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Heart failure (HF) continues to be a serious public health challenge despite significant advancements in therapeutics and is often complicated by multiple other comorbidities. Of particular concern is type 2 diabetes mellitus (T2DM) which not only amplifies the risk, but also limits the treatment options available to patients. The sodium-glucose linked cotransporter subtype 2 (SGLT2)-inhibitor class, which was initially developed as a treatment for T2DM, has shown great promise in reducing cardiovascular risk, particularly around HF outcomes – regardless of diabetes status.There are ongoing efforts to elucidate the true mechanism of action of this novel drug class. Its primary mechanism of inducing glycosuria and diuresis from receptor blockade in the renal nephron seems unlikely to be responsible for the rapid and striking benefits seen in clinical trials. Early mechanistic work around conventional therapeutic targets seem to be inconclusive. There are some emerging theories around its effect on myocardial energetics and calcium balance as well as on renal physiology. In this review, we discuss some of the cutting-edge hypotheses and concepts currently being explored around this drug class in an attempt better understand the molecular mechanics of this novel agent.

Background Abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Transient pulmonary congestion during exercise is emerging as an important determinant of reduced exercise capacity and symptoms in patients with HFpEF. Purpose We sought to determine if impaired myocardial energetics limits cardiac exercise reserve and leads to exercise-induced pulmonary congestion in HFpEF. Methods 42 patients across the spectrum of diastolic dysfunction and HFpEF (controls n=10; type 2 diabetes (T2DM) n=9; HFpEF n=14; severe diastolic dysfunction due to cardiac amyloid n=9) (Fig. 1a) underwent assessment of cardiac energetics (myocardial phosphocreatine to adenosine triphosphate ratio, PCr/ATP) and function using cardiovascular magnetic resonance (CMR) imaging and echocardiography, and lung-water using a novel pulmonary proton-density MR sequence. Studies were performed at rest and during exercise (20W for 6 minutes) using a CMR-ergometer. Results Paralleling the stepwise decline in diastolic function across the groups (E/e' ratio, p The novel pulmonary proton-density sequence provided images that scaled linearly with water content (validated using a water-doped sponge phantom; r 0.98, p Conclusion A gradient of myocardial energetic deficit exists across the spectrum of HFpEF. This energetic deficit is related to markedly abnormal cardiac exercise responses, which leads to transient pulmonary congestion. The findings support an energetic basis for impaired cardiac reserve and exercise-induced pulmonary congestion in HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Baseline clinical and CMR parametersExercise cardiopulmonary parameters

Visual Abstract, Highlights • Cardiac energy deprivation due to mitochondrial dysfunction is characteristic of heart failure. • Mitochondrial dysfunction contributes to worsening of the heart failure state. • Pharmacologic targeting of mitochondria in heart failure is an unmet need. • Mitochondrial dysfunction in heart failure can be reversed with novel experimental drugs., Summary The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as “energy-deprived” and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities. Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species and a marked reduction in on demand adenosine triphosphate synthesis. Correcting mitochondrial dysfunction therefore offers considerable potential as a new therapeutic approach to improve overall cardiac function, quality of life, and survival for patients with HF.

Objectives. Heart failure (HF) impairs resting myocardial energetics, myocardial mitochondrial performance, and maximal oxygen uptake (VO2max). Exercise training is included in most rehabilitation ...

The heart has the highest energy demands per gram of any organ in the body and energy metabolism fuels normal contractile function. Metabolic inflexibility and impairment of myocardial energetics occur with several common cardiac diseases, including ischemia and heart failure. This review explores several decades of innovation in cardiac magnetic resonance spectroscopy modalities and their use to noninvasively identify and quantify metabolic derangements in the normal, failing, and diseased heart. The implications of this noninvasive modality for predicting significant clinical outcomes and guiding future investigation and therapies to improve patient care are discussed.

Cardiac metabolism and function are intrinsically linked. High-energy phosphates occupy a central and obligate position in cardiac metabolism, coupling oxygen and substrate fuel delivery to the myocardium with external work. This insight underlies the widespread clinical use of ischaemia testing. However, other deficits in high-energy phosphate metabolism (not secondary to supply-demand mismatch of oxygen and substrate fuels) may also be documented, and are of particular interest when found in the context of structural heart disease. This review introduces the scope of deficits in high-energy phosphate metabolism that may be observed in the myocardium, how to assess for them, and how they might be interpreted.

