Cardiac Mechanical Efficiency Research Articles

Evaluation of vascular aging on measures of cardiac function and mechanical efficiency: insights from in-silico modeling.

This study evaluated the hypothesis that vascular aging (VA) reduces ventricular contractile function and mechanical efficiency (ME) using the left ventricular pressure-volume (PV) construct. A previously published in-silico computational model (CM) was modified to evaluate the hypothesis in two phases. In phase I, the CM included five settings of aortic compliance (CA) from normal to stiff, studied at a heart rate of 80 bpm, and phase II included the normal to stiff CA settings evaluated at 60, 100, and 140 bpm. The PV construct provided steady-state and transient data through a simulated vena caval occlusion (VCO). The steady-state data included left ventricular volumes (EDV and ESV), stroke work (SW), and VCO provided the PV area (PVA) data in addition to the three measures of contractile state (CS): end-systolic pressure-volume relationship (ESPVR), dP/dtmax-EDV and preload recruitable stroke work (PRSW). Finally, ME was calculated with the SW/PVA parameter. In phase I, EDV and ESV increased, as did SW and PVA. The impact on the CS parameters demonstrated a small decrease in ESPVR, no change in dP/dtmax-EDV, and a large increase in PRSW. ME decreased from 71.5 to 60.8%, respectively. In phase II, at the normal and stiff CA settings, across the heart rates studied, EDV and ESV decreased, ESPVR and dP/dtmax-EDV increased and PRSW decreased. ME decreased from 76.4 to 62.6% at the normal CA and 65.8 to 53.2% at the stiff CA. The CM generated new insights regarding how the VA process impacts the contractile state of the myocardium and ME.

C43 RELATIONSHIP BETWEEN ECHOCARDIOGRAPHIC DATA AND CARDIOPULMONARY EXERCISE TEST PARAMETERS IN ADULT CONGENITAL HEART DISEASE PATIENTS: A RETROSPECTIVE CLINICAL STUDY

Abstract Introduction The interpretation of cardiopulmonary exercise test (CPET) in adult congenital heart disease (ACHD) is challenging because of the high variability in cardiac lesions and because the poor exercise tolerance is often associated with abnormal heart function. The aim of this work is to study the correlation between echocardiographic evaluation and CPET parameters in ACHD population. Methods This is a retrospective clinical study enrolling all ACHD patients afferent to our institution from March 2016 to February 2020 collecting clinical, CPET and echocardiographic data. Population was divided into three groups and compared: patients with prevalent left heart lesions (L group), patients with prevalent right heart lesions (R group) and patients with single ventricle physiology (SV group). Finally, correlation analysis were performed to assess any relationship between echocardiographic and CPET data. Results 60 patients were included in the study, 20 were male, median age was 36 [30–46.75] years old, 23 had a prevalent left side pathology, 31 a prevalent right side pathology and 6 had a single ventricle physiology. L group had a significantly lower predicted peak VO2 in comparison to SV group (p=0.03). Statistical analysis showed a correlation between the right ventricular function and the ventilatory reserve in the R group (R2 0.517). In SV group we found correlation between ventricular–arterial coupling and Cardiac mechanical efficiency with the ventilatory reserve (R2 0.6 and 0.65, respectively) and the oxygen pulse (R2 0.97 and 0.98, respectively), and a correlation between the ejection fraction and the Oxygen pulse (R2 0.52). Finally, a correlation between the TAPSE/PAPs index and the ventilation (R2=0.79), the ratio between the oxygen uptake and the workload (R2=0.61) and the oxygen consumption (R2=0.72) was found. Coclusion:In our preliminary experience, echocardiographic parameters of cardiocirculatory efficiency correlate with the oxygen consumption per heart beat evaluated at the CPET in single ventricle patients, and the breath rate is influenced not only by ventricular function but also by the coupling between the ventricle and the arterial system. In patients affected by right–side disease, the breath rate correlate with the right ventricular function. Finally, in the left heart lesion population, a correlation between the TAPSE/PAPs index with the ventilation, the oxygen consumption per beat and the oxygen consumption was found.

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling.

