk of cardiac disease that is still largely unexplained. According to one hypothesis, improved myocardial energetics may explain the cardioprotective effects of SGLT2i. However, recent mechanistic studies that have addressed this question have lacked the power to detect discrete but still clinically significant effects. Methods: We pooled data from two recent randomized clinical trials and performed a meta-analysis to determine the effect of SGLT2 inhibition on myocardial oxygen consumption and myocardial external efficiency measured by positron emission tomography. Results: SGLT2 inhibition reduced myocardial oxygen consumption (-1.06 [95%CI: 0.22-1.89] mL/100 g/min (n = 59, p = 0.01)), but did not affect myocardial external efficiency (2.22 [95%CI: 0.66-5.11] % (n = 59, p = 0.13)). Conclusions: /interpretation: SGLT2 inhibition reduces myocardial oxygen consumption at rest, which may contribute to the drugs' cardioprotective effects.

Myocardial efficiency in patients with different aetiologies and stages of heart failure.

AIMS: Myocardial external efficiency (MEE) is the ratio of cardiac work in relation with energy expenditure. We studied MEE in patients with different aetiologies and stages of heart failure (HF) to discover the role and causes of deranged MEE. In addition, we explored the impact of patient characteristics such as sex, body mass index (BMI), and age on myocardial energetics. METHODS AND RESULTS: Cardiac energetic profiles were assessed with 11C-acetate positron emission tomography (PET) and left ventricular ejection fraction (LVEF) was acquired with echocardiography. MEE was studied in 121 participants: healthy controls (n = 20); HF patients with reduced (HFrEF; n = 25) and mildly reduced (HFmrEF; n = 23) LVEF; and patients with asymptomatic (AS-asymp; n = 38) and symptomatic (AS-symp; n = 15) aortic stenosis (AS). Reduced MEE coincided with symptoms of HF irrespective of aetiology and declined in tandem with deteriorating LVEF. Patients with AS-symp and HFmrEF had reduced MEE as compared with controls (22.2 ± 4.9%, P = 0.041 and 20.0 ± 4.2%, P < 0.001 vs. 26.1 ± 5.8% in controls) and a further decline was observed in patients with HFrEF (14.7 ± 6.3%, P < 0.001). Disproportionate left ventricular hypertrophy was a major cause of reduced MEE. Female sex (P < 0.001), a lower BMI (P = 0.001), and advanced age (P = 0.03) were associated with a lower MEE. CONCLUSION: MEE was reduced in patients with HFrEF, HFmrEF, and HF due to pressure overload and MEE may therefore constitute a treatment target in HF. Patients with LVH, advanced age, female sex, and low BMI had more pronounced reduction in MEE and personalized treatment within these patient subgroups could be relevant.

Characterization of myocardial oxidative metabolism and myocardial external efficiency in high-risk alcohol cardiotoxicity and alcoholic cardiomyopathy via dynamic 11C-Acetate positron emission tomography.

INTRODUCTION: The purpose of this study was to evaluate subjects with high-risk alcohol cardiotoxicity and patients with alcoholic cardiomyopathy (ACM) via dynamic 11C-Acetate positron emission tomography (PET) imaging as a myocardial oxidative metabolic probe. METHODS AND RESULTS: We recruited 37 subjects with chronic alcohol consumption [18 with moderate consumption (MC), 19 with heavy consumption (HC)], 5 ACM patients, and 12 healthy controls to receive dynamic 11C-Acetate PET scans. PET imaging data were analyzed to calculate kinetic parameters (e.g., Kmono, K1 and k2) based on the mono-exponential and one-tissue compartmental models. Myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE) were then derived from these kinetic parameters. MVO2 was significantly lowered in the HC group and in ACM patients (0.121± 0.018 and 0.111 ± 0.017 mL·g-1·min-1, respectively) compared with those in healthy controls and MC subjects (0.144 ± 0.023 and 0.146 ± 0.027 mL·g-1·min-1, respectively; P < .01). MEE was significantly reduced in ACM patients (13.0% ± 4.3%) compared with those of healthy controls (22.4% ± 4.6%, P < .01), MC subjects (20.1% ± 4.5%, P < .05), and HC subjects (22.3% ± 4.5%, P < .001). CONCLUSION: Functional assessment via dynamic 11C-Acetate PET imaging may represent a clinically feasible probe for identifying cohorts with high-risk cardiotoxicity due to addictive alcohol consumption and ACM.

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.

The ß3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs.

Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective ß3 adrenergic receptor (ß3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 µg/kg/min), dobutamine + L-748,337 (bolus 50 µg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA-MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dtmax; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and ß3AR blockade may attenuate this effect.

Effect of voluntary breathing exercises on stable coronary artery disease in heart rate variability and rate-pressure product: a study protocol for a single-blind, prospective, randomized controlled trial.