Purpose Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities. Methods Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1. Results The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM. Conclusions Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.

Since left ventricular hypertrophy (LVH) increases the susceptibility for the development of other cardiac conditions, pharmacotherapy that mitigates pathological cardiac remodeling may prove to be beneficial in patients with LVH. Previous work has shown that the activation of the energy-sensing kinase AMP-activated protein kinase (AMPK) can inhibit some of the molecular mechanisms that are involved in LVH. Of interest, metformin activates AMPK through its inhibition of mitochondrial complex I in the electron transport chain and can prevent LVH induced by pressure overload. However, metformin has additional cellular effects unrelated to AMPK activation, raising questions about whether mitochondrial complex I inhibition is sufficient to reduce LVH. Herein, we characterize the cardiac effects of a novel compound (R118), which is a more potent complex I inhibitor than metformin and is thus used at a much lower concentration. We show that R118 activates AMPK in the cardiomyocyte, inhibits multiple signaling pathways involved in LVH, and prevents Gq protein-coupled receptor agonist-induced prohypertrophic signaling. We also show that in vivo administration of R118 prevents LVH in a mouse model of hypertension, suggesting that R118 can directly modulate the response of the cardiomyocyte to stress. Of importance, we also show that while R118 treatment prevents adaptive remodelling in response to elevated afterload, it does so without compromising systolic function, improves myocardial energetics, and prevents a decline in diastolic function in hypertensive mice. Taken together, our data suggest that inhibition of mitochondrial complex I may be worthy of future investigation for the treatment of LVH. NEW & NOTEWORTHY Inhibition of mitochondrial complex I by R118 reduces left ventricular hypertrophy (LVH) and improves myocardial energetics as well as diastolic function without compromising systolic function. Together, these effects demonstrate the therapeutic potential of complex I inhibitors in the treatment of LVH, even in the presence of persistent hypertension.

Background: Obesity is strongly associated with exercise intolerance and the development of heart failure. Whereas myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesized that ATP transfer rate through creatine kinase (CK) ( k f CKrest ) would be increased, compensating for depleted energy stores (phosphocreatine/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesized that these changes would normalize with weight loss. Methods: We recruited 80 volunteers (35 controls [body mass index 24±3 kg/m 2 ], 45 obese [body mass index 35±5 kg/m 2 ]) without coexisting cardiovascular disease. Participants underwent body composition analysis, magnetic resonance imaging of abdominal, liver, and myocardial fat content, left ventricular function, and 31 P magnetic resonance spectroscopy to assess phosphocreatine/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before reexamination. Results: At rest, although myocardial phosphocreatine/ATP was 14% lower in obesity (1.9±0.3 versus 2.2±0.2, P k f Ckrest was 33% higher (0.23±0.07 s –1 versus 0.16±0.08 s –1 , P =0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9 µmol·g –1 ·s –1 versus control 2.2±1.1 µmol·g –1 ·s –1 , P =0.232). In controls, increasing cardiac workload led to an increase in both k f CK (+86%, P P k f CK ( P =0.117) or ATP delivery ( P =0.608). This was accompanied by reduced systolic augmentation (absolute increase in left ventricular ejection fraction, obese +16±7% versus control +21±4%, P =0.031). Successful weight loss (–11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference in comparison with controls. Conclusions: In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced phosphocreatine/ATP. During increased workload, although the nonobese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery through CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, and a fascinating modifiable pathway involved in the progression to heart failure, as well.

Ventricular pressure–volume (PV) analysis is the reference method for the study of cardiac mechanics. Advances in calibration algorithms and measuring techniques brought new perspectives for its application in different research and clinical settings. Simultaneous PV measurement in the heart chambers offers unique insights into mechanical cardiac efficiency. Beat to beat invasive PV monitoring can be instrumental in the understanding and management of heart failure, valvular heart disease, and mechanical cardiac support. This review focuses on intra cardiac left ventricular PV analysis principles, interpretation of signals, and potential clinical applications.