The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

Abstract 12092: IMB-1018792, an Investigational Agent Designed to Augment Cardiac Glucose Utlization and Energetics Reduces Cardiac Remodelling and Preserves Cardiac Function in a Model of Pressure Overload-Induced Heart Failure

Introduction: Energetic impairments play a key role in heart failure (HF). Contributors include reduced pyruvate dehydrogenase activity partially uncoupling glycolysis from glucose oxidation, increased dependence on fatty acid (FA) metabolism yielding less ATP than glucose per O 2 molecule consumed, a lower phosphate-to-O 2 ratio, mitochondrial uncoupling and futile cycling of FA intermediates. IMB-1018972 (IMB-101) is a novel investigational agent designed to increase cardiac glucose uptake to promote glucose oxidation (Randle effect) through partial inhibition of FA oxidation enhancing cardiac energetics and mechanical efficiency. Hypotheses: Administration of IMB-101 will: 1) increase cardiac glucose uptake and 2) attenuate LV hypertrophic remodelling and progression of HF resulting from chronic pressure overload. Methods: 1) Cardiac glucose metabolism was evaluated using dynamic 18 F-FDG PET/CT imaging in vivo in fasted normal rats following a subcutaneous dose of IMB-101 or saline. Each animal had 2 randomized sequenced scan sessions (n=16). 2) Male C57BL/6 mice aged 12 weeks underwent transverse aortic constriction (TAC) or sham surgery (n=15) and were treated with IMB-101 (10 mg/kg/day, n=15) or saline (n=15) from day 1 (D1) for 6 weeks by osmotic minipump. Cardiac function was assessed by conscious echocardiography (D1, week 3 and 6). Cardiac fibrosis was measured by Masson’s Trichrome staining. Results: IMB-101 robustly increased in vivo cardiac 18 F-FDG uptake vs saline in rats. In mice subjected to TAC, compared to saline controls, IMB-101 treatment: preserved LV systolic function (fractional shortening 46%±3% vs 34%±3%, at week 6, p<0.05); improved LV relaxation with less prolonged isovolumic relaxation time (32±1 ms vs 36±1 ms, p<0.05); reduced cardiac hypertrophy (LV mass 156±10 mg vs 195±12 mg, p<0.05; and heart:body weight ratio 7.4±0.3 mg/g vs. 9.1±0.5 mg/g, p<0.05); and attenuated cardiac fibrosis (6.6±0.6% vs 10.7±1%, p<0.01). Conclusions: IMB-101 increases cardiac glucose uptake and protects against LV dysfunction, hypertrophic remodelling and interstitial fibrosis after chronic pressure overload.

Mechanical Synchrony and Myocardial Work in Heart Failure Patients With Left Bundle Branch Area Pacing and Comparison With Biventricular Pacing.

Background: Little is known about the efficacy of permanent left bundle branch area pacing (LBBAP) in delivering cardiac resynchronization therapy (CRT). This study aimed to evaluate the effect of LBBAP on mechanical synchronization and myocardial work (MW) in heart failure (HF) patients and to compare LBBAP with biventricular pacing (BVP).Methods: This is a multicenter, prospective cohort study. From February 2018 to January 2021, 62 consecutive HF patients with reduced ejection fraction (LVEF ≤ 35%) and complete left bundle branch block (CLBBB) who underwent LBBAP or BVP were enrolled in this study. Echocardiograms and electrocardiograms and were conducted before and 3–6 months after implantation. Intra- and interventricular synchronization were assessed using two-dimensional speckle tracking imaging (2D-STI). The left ventricular pressure-strain loop was obtained by combining left ventricular strain with non-invasive blood pressure to evaluate mechanical efficiency.Results: The echocardiographic response rates were 68.6 and 88.9% in the BVP and LBBAP groups, respectively. Left bundle branch area pacing resulted in significant QRS narrowing (from 177.1 ± 16.7 to 113.0 ± 18.4 ms, P < 0.001) and improvement in LVEF (from 29.9 ± 4.8 to 47.1 ± 8.3%, P < 0.001). The global wasted work (GWW) (410.3 ± 166.6 vs. 283.0 ± 129.6 mmHg%, P = 0.001) and global work efficiency (GWE) (64.6 ± 7.8 vs. 80.5 ± 5.7%, P < 0.001) were significantly improved along with shorter peak strain dispersion (PSD) (143.4 ± 45.2 vs. 92.6 ± 35.1 ms, P < 0.001) and interventricular mechanical delay (IVMD) (56.4 ± 28.5 vs. 28.9 ± 19.0 ms, P < 0.001), indicating its efficiency in improving mechanical synchronization. In comparison with BVP, LBBAP delivered greater improvement of QRS narrowing (−64.1 ± 18.9 vs. −32.5 ± 22.3 ms, P < 0.001) and better mechanical synchronization and efficiency.Conclusions: Left bundle branch area pacing was effective in improving cardiac function, mechanical synchronization, and mechanical efficiency and may be a promising alternative cardiac resynchronization therapy.