BACKGROUND: At present, China has more than 11 million patients with stable coronary heart disease and this is becoming a major public health problem. The pathological changes of coronary heart disease can lead to dysfunction of the cardiac autonomic nervous system, which increases the risk of complications such as malignant arrhythmia (ventricular flutter, ventricular fibrillation, etc.), heart rate, systolic blood pressure, and rate-pressure product (RPP), which is highly correlated with myocardial oxygen consumption and indirectly reflects myocardial blood supply and oxygen consumption. Although the guidelines recommend that such patients take drugs to reduce heart rate and myocardial oxygen consumption, the clinical control of heart rate is still not ideal. Thus, in this trial, we will use voluntary breathing exercises as the strategy of exercise rehabilitation for patients with stable coronary artery disease (SCAD), in order to increase the vagus nerve activity and/or reduce the sympathetic nervous activity, help maintain or rebuild the balance of plant nerve system, improve the time-domain index of heart rate variability, reduce the burden on the heart, and relieve patients' anxiety and other negative emotions. METHODS: This is a 6-month single-blind, randomized controlled clinical trial that will be conducted in the First Affiliated Hospital of Soochow University. A total of 140 patients who fill out the Informed Consent Form are registered and randomized 1:1 into the Voluntary Breathing Exercises (VBE)-based clinical trial monitoring group (n = 70) or the Routine follow-up group (n = 70). The VBE-based clinical trial monitoring group is given VBE training on the basis of conventional treatment and health education, while the control group received conventional health education and follow-up. The primary outcomes will be measured heart rate variability and RPP. Secondary outcomes will include changes in Self-rating Anxiety Scale, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, weight, and body mass index. DISCUSSION: This trial will carry out scientific respiratory exercise for patients with SCAD, which belongs to the category of active secondary prevention for patients, and changes from remedial to pre-protective. VBE is easy to operate and is not limited by time and place. It is important and meaningful to carry out VBE for patients with SCAD. This study will provide considerable evidence for further large-scale trials and alternative strategies for the rehabilitation nursing of patients with SCAD. TRIAL REGISTRATION: Chinese Clinical Trials Registry, 1900024043 . Registered on 23 June 2019.

Temperature and flow rate limit the optimal ex-vivo perfusion of the heart - an experimental study.

BACKGROUND: Ex-vivo heart perfusion can be utilized to study a variety of physiologic and molecular pathways in a controlled system outside of the body. It can also be used in clinical settings such as for organ preservation before transplantation. Myocardial oxygen consumption (MVO2) correlates with energy production in the myocardium and can also be used to determine the balance between the oxygen supply and demand of the perfused heart. This study sought to determine an ex-vivo perfusion rate that matches the metabolic demands of the heart according to different temperatures and solution compositions (with and without the addition of erythrocytes), a flow below which the supply of oxygen is not sufficient to maintain an aerobic state of the perfused heart ("DCRIT"). METHODS: Under general anesthesia, rat hearts were procured and preserved by perfusing with the University of Wisconsin Belzer machine perfusion system (UW Belzer MPS) solution saturated with 100% O2. The key elements of this solution include supraphysiological potassium (to stop the heartbeat and reduce the cellular metabolic demand), starch, gluconate and mannitol (to maintain cell wall integrity), glucose (to sustain basal metabolism), and glutathione (to scavenge free radicals). Three groups of rat hearts (n = 7) were randomly allocated to be perfused at 15 °C, 22 °C or 37 °C, at a varying flow index (FI) starting from a minimum of 380 mL/min/100 g to less than 50 mL/min/100 g, decreasing by 50 mL/min/100 g at 10 min intervals while measuring the MVO2 at each FI. Lactate was measured from coronary sinus samples to determine the onset of tissue hypoxia/anaerobic state. RESULTS: The DCRIT at 15 °C was 99.9 ± 4.9 mL/min/100 g; however, at 22 °C and 37 °C we could not reach a DCRIT. The myocardial oxygen demand could not be met at 22 °C and 37 °C with the maximum FI above 380 mL/min/100 g even when erythrocytes (10% V/V) were added to the solution. At 15 °C, the production of lactate was evident only below the DCRIT, while at 22 °C lactate production was present at all flow indices. CONCLUSIONS: Determining the DCRIT for optimal ex-vivo perfusion of the heart is necessary to ensure adequate tissue oxygenation and limit anaerobic state. Temperatures employed above 15 °C limit the efficient ex-vivo perfusion preservation of heart with the UW Belzer MPS solution.

NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity.

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes.

AIMS: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes. METHODS AND RESULTS: Thirty-six HFrEF patients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m-2 ·106 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 ·100 g-1 ·min-1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups. CONCLUSION: Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.

Disentangling the Gordian knot of local metabolic control of coronary blood flow.

Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o2) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation. For a number of years, coronary venous Po2 has been generally accepted as a measure of myocardial tissue oxygenation and thus the classically proposed error signal for the generation of vasodilator metabolites in the heart. However, interpretation of changes in coronary venous Po2 relative to MV̇o2 are quite nuanced, inherently circular in nature, and subject to confounding influences that remain largely unaccounted for. The purpose of this review is to highlight difficulties in interpreting the complex interrelationship between key coronary outcome variables and the arguments that emerge from prior studies performed during exercise, hemodilution, hypoxemia, and alterations in perfusion pressure. Furthermore, potential paths forward are proposed to help to facilitate further dialogue and study to ultimately unravel what has become the Gordian knot of the coronary circulation.

Rationale, experimental data, and emerging clinical evidence on early and preventive use of levosimendan in patients with ventricular dysfunction.

Acute ventricular dysfunction (AVD) is a complex condition with substantial morbidity and mortality, still featuring unique therapeutic challenges. Levosimendan is a calcium sensitizer and ATP-dependent potassium channel opener that was developed as an inodilating drug for the treatment of acute heart failure and cardiogenic shock. Differently from other more widely used inotropic agents, levosimendan has some exclusive characteristics, in terms of mechanisms of action, pharmacodynamic profile, and haemodynamic effects. This may have important clinical implications. In particular, in patients with AVD or in patients with pre-existing severe ventricular impairment undergoing planned myocardial stress, the administration of levosimendan before the onset of overt symptoms or before cardiovascular therapeutic procedures may have the potential to bridge the patient through the critical phase. In this review, we will focus on the rationale, the existing experimental data, and the emerging clinical experience supporting an early, even preventive use of levosimendan in severe ventricular dysfunction, beyond its recognized indications.

Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction.

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r = -0.66, p = 0.04) and myocyte hypertrophy (r = -0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with 11C-labeled acetate positron emission tomography (r = -0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.

Myocardial Oxygen Consumption and Efficiency in Patients With Cardiac Amyloidosis.

Background This study evaluated myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE) in patients with cardiac amyloidosis (CA). Furthermore, we compared MEE and MVO2 in subjects with light chain amyloidosis versus transthyretin (ATTR) amyloidosis. Methods and Results The study population comprised 40 subjects: 25 patients with confirmed CA and 15 control subjects. All subjects underwent an 11C-acetate positron emission tomography. Furthermore, the CA patients underwent comprehensive echocardiography and right heart catheterization during a symptom-limited, semi-supine exercise test. MEE was calculated from 11C-acetate positron emission tomography as the ratio of left ventricular (LV) stroke work and the energy equivalent of MVO2. Myocardial work efficiency was calculated as echocardiography-derived work pressure product divided by three-dimensional LV mass. CA patients had significantly lower LV-ejection fraction (54±13% versus 63±4%, P<0.05) and LV-global longitudinal strain (LVGLS) (12±4% versus 19±2%, P<0.0001) and a more restrictive filling pattern (E/e'-ratio 18 [12-25] versus 8 [7-9], P<0.0001) than controls. MEE was severely reduced (13±5% versus 22±5%, P<0.0001) whereas total MVO2 was higher (18±6 mL/min versus 13±3 mL/min, P<0.01) in CA patients than controls. MEE decreased with increasing New York Heart Association symptom burden ( P<0.0001). We found a good relationship between MEE and peak exercise systolic performance (LVGLS: R2=0.60, P<0.0001; myocardial work efficiency: R2=0.48, P<0.0001; cardiac index: R2=0.52, P<0.0001) and between MEE and myocardial blood flow ( R2=0.44, P<0.0001). Conclusion Myocardial oxidative metabolism is disturbed in CA patients with increased total MVO2 and reduced MEE. MEE correlated significantly with echocardiographic derived systolic parameters such as myocardial work efficiency and LVGLS that might be used as surrogate MEE markers.

Acute effect of ivabradine on heart rate and myocardial oxygen consumption in dogs with asymptomatic mitral valve degeneration.

Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin-aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs.

Left ventricular volume analysis as a basic tool to describe cardiac function.

The heart is often regarded as a compression pump. Therefore, determination of pressure and volume is essential for cardiac function analysis. Traditionally, ventricular performance was described in terms of the Starling curve, i.e., output related to input. This view is based on two variables (namely, stroke volume and end-diastolic volume), often studied in the isolated (i.e., denervated) heart, and has dominated the interpretation of cardiac mechanics over the last century. The ratio of the prevailing coordinates within that paradigm is termed ejection fraction (EF), which is the popular metric routinely used in the clinic. Here we present an insightful alternative approach while describing volume regulation by relating end-systolic volume (ESV) to end-diastolic volume. This route obviates the undesired use of metrics derived from differences or ratios, as employed in previous models. We illustrate basic principles concerning ventricular volume regulation by data obtained from intact animal experiments and collected in healthy humans. Special attention is given to sex-specific differences. The method can be applied to the dynamics of a single heart and to an ensemble of individuals. Group analysis allows for stratification regarding sex, age, medication, and additional clinically relevant covariates. A straightforward procedure derives the relationship between EF and ESV and describes myocardial oxygen consumption in terms of ESV. This representation enhances insight and reduces the impact of the metric EF, in favor of the end-systolic elastance concept advanced 4 decades ago.