Work and oxygen consumption of isolated right ventricular papillary muscle in experimental pulmonary hypertension.

Right-sided myocardial mechanical efficiency (work output/metabolic energy input) in pulmonary hypertension can be severely reduced. We determined the contribution of intrinsic myocardial determinants of efficiency using papillary muscle preparations from monocrotaline-induced pulmonary hypertensive (MCT-PH) rats. The hypothesis tested was that efficiency is reduced by mitochondrial dysfunction in addition to increased activation heat reported previously. Right ventricular muscle preparations were subjected to 5 Hz sinusoidal length changes at 37°C. Work and suprabasal oxygen consumption ( V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ) were measured before and after cross-bridge inhibition by blebbistatin. Cytosolic cytochrome c concentration, myocyte cross-sectional area, proton permeability of the inner mitochondrial membrane and monoamine oxidase and glucose 6-phosphate dehydrogenase activities and phosphatidylglycerol/cardiolipin contents were determined. Mechanical efficiency ranged from 23% to 11% in control (n = 6) and from 22% to 1% in MCT-PH (n = 15) and correlated with work (r2  = 0.68, P < 0.0001) but not with V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (r2  = 0.004, P = 0.7919). V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ for cross-bridge cycling was proportional to work (r2  = 0.56, P = 0.0005). Blebbistatin-resistant V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (r2  = 0.32, P = 0.0167) and proton permeability of the mitochondrial inner membrane (r2  = 0.36, P = 0.0110) correlated inversely with efficiency. Together, these variables explained the variance of efficiency (coefficient of multiple determination r2  = 0.79, P = 0.0001). Cytosolic cytochrome c correlated inversely with work (r2  = 0.28, P = 0.0391), but not with efficiency (r2  = 0.20, P = 0.0867). Glucose 6-phosphate dehydrogenase, monoamine oxidase and phosphatidylglycerol/cardiolipin increased in the right ventricular wall of MCT-PH but did not correlate with efficiency. Reduced myocardial efficiency in MCT-PH is a result of activation processes and mitochondrial dysfunction. The variance of work and the ratio of activation heat reported previously and blebbistatin-resistant V ̇ O 2 ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ are discussed. KEY POINTS: Mechanical efficiency of right ventricular myocardium is reduced in pulmonary hypertension. Increased energy use for activation processes has been demonstrated previously, but the contribution of mitochondrial dysfunction is unknown. Work and oxygen consumption are determined during work loops. Oxygen consumption for activation and cross-bridge cycling confirm the previous heat measurements. Cytosolic cytochrome c concentration, proton permeability of the mitochondrial inner membrane and phosphatidylglycerol/cardiolipin are increased in experimental pulmonary hypertension. Reduced work and mechanical efficiency are related to mitochondrial dysfunction. Upregulation of the pentose phosphate pathway and a potential gap in the energy balance suggest mitochondrial dysfunction in right ventricular overload is a resiult of the excessive production of reactive oxygen species.

Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.

BACKGROUND: Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating. METHODS AND RESULTS: Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P < 0.001) without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009). CONCLUSION: A single 11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

Myocardial External Efficiency in Asymptomatic Severe Primary Mitral Regurgitation Using 11C-Acetate PET.

Subjects with asymptomatic moderate-to-severe or severe primary mitral regurgitation are closely observed for signs of progression or symptoms requiring surgical intervention. The role of myocardial metabolic function in progression of mitral regurgitation is poorly understood. We used 11C-acetate PET to noninvasively measure myocardial mechanical external efficiency (MEE), which is the energetic ratio of external cardiac work and left ventricular (LV) oxygen consumption. Methods: Forty-seven patients in surveillance with mitral regurgitation and no or minimal symptoms prospectively underwent PET, echocardiography, and cardiac MRI on the same day. PET was used to simultaneously measure cardiac output, LV mass, and oxygen consumption to establish MEE. PET findings were compared between patients and healthy volunteers (n = 9). MEE and standard imaging indicators of regurgitation severity, LV volumes, and function were studied as predictors of time to surgical intervention. Patients were followed a median of 3.0 y (interquartile range, 2.0-3.8 y), and the endpoint was reached in 22 subjects (47%). Results: MEE in patients reaching the endpoint (23.8% ± 5.0%) was lower than in censored patients (28.5% ± 4.5%, P = 0.002) or healthy volunteers (30.1% ± 4.9%, P = 0.001). MEE with a cutoff lower than 25.7% was significantly associated with the outcome (hazard ratio, 7.5; 95% CI, 2.7-20.6; P < 0.0001) and retained independent significance when compared with standard imaging parameters. Conclusion: MEE independently predicted time to progression requiring valve surgery in patients with asymptomatic moderate-to-severe or severe primary mitral regurgitation. The study suggests that inefficient myocardial oxidative metabolism precedes clinically observed progression in mitral regurgitation.