Cardiac mechanical efficiency is preserved in primary cardiac hypertrophy despite impaired mechanical function.

Increased heart size is a major risk factor for heart failure and premature mortality. Although abnormal heart growth subsequent to hypertension often accompanies disturbances in mechano-energetics and cardiac efficiency, it remains uncertain whether hypertrophy is their primary driver. In this study, we aimed to investigate the direct association between cardiac hypertrophy and cardiac mechano-energetics using isolated left-ventricular trabeculae from a rat model of primary cardiac hypertrophy and its control. We evaluated energy expenditure (heat output) and mechanical performance (force length work production) simultaneously at a range of preloads and afterloads in a microcalorimeter, we determined energy expenditure related to cross-bridge cycling and Ca2+ cycling (activation heat), and we quantified energy efficiency. Rats with cardiac hypertrophy exhibited increased cardiomyocyte length and width. Their trabeculae showed mechanical impairment, evidenced by lower force production, extent and kinetics of shortening, and work output. Lower force was associated with lower energy expenditure related to Ca2+ cycling and to cross-bridge cycling. However, despite these changes, both mechanical and cross-bridge energy efficiency were unchanged. Our results show that cardiac hypertrophy is associated with impaired contractile performance and with preservation of energy efficiency. These findings provide direction for future investigations targeting metabolic and Ca2+ disturbances underlying cardiac mechanical and energetic impairment in primary cardiac hypertrophy.

Depressed Cardiac Mechanical Energetic Efficiency: A Contributor to Cardiovascular Risk in Common Metabolic Diseases-From Mechanisms to Clinical Applications.

Cardiac mechanical energetic efficiency is the ratio of external work (EW) to the total energy consumption. EW performed by the left ventricle (LV) during a single beat is represented by LV stroke work and may be calculated from the pressure–volume loop area (PVLA), while energy consumption corresponds to myocardial oxygen consumption (MVO2) expressed on a per-beat basis. Classical early human studies estimated total mechanical LV efficiency at 20–30%, whereas the remaining energy is dissipated as heat. Total mechanical efficiency is a joint effect of the efficiency of energy transfer at three sequential stages. The first step, from MVO2 to adenosine triphosphate (ATP), reflects the yield of oxidative phosphorylation (i.e., phosphate-to-oxygen ratio). The second step, from ATP split to pressure–volume area, represents the proportion of the energy liberated during ATP hydrolysis which is converted to total mechanical energy. Total mechanical energy generated per beat—represented by pressure–volume area—consists of EW (corresponding to PVLA) and potential energy, which is needed to develop tension during isovolumic contraction. The efficiency of the third step of energy transfer, i.e., from pressure–volume area to EW, decreases with depressed LV contractility, increased afterload, more concentric LV geometry with diastolic dysfunction and lower LV preload reserve. As practical assessment of LV efficiency poses methodological problems, De Simone et al. proposed a simple surrogate measure of myocardial efficiency, i.e., mechano-energetic efficiency index (MEEi) calculated from LV stroke volume, heart rate and LV mass. In two independent cohorts, including a large group of hypertensive subjects and a population-based cohort (both free of prevalent cardiovascular disease and with preserved ejection fraction), low MEEi independently predicted composite adverse cardiovascular events and incident heart failure. It was hypothesized that the prognostic ability of low MEEi can result from its association with both metabolic and hemodynamic alterations, i.e., metabolic syndrome components, the degree of insulin resistance, concentric LV geometry, LV diastolic and discrete systolic dysfunction. On the one part, an increased reliance of cardiomyocytes on the oxidation of free fatty acids, typical for insulin-resistant states, is associated with both a lower yield of ATP per oxygen molecule and lesser availability of ATP for contraction, which might decrease energetic efficiency of the first and second step of energy transfer from MVO2 to EW. On the other part, concentric LV remodeling and LV dysfunction despite preserved ejection fraction can impair the efficiency of the third energy transfer step. In conclusion, the association of low MEEi with adverse cardiovascular outcome might be related to a multi-step impairment of energy transfer from MVO2 to EW in various clinical settings, including metabolic syndrome, diabetes, hypertension and heart failure. Irrespective of theoretical considerations, MEEi appears an attractive simple tool which couldt improve risk stratification in hypertensive and diabetic patients for primary prevention purposes. Further clinical studies are warranted to estimate the predictive ability of MEEi and its post-treatment changes, especially in patients on novel antidiabetic drugs and subjects with common metabolic diseases and concomitant chronic coronary syndromes, in whom the potential relevance of MEE can be potentiated by myocardial ischemia.