The complex nature of interaction between the heart and the circulation was well recognized among the early nineteenth-century physiologists, and despite numerous technical challenges associated with “opening of the circuit,” attempts were made to investigate the mechanical behavior of the heart itself. The ideas that led to the development and application of this radical experiment played a key role in the understanding of the mechanical and energetic function of the heart which remains incomplete. Further discussed are: recirculating and non-recirculating isolated heart preparations; Otto Frank’s and Ernest Starling’s isolated heart preparations and original formulation of the “law of the heart”; similarity between the isolated heart preparation and the hydraulic ram as a unique model of heart’s mechanical action; quantification of ventricular pump function by the “three element Windkessel”; the “physiological enigma” of the high myocardial basal metabolic rate and its low mechanical efficiency; length-dependent activation of the cardiac muscle and the reformulation of the “law of the heart” in terms of myocardial energetics; and the conceptual drawbacks of the total artificial hearts and relative success of the ventricular assist and continuous flow devices.

Background:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2extraction. Lastly, we assessed whether coupling of MVO2to EW (mechanical efficiency) was impaired in HFpEF.Methods and Results:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed11C-acetate positron emission tomography assessing MVO2and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls.Conclusions:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2supply relative to demand, and is associated with reserve dysfunction.

Background: Although metabolic alterations were observed in heart failure (HF), only recently have the mechanisms underlying these changes been identified. Tumor suppressor p53 responds to metabolic changes thorough several mechanisms. One of the p53 targets, TIGAR (TP53-induced glycolysis and apoptosis regulator) reduces glycolysis and suppresses autophagy, which augments ischemic damage, however its role on HF is unclear. Method and Results: In order to investigate TIGAR’s function in HF, we compared myocardial metabolic and functional outcomes between TIGAR deficient (TIGAR–/–) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR–/– mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared to those of TIGAR–/– mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR–/– hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice (TIGARflox/flox/ Tg(Myh6-cre/Esr1) mice). Conclusion: The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR targeted therapy to increase glucose metabolism will be a novel strategy for HF.

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism–contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR’s function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR−/−) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR−/−mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR−/−mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR−/−hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice ( TIGARflox/flox/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF.NEW & NOTEWORTHY The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.

Ronglih Liao studied hard as a teenager in Taiwan, but science was just one among many wide-ranging interests. At age 17, however, her focus abruptly became clear when her father was diagnosed with lung cancer, eventually leading Liao to a career in basic science with the potential to translate understanding into therapies for both rare and common cardiovascular diseases. After obtaining a chemistry degree, Liao fulfilled a promise to her late father to obtain an advanced degree overseas. For her PhD thesis at the University of Alabama Birmingham, she examined the interaction of troponin I with troponin C in bovine cardiac muscle.1 Then, Liao was recruited by 2 amazing mentors with independent laboratories and complementary expertise, Drs Judith Gwathmey and Joanne S. Ingwall, to undertake a collaborative project in cardiac physiology and myocardial energetics at Harvard Medical School. At the time, the concept that failing hearts were energy-starved was not yet accepted, and Liao deployed P31 nuclear magnetic resonance to detect decreased energy reserve in a model of dilated cardiomyopathy—baggy and sick turkey hearts—and establish its relationship to contractile performance.2 Liao set up her first independent laboratory at the Boston University School of Medicine, where she benefited from the university’s status as an internationally recognized center for the study of amyloidosis. Perfusing human immunoglobulin light chain proteins (amyloid precursors) into mouse heart, her laboratory was the first to demonstrate what the amyloidosis experts at Boston University had suspected—that amyloid light chain proteins were cardiotoxic and contributed directly to the pathogenesis and rapid progression of amyloid cardiomyopathy, independent of fibril formation and deposition.3 In 2005, Liao moved to Harvard Medical School, where she is now professor of medicine. At Brigham and Women’s Hospital, she directs the Cardiac Muscle Research Laboratory (since 2005), the Cardiovascular Flow Cytometry Core …

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to exert benefit on cardiac outcomes. In this review, we provide updates on available clinical data, studies on potential mechanisms for the CV effects, as well as discuss potential clinical implications of these new findings. Since the publications of the EMPA-REG and CANVAS trials, large multi-national cohort studies have further shown the cardioprotective effects of SGLT2i. Moreover, new studies examining SGLT2i action on sodium-hydrogen exchanger proteins in both the heart and the kidney, on myocardial energetics and impact on inflammation and atherosclerosis continue to shed light on the multitude of pleotropic effects of these agents. Though more data is needed to substantiate the safety and efficacy, SGLT2i should be considered as a valuable therapy to help reduce CV risk in patients with diabetes. Ultimately, SGLT2i may have utility in preventing progression to diabetes or providing CV protection in patients who do not have diabetes.

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

We congratulate Santos-Gallego et al. [(1)][1] on their paper describing functional and metabolic effects of empagliflozin in a porcine model of myocardial remodeling. We want to underscore the message from the accompanying editorial cautioning against the interpretation that empagliflozin-induced

Tako-Tsubo Cardiomyopathy (TTC), which is now known as Tako-Tsubo Syndrome (TTS) is a transient left ventricular (LV) systolic dysfunction of uncertain pathogenesis, which occurs predominantly in ageing women. There is considerable uncertainty regarding the management of TTS related acute and chronic issues and most of the evidence regarding therapy comes from retrospective data and case studies. In this review we have tried to concise the available information on the TTS therapeutics to help clinicians make treatment decisions in patients diagnosed with TTS. At the same time we have highlighted some of the uncertainties regarding TTS therapy, in particular the inability of b-blocker therapy to improve survival or prevent recurrence. We have also emphasized the issue of incomplete recovery in some cases of TTS where there is ongoing inflammation and evidence of impaired myocardial energetics despite normalization of LV ejection fraction. Although there is no scientific evidence on how to improve or fasten the recovery of TTS, we believe therapy improving energy efficiency may play some role in future. Lastly, we would like to reiterate that in the absence of randomized studies evaluating medical therapy in TTS, the treatment for this syndrome remains entirely empirical and should be individualized according to the patient characteristics at the time of presentation.

The examination of the relationships between chamber pressure and volume has been used to describe the function of a pump for centuries. Indeed this framework was used by James Watt in the late 18th century to quantify the work of the steam engine, using his so-called “indicator diagram,” which was published in The Quarterly Journal of Science in 1822 [1] . In 1899 Otto Frank published a theoretical paper entitled “Die Grundform des arteriellen Pulses” [2] , an English translation of which was published by Sagawa in 1990 [3] , which characterized the function of the frog ventricle in a pressure–volume domain. The work of Suga and coworkers [4] , beginning in the late 1960s greatly extended previous work, using the pressure–volume loop to provide insights into cardiac contractility and myocardial energetics. The clinical application of the pressure–volume framework was greatly accelerated by the description by Baan of the “impedance” catheter, (subsequently referred to as the “conductance” catheter) to provide instantaneous measurement of ventricular volume [5] . Potentially, the next impetus will occur from the development of high-fidelity noninvasive or less-invasive methods [6] .

We appreciate the comments by Baker and colleagues on our paper [(1)][1]. We described that empagliflozin ameliorates adverse cardiac remodeling, enhances systolic function, switches myocardial fuel utilization, and improves myocardial energetics in a nondiabetic heart failure (HF) model. Baker and

Introduction Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM. Methods Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group. Endpoints Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.

Salt-induced hypertension leads to development of left ventricular hypertrophy in the Dahl salt-sensitive (Dahl/SS) rat. Before progression to left ventricular failure, the heart initially undergoes a compensated hypertrophic response. We hypothesized that changes in myocardial energetics may be an early indicator of transition to failure. Dahl/SS rats and their salt-resistant consomic controls (SS-13BN) were placed on either a low- or high-salt diet to generate four cohorts: Dahl-SS rats on a low- (Dahl-LS) or high-salt diet (Dahl-HS), and SS-13BN rats on a low- (SSBN-LS) or high-salt diet (SSBN-HS). We isolated left ventricular trabeculae and characterized their mechanoenergetic performance. Our results show, at most, modest effects of salt-induced compensated hypertrophy on myocardial energetics. We found that the Dahl-HS cohort had a higher work-loop heat of activation (estimated from the intercept of the heat vs. relative afterload relationship generated from work-loop contractions) relative to the SSBN-HS cohort and a higher economy of contraction (inverse of the slope of the heat vs. active stress relation) relative to the Dahl-LS cohort. The maximum extent of shortening and maximum shortening velocity of the Dahl/SS groups were higher than those of the SS-13BN groups. Despite these differences, no significant effect of salt-induced hypertension was observed for either peak work output or peak mechanical efficiency during compensated hypertrophy.

Myocardial glucose uptake and metabolism are essential for maintaining myocardial energetics under circumstances of stress, such as myocardial ischemia or hypertrophy. We will discuss new information as to the mechanisms of altered glucose uptake as a consequence of impaired insulin action as well as emerging alternative cellular signaling mechanisms that lead to increased noninsulin dependent glucose uptake and metabolism. We will also review provocative clinical data that demonstrate the limitations of tight glycemic control as a mechanism to confer myocardial protection in patients with type 2 diabetes and discuss potential mechanistic explanations for the paradoxical results.New studies have shed important light on the distal mechanisms involved in insulin-mediated Glut 4 translocation. There are also important new insights into the role of AMP kinase and hypoxia-induced factor-1alpha in mediating myocardial glucose uptake while conferring cardioprotection.The importance of understanding the link between glucose uptake and cardioprotection is underscored by recent clinical trials that have failed to demonstrate a benefit between tight glycemic control and reduced cardiovascular events. These data underscore the need for additional agents that affect both outcomes.

Heart failure is the major cause of morbidity and mortality in the developed world, with over 5 million people afflicted in the U.S. alone ([1][1]). From 30% to 40% of patients die within the first year after receiving the diagnosis of heart failure ([1][1]). Further, heart failure consumes a

This research is aimed to the determination of the changes in the cardiac energetic output for three different modes of cardiac rhythm pacing. The clinical investigation of thirteen patients with the permanent dual-chamber pacemaker implantation was carried out. The patients were taken to echocardiography examination conducted by way of three pacing modes (AAI, VVI and DDD). The myocardial energetic parameters—the stroke work index (SWI) and the myocardial oxygen consumption (MVO2) are not directly measurable, however, their values can be determined using the numerical model of the human cardiovascular system. The 24-segment hemodynamical model (pulsating type) of the human cardiovascular system was used for the numerical simulation of the changes of myocardial workload for cardiac rhythm pacing. The model was fitted by well-measurable parameters for each patient. The calculated parameters were compared using the two-tailed Student’s test. The differences of SWI and MVO2 between the modes AAI and VVI and the modes DDD and VVI are statistically significant (P 0.05).

Food restriction (FR) may increase longevity by increasing the efficiency of energy utilization by some organs. We tested whether any effect of FR on the energy efficiency of isolated, isovolumically beating hearts could be observed, by studying four groups of rats: (1) AL fed (AL) 10–13-month-old rats, (2) age matched, FR at 60% of AL rats, (3) young AL, heart weight matched to FR rats and (4) 10–13-month-old AL rats, short-term FR for the last 3 weeks of life. The oxygen cost of tension development was not different among the groups. With contractility changed by calcium, the oxygen cost of contractility was higher in the young AL than in the adult rats either AL or short-term FR. With isoproterenol, it was higher in FR than in AL groups. The basal metabolic rate of hearts was higher in the adult AL than in the short-term, but not long-term, FR rats. In the long run, FR did not significantly change the pattern of cardiac energy utilization of isolated, isovolumically beating hearts. Our observations do not lend support to the hypothesis that the anti-aging action of FR is mediated by changes in cardiac efficiency.

Background: Myocardial energetics is essential for cardiac contractility and electrical property. However, it is not known whether atrial myocardial energetics is disrupted in disease condition such as atrial fibrillation (AF) and heart failure (HF). We hypothesized that AF and HF are associated

Background: By exploiting the paramagnetic properties of deoxyhemoglobin, blood oxygen-level dependent (BOLD) cardiac magnetic resonance (CMR) can detect myocardial ischemia. Our aim was to validate whether BOLD detects microvascular abnormalities. We employed a porcine model of post-infarction LV

s S307 (p= 6.22e-06 for interaction) and may play a role in disease progression and impaired myocardial energetics. Conclusion: A bioinformatic analysis may identify previously unreported miRs potentially involved in HF development. This is a novel approach using public access data for identify potential biomarkers of subjects with high risk for HF development or progression. FONDAP 15130011 ACCDIS.

There is now little doubt that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) play a role in cardiac development and in cardiovascular physiology in adult life. Congenital lack of GH is associated with defective cardiac growth, ventricular wall thinning, and impaired systolic function. These abnormalities limit exercise capacity and contribute to the poor quality of life in patients with GH deficiency. In addition, studies with in vitro muscle preparations have shown that IGF-1 affects myocardial contractility by a direct mechanism. These findings suggested that GH would benefit patients affected by heart failure. Indeed, GH and/or IGF-1 have proven beneficial in various models of experimental heart failure. Tested in patients with classes II–IV heart failure, they improved cardiac performance and clinical status. These effects were associated with improved myocardial energetics and de-activation of the neurohormonal system. Because of the uncontrolled nature of the studies and the small number of cases examined, conclusions as to the effectiveness of GH and IGF-1 must await the results from larger trials.

An increase in the responsiveness of the contractile machinery to Ca2+could theoretically enhance the mechanoenergetics of the heart. To clarify this unresolved issue, we studied the effects of MCI-154, a Ca2+ sensitizer, on the mechanoenergetics in terms of the left ventricular contractility index [slope of end-systolic pressure-volume relationship ( E max)] and the relationship between myocardial oxygen consumption (Vo 2) and left ventricular pressure-volume area in excised cross-circulated canine hearts. MCI-154 increased E max by 42 ± 31% (SD), although the slope of the Vo 2-PVA relationship (an indicator of contractile efficiency) was unchanged by MCI-154. Despite equal increases in E max, the relative increase in unloaded Vo 2(ΔVo 2/Δ E max) during infusion of MCI-154 was, however, significantly less than that during CaCl2 infusion (0.0016 ± 0.0018 vs. 0.0059 ± 0.0054; P < 0.05). By contrast, ΔVo 2/Δ E maxfor milrinone was the same as that for CaCl2 (0.0043 ± 0.0041 vs. 0.0039 ± 0.0045; P > 0.05). Basal metabolism in KCl-arrested hearts was unchanged by MCI-154, indicating that MCI-154 consumes less energy than CaCl2 for excitation-contraction coupling. These findings suggest that MCI-154 acts energetically as a Ca2+ sensitizer in beating canine whole hearts.

The detrimental pathophysiology of heart failure (HF) leaves room for physiologic and metabolomic concepts that include supplementation of micronutrients and macronutrients in these patients. Hence myocardial energetics and nutrient metabolism may represent relevant treatment targets in HF. This review focuses on the role of nutritive compounds such as lipids, amino acids, antioxidants, and other trace elements in the setting of HF. Supplementation of ferric carboxymaltose improves iron status, functional capacity, and quality of life in HF patients. To close the current gap in evidence further interventional studies investigating the role of micro- and macronutrients are needed in this setting.

To the Editor: We read with interest the article by Dass et al1 on the use of a noncontrast cardiac magnetic resonance T1 mapping technique to characterize the myocardium of patients with hypertrophic and dilated cardiomyopathies. They demonstrated that both cardiomyopathy groups had significantly higher noncontrast T1 relaxation times compared with healthy control subjects and that these values correlated with circumferential strain and myocardial energetics. However, as the authors …

Background: Elevated pulmonary arterial pressure may increase right ventricular (RV) oxidative metabolism in patients with pulmonary hypertension (PH). A pulmonary hypertension (PH)-speciic vasodilator decreases pulmonary arterial pressure. However, it is not clear whether such a treatment favorably affects RV myocardial oxidative metabolism. The purpose of this study was to investigate the possible impacts of the intensiied PH-speciic vasodilator therapy on myocardial energetics using 11C acetate PET.

To study the relationship between myocardial energetics and contractile reserve, we acutely and selectively inhibited creatine kinase (CK) activity in isolated perfused rat hearts, using increasing doses of iodoacetamide. 31P nuclear magnetic resonance spectroscopy was used to measure intracellular pH and the concentrations of ATP, phosphocreatine, and inorganic phosphate. Contractile reserve was assessed as the increase of rate-pressure product (RPP) from baseline during high-calcium perfusion. Contractile reserve was reduced by 9, 35, and 72% in hearts with 26, 6, and 1% CK activity, respectively. An inverse linear relationship between RPP and the free energy release from ATP hydrolysis ([delta G approximately P[) was shown for all groups. Furthermore, the maximal RPPs of all hearts were achieved at the same level of [delta G approximately P[ (52-53 kJ/mol), which is equal to the free energy requirement of sarcoplasmic reticulum Ca2+ adenosine 5'-triphosphatase (ATPase). We suggest that inhibition of the CK reaction caused a decrease of [delta G approximately P[ which, in turn, limits the Ca(2+)-handling capacity of sarcoplasmic reticulum Ca2+ ATPase. In this way, the ability of the heart to increase its contractile performance is restricted.

It has become common sense that the failing heart is an "engine out of fuel". However, undisputable evidence that, indeed, the failing heart is limited by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggests that potentially metabolic intermediates and redox state could play the more dominant roles for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the pathophysiology of heart failure, mitochondria emerge in the crossfire of defective excitation-contraction coupling and increased energetic demand, which may provoke oxidative stress as an important upstream mediator of cardiac remodeling and cell death. Thus, future therapies may be guided towards restoring defective ion homeostasis and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP.

Ranolazine is a new, orally active pharmacologic agent that experimentally has been shown to favorably affect myocardial metabolism during myocardial ischemia. It has no direct action on myocardial hemodynamics but appers to improve ventricular functioning by blocking uptake of free fatty acids by the heart while shifting metabolism to anaerobic glycolysis during myocardial ischemia. Preliminary clinical studies suggest a dose-dependent antianginal, and anti-ischemic effect and an excellent safety profile for this unique drug. However, the results of a recent double-blind efficacy and safety study showed no antianginal effect of ranolazine (30--120 mg thrice daily) when compared to placebo.

A reduced myocardial phosphocreatine/adenosine triphosphate (PCr/ATP) ratio is linked to both diastolic dysfunction and heart failure. Although obesity is well known to cause diastolic dysfunction a link to impaired cardiac energetics has only recently been established. We assessed whether or not long-term weight loss in obesity, which is known to reduce mortality, is accompanied by both improved cardiac energetics and diastolic function. Normal weight (BMI 22 ± 2; n = 18) and obese subjects (BMI 34 ± 4; n = 13) underwent cine-MRI (1.5 Tesla) to determine left ventricular diastolic function using volume-time curve analysis, and 31P-MR spectroscopy (3 Tesla) to assess cardiac energetics (PCr/ATP ratio). Obese subjects (n = 13) underwent repeat assessment after 1 year of supervised weight loss. Obesity, in the absence of identifiable cardiovascular risk factors, was associated with significantly impaired myocardial high energy phosphate metabolism (PCr/ATP ratio, normal; 2.03 ± 0.27 vs. obese; 1.58 ± 0.47, p = 0.002) and significantly lower peak diastolic filling rate (normal; 4.8 ± 0.8 vs. obese; 3.8 ± 0.7 EDV/s, p = 0.01). Weight loss (on average 9 kg, 55 % excess weight) over 1 year resulted in a 24 % increase in PCr/ATP ratio (p = 0.01) and an 18 % improvement in peak diastolic filling rate (p = 0.01). Myocardial PCr/ATP ratio remained positively correlated with peak diastolic filling rate after weight loss (r = 0.63, p = 0.02). In obesity, weight loss improves impaired cardiac energetics and myocardial relaxation. Improved myocardial energetics appear to play a key role in diastolic functional recovery accompanying weight loss.

Significant technical advances in small animal molecular imaging techniques and in imaging probes with high specificity for various molecular targets have been produced in the last ten years. Notwithstanding, the clinical applicability of molecular imaging proceeds slowly. In animal experiments, multimodality molecular imaging techniques based on hybrid scanners are increasing, providing more insight into path physiologic phenomena associated with cardiovascular disease. In parallel, we assisted in the development of a new generation of multi-imaging probes, such as PET/MRI probes, particularly effective in hybrid scanners. More recently, in order to gain in inherently low sensitivity of MRI, hyperpolarized magnetic resonance spectroscopy using hyperpolarized (13)C was proposed. Preliminary results obtained in experimental animal studies seem to confirm the potentialities of hyperpolarized (13)C magnetic resonance to monitor myocardial energetics. In this review the preclinical cardiovascular applications and the potential for clinical translation are discussed.

The heart is an example of a specialized type I (‘red’) striated muscle in that it is continuously active and reliant principally on aerobic metabolism for its energy supply. Although much of the myocyte volume is taken up by myofibrils, the mitochondria constitute about 30%. In the heart, these subcellular organelles regenerate the bulk of ATP from ADP and inorganic phosphate. ATP is an ‘energy transducing molecule’ which couples the energy available from fuel metabolism into external work (principally myofibrillar contraction). In order to maintain fuel oxidation, ATP regeneration, and muscle contraction, a highly developed coronary circulation and uninterrupted coronary blood flow are necessary to ensure adequate delivery of O2 and fuels, and to remove the product of aerobic metabolism, CO2. The heart is omnivorous and utilizes any metabolic fuel presented to it, within the constraints of metabolic regulation. The major substrates for oxidation in humans are lipid-derived fuels (principally long-chain fatty acids (LCFAs) such as palmitate, but also triglycerides and ketone bodies (acetoacetate and its reduction product, 3-hydroxybutyrate) in specialized circumstances) and the carbohydrate-derived fuels (glucose, lactate, and pyruvate). Although the heart can oxidize amino acids, these are of minor importance. The accepted dogma is that the human heart relies predominantly (70% ) on lipid-derived fuels for its energy supply, but the majority of investigations have involved postabsorptive subjects where lipid metabolism is generally more favoured than in the immediately postprandial state. The role of cardiac energetics and ‘metabolic remodelling’ are discussed with regards to the transition of the healthy heart into failure.

Timmer SA, Knaapen P, Germans T, Dijkmans PA, Lubberink M, ten Berg JM, ten Cate FJ, Russel IK, Gotte MJ, Lammertsma AA, van Rossum AC. Effects of alcohol septal ablation on coronary microvascular function and myocardial energetics in hypertrophic obstructive cardiomyopathy. Am J Physiol Heart Circ Physiol 301: H129-H137, 2011. First published February 18, 2011; doi:10.1152/ajpheart.00077.2011.-This study investigated the effects of alcohol septal ablation (ASA) on microcirculatory function and myocardial energetics in patients with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction. In 15 HCM patients who underwent ASA, echocardiography was performed before and 6 mo after the procedure to assess the LVOT gradient (LVOTG). Additionally, [(15)O] water PET was performed to obtain resting myocardial blood flow (MBF) and coronary vasodilator reserve (CVR). Changes in LV mass (LVM) and volumes were assessed by cardiovascular magnetic resonance imaging. Myocardial oxygen consumption (M(V) over dotO(2)) was evaluated by [(11)C] acetate PET in a subset of seven patients to calculate myocardial external efficiency (MEE). After ASA, peak LVOTG decreased from 41 +/- 32 to 23 +/- 19 mmHg (P = 0.04), as well as LVM (215 +/- 74 to 169 +/- 63 g; P < 0.001). MBF remained unchanged (0.94 +/- 0.23 to 0.98 +/- 0.15 ml.min(-1).g(-1); P = 0.45), whereas CVR increased (2.55 +/- 1.23 to 3.05 +/- 1.24; P = 0.05). Preoperatively, the endo-to-epicardial MBF ratio was lower during hyperemia compared with rest (0.80 +/- 0.18 vs. 1.18 +/- 0.15; P < 0.001). After ASA, the endo-to-epicardial hyperemic (h)MBF ratio increased to 1.03 +/- 0.26 (P = 0.02). Delta CVR was correlated to Delta LVOTG (r = -0.82; P < 0.001) and Delta LVM (r = -0.54; P = 0.04). MEE increased from 15 +/- 6 to 20 +/- 9% (P = 0.04). Coronary microvascular dysfunction in obstructive HCM is at least in part reversible by relief of LVOT obstruction. After ASA, hMBF and CVR increased predominantly in the subendocardium. The improvement in CVR was closely correlated to the absolute reduction in peak LVOTG, suggesting a pronounced effect of LV loading conditions on microvascular function of the subendocardium. Furthermore, ASA has favorable effects on myocardial energetics.

Profound abnormalities in myocardial energy metabolism occur in heart failure and correlate with clinical symptoms and survival. Available comprehensive human metabolic data come from small studies, enrolling patients across heart failure causes, at different disease stages, and using different methodologies, and is often contradictory. Remaining fundamental gaps in knowledge include whether observed shifts in cardiac substrate utilization are adaptive or maladaptive, causal or an epiphenomenon of heart failure.Recent studies have characterized the temporal changes in myocardial substrate metabolism involved in progression of heart failure, the role of insulin resistance, and the mechanisms of mitochondrial dysfunction in heart failure. The concept of metabolic inflexibility has been proposed to explain the lack of energetic and mechanical reserve in the failing heart.Despite current therapies, which provide substantial benefits to patients, heart failure remains a progressive disease, and new approaches to treatment are necessary. Developing metabolic interventions would be facilitated by systems-level integration of current knowledge on myocardial metabolic control. Although preliminary evidence suggests that metabolic modulators inducing a shift towards carbohydrate utilization seem generally beneficial in the failing heart, such interventions should be matched to the stage of metabolic deregulation in the progression of heart failure.