Advanced echocardiographic assessment in adults with repaired aortic coarctation: myocardial work analysis provides novel insights on left ventricular mechanics.

AIM: To analyze left ventricular (LV) mechanics through advanced echocardiography, including speckle tracking analysis and myocardial work (MW) in a cohort of adults with repaired aortic coarctation (CoA). METHODS: Data on standard echocardiography, LV speckle-tracking and MW analysis were collected in CoA patients > 18 years with no significant recoartation or valvular disease and normal LV ejection fraction at the time of the exam. MW indices were calculated using the blood pressure measured in the right arm. A group of healthy subjects with comparable sex, age and body surface area was included for comparison. RESULTS: Eighty-nine CoA patients and 70 healthy subjects were included. Patients had higher systolic blood pressure (p < 0.0001), LV mass index (p < 0.0001), left atrial volume index (p = 0.005) and E/E' ratio (p = 0.001). Despite similar LV ejection fraction, speckle tracking analysis revealed lower global longitudinal strain (GLS: - 18.3[17-19] vs - 20.7[19-22]%, p < 0.0001) and increased peak systolic dispersion (PSD: 45[40-54] vs 37.5[32-43] ms, p < 0.0001) in CoA patients. Global work index (GWI) and global constructive work were similar to healthy controls (p = 0.6 and 0.5, respectively), whereas CoA patients showed significant increased wasted work (GWW: 125[90-185] vs 89.5[64-127]mmHg%, p < 0.0001) and a mild but significant reduction in global work efficiency (GWE: 93%[92-95] vs 95%[94-97], p < 0.0001). Moreover, when stratifying for GLS values, MW analysis showed increased GWW and PSD with impaired GWE in 54(61%) patients with normal GLS compared to healthy individuals. Spearman's linear method illustrated an inverse relation between GWE and PSD (r: - 0.53, p < 0.0001), while GCW was associated with peak (r: 0.2, p = 0.01) and mean gradient across the descending aorta (r: 0.3, p = 0.004) and with systolic blood pressure (r: 0.48, p < 0.0001). PSD was the sole univariate predictor of GWE on linear regression analysis (ß: - 0.1 [- 0.16 to - 0.07], p < 0.0001), whereas female sex, SBP and gradients across the descending aorta were independently associated with higher GCW values. When CoA patients were divided based on the history of redo CoA repair and arterial hypertension, no significant differences in MW indices were found. CONCLUSIONS: MW is a novel echocardiographic tool, which provides additional information on LV performance in CoA patients over GLS allowing a more comprehensive understanding of LV dysfunction mechanisms in a setting of increased afterload.

Determinants of improvement of left ventricular mechano-energetic efficiency in hypertensive patients.

Background: Arterial hypertension, especially when coexisting with other cardiovascular risk factors, could determine an imbalance between myocardial energetic demand and altered efficiency, leading to an early left ventricular (LV) systolic dysfunction, even in terms of echo-derived mechano-energetic efficiency indexed for myocardial mass (MEEi). We aim to analyse an improvement in LV MEEi, if any, in a population of hypertensive patients with a long-term follow-up and to identify clinical, metabolic and therapeutic determinants of LV MEEi amelioration. Materials and methods: In total, 7,052 hypertensive patients, followed-up for 5.3 ± 4.5 years, enrolled in the Campania Salute Network, underwent echocardiographic and clinical evaluation. LV MEEi was obtained as the ratio between stroke volume and heart rate and normalized per grams of LV mass and ΔMEEi was calculated as difference between follow-up and baseline MEEi. Patients in the highest ΔMEEi quartile (≥0.0454 mL/s/g) (group 1) were compared to the merged first, second and third quartiles (<0.0454 mL/s/g) (group 2). METS-IR (Metabolic Score for Insulin Resistance), an established index of insulin sensitivity, was also derived. Results: Patients with MEEi improvement experienced a lower rate of major cardiovascular events (p = 0.02). After excluding patients experiencing cardiovascular events, patients in group 1 were younger (p < 0.0001), less often diabetic (p = 0.001) and obese (p = 0.035). Group 1 experienced more frequently LV mass index reduction, lower occurrence of LV ejection fraction reduction, and had a better metabolic control in terms of mean METS-IR during the follow-up (all p < 0.0001). Beta-blockers were more often used in group 1 (p < 0.0001) than group 2. A logistic regression analysis showed that younger age, lower mean METS-IR values, more frequent LV mass index reduction and therapy with beta-blockers were significantly associated with LV MEEi improvement, independently of presence of diabetes and obesity. Conclusion: Metabolic control and therapy with beta-blockers could act in a synergic way, determining an improvement in LV MEEi in hypertensive patients over time, possibly confining cardiac damage and hampering progression toward heart failure.

Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to examine the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency, and myocardial contractile work in subjects with type 2 diabetes mellitus. As a complement to the clinical study, a mechanistic mathematical model of cardiorenal physiology was used to quantify the influence of established natriuretic/diuretic effects of SGLT2i on cardiac function (myocardial efficiency and global longitudinal strain). Virtual participants reflecting the participant-level characteristics in the DAPACARD trial were produced by varying model parameters over physiologically plausible ranges. A second virtual population was generated by inducing a state of HFrEF in the DAPACARD virtual participants with type 2 diabetes mellitus for comparison. Cardiac responses to placebo and SGLT2i were simulated over 42 days. Cardiac hemodynamic improvements were predicted in DAPACARD-HFrEF virtual participants but not in DAPACARD virtual participants. In particular, the natriuresis/diuresis induced by SGLT2i improved the global longitudinal strain and myocardial efficiency in DAPACARD-HFrEF virtual participants within the first 14 days (change from baseline: global longitudinal strain, -0.95%; and myocardial efficiency, 0.34%), whereas the global longitudinal strain and myocardial efficiency in DAPACARD virtual participants were slightly worse (change from baseline: global longitudinal strain, 0.35%; and myocardial efficiency: -0.01%). The results of the DAPACARD virtual participants modeling were in line with the clinical data but do not preclude additional effects from other mechanisms of SGLT2i.

Myocardial inefficiency is an early indicator of exercise-induced myocardial fatigue.

Background: The effect of prolonged, high-intensity endurance exercise on myocardial function is unclear. This study aimed to determine the left ventricular (LV) response to increased exercise duration and intensity using novel echocardiographic tools to assess myocardial work and fatigue. Materials and methods: LV function was assessed by echocardiography before, immediately, and 24 h after a cardiopulmonary exercise test (CPET) and a 91-km mountain bike leisure race. Cardiac Troponin I (cTnI) was used to assess myocyte stress. Results: 59 healthy recreational athletes, 52 (43-59) years of age, 73% males, were included. The race was longer and of higher intensity generating higher cTnI levels compared with the CPET (p < 0.0001): Race/CPET: exercise duration: 230 (210, 245)/43 (40, 45) minutes, mean heart rate: 154 ± 10/132 ± 12 bpm, max cTnI: 77 (37, 128)/12 (7, 23) ng/L. Stroke volume and cardiac output were higher after the race than CPET (p < 0.005). The two exercises did not differ in post-exercise changes in LV ejection fraction (LVEF) or global longitudinal strain (GLS). There was an increase in global wasted work (p = 0.001) following the race and a persistent reduction in global constructive work 24 h after exercise (p = 0.003). Conclusion: Increased exercise intensity and duration were associated with increased myocardial wasted work post-exercise, without alterations in LVEF and GLS from baseline values. These findings suggest that markers of myocardial inefficiency may precede reduction in global LV function as markers of myocardial fatigue.

A computational study of aortic insufficiency in patients supported with continuous flow left ventricular assist devices: Is it time for a paradigm shift in management?