Effects of levosimendan on ventriculo-arterial coupling and cardiac efficiency in paediatric patients with single-ventricle physiology after surgical palliation: retrospective study.

The use of levosimendan for paediatric patients with low cardiac output after congenital heart surgery has been recently described. We sought to evaluate ventriculo-arterial coupling (VAC) and other ventricular energetic parameters before and after 72 h from levosimendan start in infants with single-ventricle physiology and cardiac failure after palliation with Norwood or hybrid procedures. In this single-centre retrospective study, 9 consecutive patients affected by hypoplastic left heart syndrome-like anatomy were retrospectively analysed. Systolic elastance, diastolic elastance, arterial elastance, VAC and cardiac mechanical efficiency were calculated by measuring, through 2-dimensional echocardiography, end-systolic volume and end-diastolic volume and by recording mean arterial pressure and central venous pressure. The median (range) weight and age were 2.8 (2.3-6) kg and 16.5 (6-116) days, respectively. After 72 h from levosimendan start, end-systolic volume significantly decreased (-1 ml, -3.2 to -0.1, P = 0.007), whereas mean arterial pressure and end-diastolic volume remained stable. Heart rate showed a significant decrease (-28 beats/min, -41 to 22, P = 0.008). Systolic elastance (2.9 mmHg/ml, 0.4-5.4, P = 0.008), arterial elastance (-5.9, -24 to -0.5, P = 0.038), VAC (-0.86, -1.5 to -0.16, P = 0.009) and cardiac mechanical efficiency (0.18, 0.03-0.22, P = 0.008) differences also showed significant modifications. In a small case series of patients with single-ventricle physiology, levosimendan showed to improve contractility and optimize VAC, with a reduction of heart rate. Monitoring of VAC and ventricular energetics can be an interesting aspect to improve the management of heart failure in infants with univentricular anatomy.

RF21 EVOLUTION OF VENTRICULAR ENERGETICS IN THE DIFFERENT STAGES OF PALLIATION OF HYPOPLASTIC LEFT HEART SYNDROME: A RETROSPECTIVE CLINICAL STUDY.

Introduction: Hyperplastic left heart syndrome (HLHS) patients are palliated by creating a Fontan-type circulation passing from different surgical stages. The aim of this work is to describe the evolution of ventricular energetics parameters in HLHS patients during the different stages of palliation. Methods: We conducted a retrospective clinical study enrolling all HLHS patients surgically treated with hybrid procedure and/or Norwood and/or Bidirectional Glenn (BDG) and/or Fontan operation from 2011 to 2016 collecting echocardiographic and hemodynamic data. Measured data were used to calculate energetic variables such as ventricular elastances, external and internal work, ventriculo-arterial coupling and cardiac mechanical efficiency. Results: From 2010 to 2016, a total of 29 HLHS patients undergoing cardiac catheterization after hybrid (n = 7) or Norwood (n = 6) or Glenn (n = 8) or Fontan (n = 8) procedure were retrospectively enrolled. Ventricular volumes were significantly higher in the Norwood circulation than in the hybrid circulation (p = 0.03) with a progressive decrement from the first stage to the Fontan completion. Ventricular elastances were lower in the Norwood circulation than in the hybrid circulation and progressively increased passing from the first stage to the Fontan completion. The arterial elastance and Rtot increased in the Fontan circulation. The ventricular work progressively increased. Finally, the ventricular efficiency improves passing from the first to the last stage of palliation. Conclusion: The use of ventricular energetic parameters could lead to a more complete evaluation of such complex patients to better understand their adaptation to different pathophysiological conditions.

The influence of esmolol on right ventricular function in early experimental endotoxic shock.