Background: De novo aortic insufficiency (AI) following continuous flow left ventricular assist device (CF-LVAD) implantation is a common complication. Traditional early management utilizes speed augmentation to overcome the regurgitant flow in an attempt to augment net forward flow, but this strategy increases the aortic transvalvular gradient which predisposes the patient to progressive aortic valve pathology and may have deleterious effects on aortic shear stress and right ventricular (RV) function. Materials and methods: We employed a closed-loop lumped-parameter mathematical model of the cardiovascular system including the four cardiac chambers with corresponding valves, pulmonary and systemic circulations, and the LVAD. The model is used to generate boundary conditions which are prescribed in blood flow simulations performed in a three-dimensional (3D) model of the ascending aorta, aortic arch, and thoracic descending aorta. Using the models, impact of various patient management strategies, including speed augmentation and pharmacological treatment on systemic and pulmonary (PA) vasculature, were investigated for four typical phenotypes of LVAD patients with varying degrees of RV to PA coupling and AI severity. Results: The introduction of mild/moderate or severe AI to the coupled RV and pulmonary artery at a speed of 5,500 RPM led to a reduction in net flow from 5.4 L/min (no AI) to 4.5 L/min (mild/moderate) to 2.1 L/min (severe). RV coupling ratio (Ees/Ea) decreased from 1.01 (no AI) to 0.96 (mild/moderate) to 0.76 (severe). Increasing LVAD speed to 6,400 RPM in the severe AI and coupled scenario, led to a 42% increase in net flow and a 16% increase in regurgitant flow (RF) with a nominal decrease of 1.6% in RV myocardial oxygen consumption (MVO2). Blood pressure control with the coupled RV with severe AI at 5,500 RPM led to an 81% increase in net flow with a 15% reduction of RF and an 8% reduction in RV MVO2. With an uncoupled RV, the introduction of mild/moderate or severe AI at a speed of 5,500 RPM led to a reduction in net flow from 5.0 L/min (no AI) to 4.0 L/min (mild/moderate) to 1.8 L/min (severe). Increasing the speed to 6,400 RPM with severe AI and an uncoupled RV increased net flow by 45%, RF by 15% and reduced RV MVO2 by 1.1%. For the uncoupled RV with severe AI, blood pressure control alone led to a 22% increase in net flow, 4.2% reduction in RF, and 3.9% reduction in RV MVO2; pulmonary vasodilation alone led to a 18% increase in net flow, 7% reduction in RF, and 26% reduction in RV MVO2; whereas, combined BP control and pulmonary vasodilation led to a 113% increase in net flow, 20% reduction in RF and 31% reduction in RV MVO2. Compared to speed augmentation, blood pressure control consistently resulted in a reduction in WSS throughout the proximal regions of the arterial system. Conclusion: Speed augmentation to overcome AI in patients supported by CF-LVAD appears to augment flow but also increases RF and WSS in the aorta, and reduces RV MVO2. Aggressive blood pressure control and pulmonary vasodilation, particularly in those patients with an uncoupled RV can improve net flow with more advantageous effects on the RV and AI RF.

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.

The Utility of Myocardial Work in Clinical Practice.

Myocardial work (MW) is a novel technique used in the advanced assessment of left ventricular function. In the past few years, this invasive measure has evolved to become a more attainable noninvasive technique. MW has benefits over left ventricular ejection fraction and global longitudinal strain by speckle-tracking echocardiography, as it includes the afterload-dependent limitation and dynamic myocardial contraction in relationship to various loading conditions. In this article, the authors provide a summary overview and discuss the additive value noninvasive MW provides to left ventricular systolic function assessment. The authors explore the evolution of invasive to noninvasive MW, examine how to acquire and measure, discuss normal reference values, examine its role in a multitude of cardiac conditions that have been investigated in current research, review a variety of clinical applications, and discuss potential limitations. The goal is to allow the reader to see the benefits of this rapidly emerging application and be able to incorporate it into everyday practice.

Non-invasive CMR-Based Quantification of Myocardial Power and Efficiency Under Stress and Ischemic Conditions in Landrace Pigs.

Background: Myocardial efficiency should be maintained stable under light-to-moderate stress conditions, but ischemia puts the myocardium at risk for impaired functionality. Additionally, the measurement of such efficiency typically requires invasive heart catheterization and exposure to ionizing radiation. In this work, we aimed to non-invasively assess myocardial power and the resulting efficiency during pharmacological stress testing and ischemia induction. Methods: In a cohort of n = 10 healthy Landrace pigs, dobutamine stress testing was performed, followed by verapamil-induced ischemia alongside cardiac magnetic resonance (CMR) imaging. External myocardial power, internal myocardial power, and myocardial efficiency were assessed non-invasively using geometrical and functional parameters from CMR volumetric as well as blood flow and pressure measurements. Results: External myocardial power significantly increased under dobutamine stress [2.3 (1.6-3.1) W/m2 vs. 1.3 (1.1-1.6) W/m2, p = 0.005] and significantly decreased under verapamil-induced ischemia [0.8 (0.5-0.9) W/m2, p = 0.005]. Internal myocardial power [baseline: 5.9 (4.6-8.5) W/m2] was not affected by dobutamine [7.5 (6.9-9.0) W/m2, p = 0.241] nor verapamil [5.8 (4.7-8.8) W/m2, p = 0.878]. Myocardial efficiency did not change from baseline to dobutamine [21% (15-27) vs. 31% (20-44), p = 0.059] but decreased significantly during verapamil-induced ischemia [10% (8-13), p = 0.005]. Conclusion: In healthy Landrace pigs, dobutamine stress increased external myocardial power, whereas myocardial efficiency was maintained stable. On the contrary, verapamil-induced ischemia substantially decreased external myocardial power and myocardial efficiency. Non-invasive CMR was able to quantify these efficiency losses and might be useful for future clinical studies evaluating the effects of therapeutic interventions on myocardial energetics.

An Analysis of Myocardial Efficiency in Patients with Severe Asymptomatic Mitral Regurgitation.

BACKGROUND: It is difficult to determine left ventricular systolic performance in patients with severe mitral regurgitation (MR) since left ventricular ejection fraction (EF) could be preserved until the end stages of the disease. Myocardial efficiency (MEf) describes the amount of external work (EW) done by the left ventricle per unit of oxygen consumed (mVO2). In the present study, we aimed to investigate MEf in patients with asymptomatic severe MR using a novel echocardiographic method. METHODS: A total of 27 patients with severe asymptomatic MR and 26 healthy volunteers were included in this cross-sectional study. EW was measured using stroke volume and blood pressure, while mVO2 was estimated using double product and left ventricular mass. RESULTS: There were no differences between the groups with regards to EF (66% ± 5% vs. 69% ± 7%), while MEf was significantly reduced in patients with severe MR (25% ± 11% vs. 44% ± 12%, p < 0.001). This difference was maintained even after adjustment for age, gender and body surface area (adjusted x̅: 0.44, 95% CI: 0.39-0.49 for controls and adjusted x̅: 0.24, 95% CI: 0.19-0.29 for patients with severe MR). Further analysis showed that this reduction was due to an increase in total mVO2 in the severe MR group. MEf of thepatients who were both on ß-blockers and angiotensin converting enzyme inhibitors/angiotensin receptor blockers were higher than those who were not on any drugs, but this difference was not statistically significant (32% ± 15% vs. 23% ± 9%, p = 0.41). CONCLUSIONS: MEf was significantly lower in patients with asymptomatic severe MR and preserved EF.

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.

Transcatheter aortic valve replacement acutely improves left ventricular mechanical efficiency in severe aortic stenosis: effects of different phenotypes.

AIM: Aortic stenosis is a frequent valvular disease, with transcatheter aortic valve implantation (TAVI) being performed when surgical replacement is at increased risk. However, TAVI-induced effects on myocardial efficiency are unknown. We aimed to investigate changes in LV mechano-energetic pre-/post-TAVI and their prognostic impact. METHODS: A total of 46 patients (25 males) received transesophageal and simultaneous radial pressure plus transaortic gradient monitoring before/immediately after prosthesis deployment. Efficiency was computed as external work/potential energy, as derived from LV pressure-volume plots; myocardial oxygen consumption (MVO2) was estimated as PWImod, i.e. a noninvasively validated alternative for MVO2 estimation. RESULTS: TAVI was successful in all patients, peak transaortic gradient decreasing - 40 ± 20 mmHg (p < 0.001). Efficiency improved post-TAVI (+ 0.6 ± 0.12; p = 0.004), with a concomitant PWImod reduction (- 16 ± 31%; p < 0.001). When contextualized to fixed PWImod value (5 ml/min/100 g), efficiency significantly affected survival (p = 0.029). Over 1026 ± 450-day follow-up, a change in efficiency pre-/post-TAVI ≤ 0.021 (median of the difference) predicted more deaths from any cause (30%) as compared with a change > 0.021 (17%), particularly in those patients with a pre-TAVI mean high-gradient (HG ≥ 40 mmHg) phenotype (p < 0.05). In particular, HG patients exhibited the lowest efficiency/PWImod ratio pre-/post-TAVI (p = 0.048), relative to the other aortic stenosis patients, suggestive of an unfavourable matching between cardiac function and metabolic demand, which foreshortens some intrinsic damaged muscle condition in these patients. CONCLUSION: LV mechanical efficiency improves immediately post-TAVI, notwithstanding an inhomogeneous mechano-energetic matching among the aortic stenosis patients, which can impact negatively on their long-term prognosis, particularly in those with the HG phenotype.