The mechanism by which heart rate (HR) control with esmolol improves hemodynamics during septic shock remains unclear. Improved right ventricular (RV) function, thereby reducing venous congestion, may play a role. We assessed the effect of HR control with esmolol during sepsis on RV function, macrocirculation, microcirculation, end‐organ‐perfusion, and ventricular‐arterial coupling. Sepsis was induced in 10 healthy anesthetized and mechanically ventilated sheep by continuous IV administration of lipopolysaccharide (LPS). Esmolol was infused after successful resuscitation of the septic shock, to reduce HR and stopped 30‐min after reaching targeted HR reduction of 30%. Venous and arterial blood gases were sampled and the small intestines’ microcirculation was assessed by using a hand‐held video microscope (CytoCam‐IDF). Arterial and venous pressures, and cardiac output (CO) were recorded continuously. An intraventricular micromanometer was used to assess the RV function. Ventricular–arterial coupling ratio (VACR) was estimated by catheterization‐derived single beat estimation. The targeted HR reduction of >30% by esmolol infusion, after controlled resuscitation of the LPS induced septic shock, led to a deteriorated RV‐function and macrocirculation, while the microcirculation remained depressed. Esmolol improved VACR by decreasing the RV end‐systolic pressure. Stopping esmolol showed the reversibility of these effects on the RV and the macrocirculation. In this animal model of acute severe endotoxic septic shock, early administration of esmolol decreased RV‐function resulting in venous congestion and an unimproved poor microcirculation despite improved cardiac mechanical efficiency.

L-carnitine supplementation in the recovery of plasma L-carnitine in patients with heart failure submitted to coronary artery bypass grafting.

Coronary artery bypass grafting reduces plasma L-carnitine and may impair the production of myocardial energy. L-carnitine supplementation may elevate plasma L-carnitine and increase cardiac mechanical efficiency. The objective of this study was to verify the recovery of preoperative plasma LC in patients with heart failure undergoing coronary artery bypass grafting supplemented with a daily oral dose of 50 mg / kg. Volunteers with ischemic heart failure who underwent surgery were randomized into a supplemented group (A-received 50 mg / kg L-carnitine) or placebo group (B) for 60 days. Supplementation was started on the third postoperative day. The spectrophotometric enzymatic method was used to quantify plasma L-carnitine. In the preoperative period, both groups had plasma L-carnitine adequate to the reference range (18.9-71.1 μM). On the second postoperative day, there was a reduction in plasma L-carnitine in groups A (17.4%) and B (14.4%). In the comparison between the groups, plasma L-carnitine was higher in group A than B in 10º (p = 0.024), 30º (p = 0.001), and 60º postoperative day (p = 0.008). Supplementation of L-carnitine at a daily oral dose of 50 mg / kg in patients with heart failure undergoing coronary artery bypass grafting may recover preoperative plasma L-carnitine within 10 days.

Arterial Chemoreflex Protective Effect on Left Ventricle Energetics and Changes after Myocardial Infarct

The Arterial Chemoreflex negative feedback mechanism regulates the cardiovascular responses to arterial oxygen and carbon dioxide concentrations as sensed by carotid chemoreceptors. Whenever the arterial pressure of oxygen chnages the Autonomic Nervous System madulates heart rate and arterial blood pressure. As the Arterial Chemoreflex influences cardiac output to compensate for changes in oxygen arterial pressure, we hypothesized that it must influence the mechanical interaction between the left ventricle and the arterial tree, as well as cardiac energy consumption and efficiency during Myocardial Infarct. The Arterial Chemoreflex was provoked by the application of lobeline in the left-carotid sinus of 11 rabbits anesthetized, paralyzed and artificially ventilated; an intraventricular impedance catheter was used to measure simultaneously ventricular pressure and volume. All experiments were performed according to national laws and international guidelines. We designed a custom software to compute beat by beat left-ventricle end-systolic elastance (Ees), arterial elastance (Ea) and the ventriculo arteral coupling ratio (Ea/Ees); from this data we calculated left-ventricular stroke work (SW), total energy expenditure (PVA), ratio of the SW to its theoretical maximum (Qload) and cardiac energetic efficiency (CEE=SW/PVA). Under Basal Conditions and after Myocardial Infarct the Arterial Chemoreflex increased Ees and Ea in paralell, without any change in Ees/Ea. SW and PVA both decreased, without any change of Qload or CEE (Table). Ventriculo-arterial coupling was maintained in the interval of optimal cardiac mechanical and energetic efficiency. In conclusion, the Arterial Chemoreflex is a control mechanism of the cardiovascular system that exerts a feedback modulation on cardiovascular responses through an increase in both left ventricle contractility and arterial elastance, in such a balanced way that ventriculo-arterial coupling is mantained, mechanical and energetic efficiency are maintained at optimal values. Most remarckably the increase in ventricular and arterial elastance is acomplished decreasing the SW and PVA(equivalent to myocardial oxygen demand), therefore emphasizing the protective effect of the Arterial Chemoreflex the myocardial oxygen comnsumption is ischemic conditions. Support or Funding Information PHYSIOMAT - Modelação Matemática e Computacional da Fisiologia Humana (2013) Fundação para a Ciência e Tecnologia EXCL/MAT-NAN/0114/2012 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study

BackgroundIt has been hypothesized that the supply of chemical energy may be insufficient to fuel normal mechanical pump function in heart failure (HF). The creatine kinase (CK) reaction serves as the heart’s primary energy reserve, and the supply of adenosine triphosphate (ATP flux) it provides is reduced in human HF. However, the relationship between the CK energy supply and the mechanical energy expended has never been quantified in the human heart. This study tests whether reduced CK energy supply is associated with reduced mechanical work in HF patients.MethodsCardiac mechanical work and CK flux in W/kg, and mechanical efficiency were measured noninvasively at rest using cardiac pressure-volume loops, magnetic resonance imaging and phosphorus spectroscopy in 14 healthy subjects and 27 patients with mild-to-moderate HF.ResultsIn HF, the resting CK flux (126 ± 46 vs. 179 ± 50 W/kg, p < 0.002), the average (6.8 ± 3.1 vs. 10.1 ± 1.5 W/kg, p <0.001) and the peak (32 ± 14 vs. 48 ± 8 W/kg, p < 0.001) cardiac mechanical work-rates, as well as the cardiac mechanical efficiency (53% ± 16 vs. 79% ± 3, p < 0.001), were all reduced by a third compared to healthy subjects. In addition, cardiac CK flux correlated with the resting peak and average mechanical power (p < 0.01), and with mechanical efficiency (p = 0.002).ConclusionThese first noninvasive findings showing that cardiac mechanical work and efficiency in mild-to-moderate human HF decrease proportionately with CK ATP energy supply, are consistent with the energy deprivation hypothesis of HF. CK energy supply exceeds mechanical work at rest but lies within a range that may be limiting with moderate activity, and thus presents a promising target for HF treatment.Trial registrationClinicalTrials.gov Identifier: NCT00181259.

Ventricular Energetics in Pediatric Left Ventricular Assist Device Patients: A Retrospective Clinical Study.

The aim of this study is to estimate the trend of right and left energetic parameters in left ventricular assist device (LVAD) pediatric patients. Echocardiographic data were retrospectively collected at the baseline, in the acute phase after and at the monthly follow-ups till the LVAD explantation to estimate left and right ventricular energetic parameters. A significant relationship between the left and right ventricular energetic parameter trends was found along all the study period. Left ventricular end-systolic pressure-volume relationship improved till the follow-up of 2 months and then progressively decreases. Left arteroventricular coupling decreases after the LVAD, and right arteroventricular coupling decreases at the short-term follow-up. Left ventricular external work, potential energy, and pressure-volume area decrease at the short-term follow-up and then increase progressively. Right ventricular external work, potential energy, and pressure-volume area increase after the LVAD implantation. Left (right) cardiac mechanical efficiency is improved (worsened) by the LVAD. Energetic variables show that the LVAD benefits could decrease over time. A continuous and patient tailored LVAD setting could contribute to prolong LVAD benefits. The introduction of energetic parameters could lead to a more complete evaluation of LVAD patients' outcome which is a multiparametric process.

Heat shock protein 72 may improve hypotension by increasing cardiac mechanical efficiency and arterial elastance in heatstroke rats

ObjectiveWe attempted to test the hypothesis that preinduction of heat shock protein (HSP) 72 in the heart would improve left ventricular performance in rat heatstroke. MethodsCardiac expression of HSP 72 was quantitatively evaluated by western blot analysis in rats 0h, 12h, or 72h after mild heat preconditioning (MHP; 43°C for 30min). They were subjected to severe heat stress (SHS; 43°C for 70min) to induce heatstroke. A 1.2F catheter-tip pressure transducer was inserted into the left ventricle of these group rats under general anesthesia to record hemodynamic in the closed chest with a pressure–volume loop module data recording and analysis system. ResultsAt the time point of heatstroke onset, compared with normothermic controls, group rats with 12h post-MHP had significantly increased cardiac HSP 72, decreased hyperthermia, decreased hypotension, decreased bradycardia, increased end-systolic pressure, increased end-diastolic pressure, increased stroke volume, decreased end-systolic volume, decreased end-diastolic pressure, increased cardiac output, increased ejection fraction, increased stroke work, increased arterial elastance, and decreased time constant of fall in ventricular pressure by Glantz-methods. With the loss of cardiac HSP 72 expression observed at 72h in post-MHP group rats, an insignificant protection against left ventricular performance was observed. ConclusionPreinduction of cardiac HSP 72 may improve hypotension in heatstroke rats by increasing both cardiac mechanical efficiency and arterial elastance.

Cardiac Energetics in Presence of Lung Assist Devices: &amp;lt;i&amp;gt;In Silico&amp;lt;/i&amp;gt; Study

The treatment with a mechanical ventilator is required whenever a patient’s respiratory system becomes unable to keep the concentrations of O2 and CO2 in blood at tolerable levels. However, in particular cases, the thoracic artificial lung (TAL) can be regarded as a viable alternative to mechanical ventilation (MV). We aim at studying the effects of mechanical ventilators and thoracic artificial lungs devices will have on the cardiovascular system. We will give careful consideration to cardiovascular energetic parameters, such as left and right ventricular external work, pressure-volume area, and cardiac mechanical efficiency. We simulated both, mechanically ventilated patients who are not subject to the application of an artificial lung and patients who are provided with a thoracic artificial lung (TAL). In the case of a thoracic artificial lung, we involved in our simulation studies all the usual operating modes of a TAL, viz. series mode, parallel mode, and hybrid mode of the TAL with regard to the native lung. In particular, the presented simulation results will contribute to elucidate the specific characteristics of each of the aforementioned operating modes. Generally, the energetic variables are influenced by different values of input TAL resistance in both modes: parallel and in series. In this paper, we concentrated on simulation studies of the effects evoked by TAL assistance on cardiac energetic and some other important circulatory parameters. The simulation results presented show that at all modes of TAL assistance exists a strong dependency on the TAL input variables and on the value of the mean intrathoracic pressure which has been assumed for a given situation.

Lung assist devices influence cardio-energetic parameters: Numerical simulation study.

We aim at an analysis of the effects mechanical ventilators (MVs) and thoracic artificial lungs (TALs) will have on the cardiovascular system, especially on important quantities, such as left and right ventricular external work (EW), pressure-volume area (PVA) and cardiac mechanical efficiency (CME). Our analyses are based on simulation studies which were carried out by using our CARDIOSIM(©) software simulator. At first, we carried out simulation studies of patients undergoing mechanical ventilation (MV) without a thoracic artificial lung (TAL). Subsequently, we conducted simulation studies of patients who had been provided with a TAL, but did not undergo MV. We aimed at describing the patient's physiological characteristics and their variations with time, such as EW, PVA, CME, cardiac output (CO) and mean pulmonary arterial/venous pressure (PAP/PVP). We were starting with a simulation run under well-defined initial conditions which was followed by simulation runs for a wide range of mean intrathoracic pressure settings. Our simulations of MV without TAL showed that for mean intrathoracic pressure settings from negative (-4 mmHg) to positive (+5 mmHg) values, the left and right ventricular EW and PVA, right ventricular CME and CO decreased, whereas left ventricular CME and the PAP increased. The simulation studies of patients with a TAL, comprised all the usual TAL arrangements, viz. configurations "in series" and in parallel with the natural lung and, moreover, hybrid configurations. The main objective of the simulation studies was, as before, the assessment of the hemodynamic response to the application of a TAL. We could for instance show that, in case of an "in series" configuration, a reduction (an increase) in left (right) ventricular EW and PVA values occurred, whereas the best performance in terms of CO can be achieved in the case of an in parallel configuration.

The gut hormone ghrelin partially reverses energy substrate metabolic alterations in the failing heart.

The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects; hence, it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. Human des-acyl ghrelin [1.2 nmol/kg per hour] was infused intravenously for 15 minutes, followed by washout (rebaseline) and infusion of acyl ghrelin at the same dose. (3)H-oleate and (14)C-glucose were coinfused and arterial and coronary sinus blood sampled to measure cardiac free fatty acid and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF because baseline oxidation levels of free fatty acids and glucose were, respectively, >70% lower and >160% higher compared with control. Neither des-acyl ghrelin nor acyl ghrelin significantly affected function and metabolism in normal hearts. However, in HF, des-acyl and acyl ghrelin enhanced myocardial oxygen consumption by 10.2±3.5% and 9.9±3.7%, respectively (P<0.05), and cardiac mechanical efficiency was not significantly altered. This was associated, respectively, with a 41.3±6.7% and 32.5±10.9% increase in free fatty acid oxidation and a 31.3±9.2% and 41.4±8.9% decrease in glucose oxidation (all P<0.05). Acute increases in des-acyl or acyl ghrelin do not interfere with cardiac metabolism in normal dogs, whereas they enhance free fatty acid oxidation and reduce glucose oxidation in HF dogs, thus partially correcting metabolic alterations in HF. This novel mechanism might contribute to the cardioprotective effects of ghrelin in HF.

Most Important Outcomes Research Papers on Device Therapies for Cardiomyopathies

Disorders of the cardiac muscle or cardiomyopathies are a broad, yet collectively common, group of conditions. Despite the heterogeneous etiologies, mode of death from these conditions is remarkably similar - progressive decline in cardiac function leading to intractable heart failure (HF) and sustained ventricular arrhythmias resulting in sudden cardiac death (SCD). Nearly 50% of patients die within 5 years of a HF diagnosis.1 Indeed, in the United States, HF alone is thought to cause 55,000 deaths per year2 and further contribute to 1 in 9 deaths overall.1 However, while advanced HF and the risk of SCD were once thought to be untreatable, technological advances has seen the emergence of device therapies as viable treatment options. Specifically, implantable cardioverter-defibrillator (ICD) therapy for treatment of ventricular arrhythmias, cardiac resynchronization therapy (CRT) for restoring cardiac synchrony and mechanical efficiency, and ventricular assist device (VAD) therapy to temporarily or permanently replace the function of the failing heart, have all emerged as highly efficacious therapies. The expanding use of device therapies, however, poses many challenges. First, while the indications for these devices are well summarized in clinical guidelines,3,4 considerable hurdles remain in ensuring eligible patients receive these therapies.5 By the same token, establishing the safety and effectiveness of these therapies in populations that are found in clinical practice, yet commonly excluded from trials, such as the elderly6 and uncommon forms of cardiomyopathies,7 is a high priority. Second, rapid dissemination of technologies frequently results in disparities in care. Indeed, age, gender, and racial disparities, in both receipt of these devices and outcomes following implantation, have been well documented. Whether these disparities have persisted, and the potential causative mechanisms underlying these disparities, however, are uncertain.8,9 Third, these devices are not without significant untoward effects; understanding …

Electromechanical Dyssynchrony and Resynchronization of the Failing Heart

Patients with heart failure and decreased function frequently develop discoordinate contraction because of electric activation delay. Often termed dyssynchrony, this further decreases systolic function and chamber efficiency and worsens morbidity and mortality. In the mid- 1990s, a pacemaker-based treatment termed cardiac resynchronization therapy (CRT) was developed to restore mechanical synchrony by electrically activating both right and left sides of the heart. It is a major therapeutic advance for the new millennium. Acute chamber effects of CRT include increased cardiac output and mechanical efficiency and reduced mitral regurgitation, whereas reduction in chamber volumes ensues more chronically. Patient candidates for CRT have a prolonged QRS duration and discoordinate wall motion, although other factors may also be important because ≈30% of such selected subjects do not respond to the treatment. In contrast to existing pharmacological inotropes, CRT both acutely and chronically increases cardiac systolic function and work, yet it also reduces long-term mortality. Recent studies reveal unique molecular and cellular changes from CRT that may also contribute to this success. Heart failure with dyssynchrony displays decreased myocyte and myofilament function, calcium handling, β-adrenergic responsiveness, mitochondrial ATP synthase activity, cell survival signaling, and other changes. CRT reverses many of these abnormalities often by triggering entirely new pathways. In this review, we discuss chamber, circulatory, and basic myocardial effects of dyssynchrony and CRT in the failing heart, and we highlight new research aiming to better target and implement CRT, as well as leverage its molecular effects.