Prognostic significance of myocardial energy expenditure and myocardial efficiency in patients with heart failure with reduced ejection fraction.

In heart failure with reduced ejection fraction (HFrEF) patients, myocardial blood flow (MBF), myocardial energy expenditure (MEE), myocardial efficiency has been poorly evaluated because of the necessity of invasive procedures in the determination of these parameters. Transthoracic echocardiography (TTE) can provide reliable data for MEE, MBF (via coronary sinus (CS) flows). Also, myocardial efficiency can be evaluated by the MEE to MBF ratio. We aim to assess MBF, MEE and energy efficiency and the prognostic value of these parameters in HFrEF. In this prospective study, a total of 80 patients with HFrEF due to either ischemic or non-ischemic etiology and 20 healthy control subjects were included. Median follow-up duration was 901 (27-1004) days. MBF was calculated via coronary sinus blood flow. MEE was measured from circumferential end-systolic stress, stroke volume and left ventricular ejection time. MEE to MBF ratio was determined as MEf. Primary composite end-point (CEP) was cardiovascular mortality, heart transplantation or mechanical circulatory support. MEE and MEf were lower and MBF per minute was higher in HF group compared to control subjects whereas MBF per 100 g left ventricular mass was not different. MEE and MEf have significantly negative correlation with troponin I, BNP, uric acid and positive correlation with epicardial fat thickness. In Cox regression analysis, per one calorie decrease of MEE was associated 4.3 times increased risk [HR 4.396 (95% CI 1.230-15.716)] and per one percent decrease of MEf was associated 3.3 times increased risk of CEP [HR 3.343 (95% CI 1.025-10.905)]. Our study demonstrated that while MEE and MEf diminished in HFrEF, MBF preserved with the symptomatic progression of HF. MEE and MEf were found to be associated with important prognostic markers and independent predictors of CEP in HFrEF. Evaluation of MEE, MBF and MEf with echocardiography may provide an additional data regarding prognostic assessment of HFrEF population.

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 is an important determinant of functional improvement after aortic valve replacement in aortic valve stenosis patients: a combined PET and CMR study.

AIMS: The pathophysiology underlying aortic valve stenosis (AVS)-induced cardiac dysfunction and reduced exercise capacity is unclear. We hypothesize that improvement of myocardial external efficiency (MEE)--the ratio between external work and myocardial oxygen consumption (MVO2)--underlies functional improvement of AVS patients after aortic valve replacement (AVR). Therefore, the aim of this proof-of-concept study was to investigate whether myocardial efficiency is reduced in patients with cardiac hypertrophy caused by AVS and to assess the effect of AVR on myocardial efficiency in relation to exercise capacity. METHODS AND RESULTS: Echocardiography, cardiopulmonary exercise test, [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging were performed in 10 AVS patients prior to (pre-AVR) and 4 months after AVR (post-AVR). Fourteen healthy individuals served as control group. MEE was significantly lower in pre-AVR patients (32 ± 7%) than in controls (49 ± 6%). AVR significantly decreased left ventricle mass and MVO2. Also, external work significantly decreased post-AVR reaching similar values as in controls. AVR significantly improved MEE from 32 ± 7 to 37 ± 5% (P = 0.02). Moreover, significant correlations were present between the AVR-induced increase in MEE and changes in both exercise work (r = 0.74, P = 0.01) and peak VO2 (r = 0.67, P = 0.03). However, four AVS patients did not show improved MEE, which was associated with no or minimal improvement in exercise parameters. CONCLUSION: MEE is significantly reduced in patients with AVS-induced hypertrophy. Improved MEE is an important predictor of AVR-induced improvement of exercise capacity in AVS patients. Future investigation is needed to confirm our observations in a large prospective, multicenter clinical trial.

Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations.

AIMS: Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. METHODS AND RESULTS: Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. CONCLUSION: We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers.