Retained Metabolic Flexibility of the Failing Human Heart.

BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.

Neutrophils incite and macrophages avert electrical storm after myocardial infarction.

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2 -/- mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36 -/- and Mertk -/- mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Adverse right ventricular remodelling, function, and stress responses in obesity: insights from cardiovascular magnetic resonance.

AIMS: We aimed to determine the effect of increasing body weight upon right ventricular (RV) volumes, energetics, systolic function, and stress responses using cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: We first determined the effects of World Health Organization class III obesity [body mass index (BMI) > 40 kg/m2, n = 54] vs. healthy weight (BMI < 25 kg/m2, n = 49) upon RV volumes, energetics and systolic function using CMR. In less severe obesity (BMI 35 ± 5 kg/m2, n = 18) and healthy weight controls (BMI 21 ± 1 kg/m2, n = 9), we next performed CMR before and during dobutamine to evaluate RV stress response. A subgroup undergoing bariatric surgery (n = 37) were rescanned at median 1 year to determine the effects of weight loss. When compared with healthy weight, class III obesity was associated with adverse RV remodelling (17% RV end-diastolic volume increase, P < 0.0001), impaired cardiac energetics (19% phosphocreatine to adenosine triphosphate ratio reduction, P < 0.001), and reduction in RV ejection fraction (by 3%, P = 0.01), which was related to impaired energetics (R = 0.3, P = 0.04). Participants with less severe obesity had impaired RV diastolic filling at rest and blunted RV systolic and diastolic responses to dobutamine compared with healthy weight. Surgical weight loss (34 ± 15 kg weight loss) was associated with improvement in RV end-diastolic volume (by 8%, P = 0.006) and systolic function (by 2%, P = 0.03). CONCLUSION: Increasing body weight is associated with significant alterations in RV volumes, energetic, systolic function, and stress responses. Adverse RV modelling is mitigated with weight loss. Randomized trials are needed to determine whether intentional weight loss improves symptoms and outcomes in patients with obesity and heart failure.

Cardiovascular magnetic resonance facilitates entirely contrast-free transcatheter aortic valve implantation: case report.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is usually planned using contrast-enhanced computed tomography (CT) to determine the suitability of cardiovascular anatomy. Computed tomography for TAVI planning requires the administration of intravenous contrast, which may not be desirable in patients with severely reduced renal function. CASE SUMMARY: We present an unusual case of an 89-year-old patient with an urgent need for treatment of critical, symptomatic aortic stenosis who also had severe chronic kidney disease. We judged that this posed a relative contraindication to the use of intravenous contrast. We designed and implemented a novel, contrast-free cardiovascular magnetic resonance (CMR) protocol and used this to plan all aspects of the procedure. Transcatheter aortic valve implantation was conducted successfully with zero contrast medium administration leading to an excellent clinical result and recovery of renal function. CONCLUSION: Contrast-free CMR appears to be a viable alternative to CT for planning structural aortic valve intervention in the rare cases where intravenous contrast is relatively contraindicated.

Energetic Basis for Exercise-Induced Pulmonary Congestion in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Transient pulmonary congestion during exercise is emerging as an important determinant of reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF). We sought to determine whether an abnormal cardiac energetic state underpins this process. METHODS: We recruited patients across the spectrum of diastolic dysfunction and HFpEF (controls, n=11; type 2 diabetes, n=9; HFpEF, n=14; and severe diastolic dysfunction attributable to cardiac amyloidosis, n=9). Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to ATP ratio. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging and echocardiography and lung water using magnetic resonance proton density mapping. Studies were performed at rest and during submaximal exercise using a magnetic resonance imaging ergometer. RESULTS: Paralleling the stepwise decline in diastolic function across the groups (E/e' ratio; P<0.001) was an increase in NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001) and a reduction in phosphocreatine/ATP ratio (control, 2.15 [2.09, 2.29]; type 2 diabetes, 1.71 [1.61, 1.91]; HFpEF, 1.66 [1.44, 1.89]; cardiac amyloidosis, 1.30 [1.16, 1.53]; P<0.001). During 20-W exercise, lower left ventricular diastolic filling rates (r=0.58; P<0.001), lower left ventricular diastolic reserve (r=0.55; P<0.001), left atrial dilatation (r=-0.52; P<0.001), lower right ventricular contractile reserve (right ventricular ejection fraction change, r=0.57; P<0.001), and right atrial dilation (r=-0.71; P<0.001) were all linked to lower phosphocreatine/ATP ratio. Along with these changes, pulmonary proton density mapping revealed transient pulmonary congestion in patients with HFpEF (+4.4% [0.5, 6.4]; P=0.002) and cardiac amyloidosis (+6.4% [3.3, 10.0]; P=0.004), which was not seen in healthy controls (-0.1% [-1.9, 2.1]; P=0.89) or type 2 diabetes without HFpEF (+0.8% [-1.7, 1.9]; P=0.82). The development of exercise-induced pulmonary congestion was associated with lower phosphocreatine/ATP ratio (r=-0.43; P=0.004). CONCLUSIONS: A gradient of myocardial energetic deficit exists across the spectrum of HFpEF. Even at low workload, this energetic deficit is related to markedly abnormal exercise responses in all 4 cardiac chambers, which is associated with detectable pulmonary congestion. The findings support an energetic basis for transient pulmonary congestion in HFpEF.

Obesity in the absence of comorbidities is not related to clinically meaningful left ventricular hypertrophy.

Obesity is associated with the development of left ventricular (LV) hypertrophy. Whether obesity in in the absence of comorbidities can cause LV hypertrophy to an extent which could create diagnostic uncertainty with pathological states (such as hypertrophic cardiomyopathy) is unknown. We used cine cardiovascular magnetic resonance imaging to precisely measure LV wall thickness in the septum and lateral wall in 764 people with body mass indices ranging from 18.5 kg/m2 to 59.2 kg/m2 in the absence of major comorbidities. Obesity was related to LV wall thickness across the cohort (basal septum r 0.30, P < 0.001 and basal lateral wall r 0.18, P < 0.001). Although no participant had hypertension, these associations remained highly significant after controlling for systolic blood pressure (all P < 0.01). Each 10 kg/m2 increase in BMI was associated with an increase in basal septal wall thickness of 1.0 mm males and 0.8 mm in females, with no statistically significant difference between genders (P = 0.1). Even in class 3 obesity (BMI > 40 kg/m2), no LV wall thickness > 13.4 mm in males or > 12.7 mm in females was observed in this cohort. We confirm that obesity in the absence of comorbidities is associated with LV hypertrophy, and establish that the magnitude of this change is modest even in severe obesity. LV hypertrophy > 14 mm cannot safely be attributed to obesity alone and alternative diagnoses should be considered.

The use of cardiovascular magnetic resonance for the assessment of left ventricular hypertrophy.

Cardiovascular magnetic resonance (CMR) is a powerful tool to assess and diagnose the cause of left ventricular hypertrophy (LVH). This review provides an overview of the typical CMR findings in the various causes of LVH, focusing mainly on late gadolinium enhancement (LGE) imaging. It will also cover the more novel techniques of T1 mapping, extracellular volume (ECV) fraction estimation and diffusion tensor imaging (DTI) and their role in the imaging assessment of LVH.

Cardiovascular magnetic resonance imaging for inflammatory heart diseases.

Inflammatory myocardial diseases represent a diverse group of conditions in which abnormal inflammation within the myocardium is the primary driver of cardiac dysfunction. Broad causes of myocarditis include infection by cardiotropic viruses or other infectious agents, to systemic autoimmune disease, or to toxins. Myocarditis due to viral aetiologies is a relatively common cause of acute chest pain syndromes in younger and middle-aged patients and often has a benign prognosis, though this and other forms of myocarditis also cause serious sequelae, including heart failure, arrhythmia and death. Endomyocardial biopsy remains the gold standard tool for tissue diagnosis of myocarditis in living individuals, although new imaging technologies have a crucial and complementary role. This review outlines the current state-of-the-art and future experimental cardiovascular magnetic resonance (CMR) imaging approaches for the detection of inflammation and immune cell activity in the heart. Multiparametric CMR, particularly with novel quantitative T1- and T2-mapping, is a valuable and widely-available tool for the non-invasive assessment of inflammatory heart diseases. Novel CMR molecular contrast agents will enable a more targeted assessment of immune cell activity and may be useful in guiding the development of novel therapeutics for myocarditis.

Non-invasive investigation of myocardial energetics in cardiac disease using 31P magnetic resonance spectroscopy.

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.

Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI.

RATIONALE: The recent development of hyperpolarized 13C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time. OBJECTIVE: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. METHODS AND RESULTS: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-magnetic resonance spectroscopy), and lipid content (1H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via PDH (pyruvate dehydrogenase, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate), and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P<0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort. CONCLUSIONS: This work represents the first demonstration of the ability of hyperpolarized 13C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

Clinical Cardiovascular Applications of Hyperpolarized Magnetic Resonance.

Current cardiovascular magnetic resonance imaging techniques provide an exquisite assessment of the structure and function of the heart and great vessels, but their ability to assess the molecular processes that underpin changes in cardiac function in health and disease is limited by inherent insensitivity. Hyperpolarized magnetic resonance is a new technology which overcomes this limitation, generating molecular contrast agents with an improvement in magnetic resonance signal of up to five orders of magnitude. One key molecule, hyperpolarized [1-13C]pyruvate, shows particular promise for the assessment of cardiac energy metabolism and other fundamental biological processes in cardiovascular disease. This molecule has numerous potential applications of clinical relevance and has now been translated to human use in early clinical studies. This review outlines the principles of hyperpolarized magnetic resonance and key potential cardiovascular applications for this new technology. Finally, we provide an overview of the pipeline for forthcoming hyperpolarized agents and their potential applications in cardiovascular disease.

Noninvasive Immunometabolic Cardiac Inflammation Imaging Using Hyperpolarized Magnetic Resonance.

RATIONALE: Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping. OBJECTIVE: To determine whether hyperpolarized MR using [1-13C]pyruvate can assess the local cardiac inflammatory response after MI. METHODS AND RESULTS: We performed hyperpolarized [1-13C]pyruvate MR studies in small and large animal models of MI and in macrophage-like cell lines and measured the resulting [1-13C]lactate signals. MI caused intense [1-13C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1-13C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1-13C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2-deoxyglucose after rodent MI normalized the hyperpolarized [1-13C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1ß expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)-treated rats at 3 months. CONCLUSIONS: Hyperpolarized MR using [1-13C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation.

Assessment of Metformin-Induced Changes in Cardiac and Hepatic Redox State Using Hyperpolarized[1-13C]Pyruvate.

Metformin improves cardiovascular outcomes in type 2 diabetes, but its exact mechanisms of action remain controversial. We used hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to determine the effects of metformin treatment on heart and liver pyruvate metabolism in rats in vivo. Both oral treatment for 4 weeks and a single intravenous metformin infusion significantly increased the cardiac [1-13C]lactate:[1-13C]pyruvate ratio but had no effect on the [1-13C]bicarbonate + 13CO2:[1-13C]pyruvate ratio, an index of pyruvate dehydrogenase flux. These changes were paralleled by a significant increase in the heart and liver cytosolic redox state, estimated from the [lactate]:[pyruvate] ratio but not the whole-cell [NAD+]/[NADH] ratio. Hyperpolarized MRI localized the increase in cardiac lactate to the left ventricular myocardium, implying a direct myocardial effect, though metformin had no effect on systolic or diastolic cardiac function. These findings demonstrate the ability of hyperpolarized pyruvate magnetic resonance spectroscopy to detect metformin-induced changes in cytosolic redox biology, suggest that metformin has a previously unrecognized effect on cardiac redox state, and help to refine the design of impending hyperpolarized magnetic resonance studies in humans.

Obese subjects show sex-specific differences in right ventricular hypertrophy.

BACKGROUND: As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. METHODS AND RESULTS: Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001). CONCLUSIONS: A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling.

Aortic 4D flow: quantification of signal-to-noise ratio as a function of field strength and contrast enhancement for 1.5T, 3T, and 7T.

PURPOSE: To investigate for the first time the feasibility of aortic four-dimensional (4D) flow at 7T, both contrast enhanced (CE) and non-CE. To quantify the signal-to-noise ratio (SNR) in aortic 4D flow as a function of field strength and CE with gadobenate dimeglumine (MultiHance). METHODS: Six healthy male volunteers were scanned at 1.5T, 3T, and 7T with both non-CE and CE acquisitions. Temporal SNR was calculated. Flip angle optimization for CE 4D flow was carried out using Bloch simulations that were validated against in vivo measurements. RESULTS: The 7T provided 2.2 times the SNR of 3T while 3T provided 1.7 times the SNR of 1.5T in non-CE acquisitions in the descending aorta. The SNR gains achieved by CE were 1.8-fold at 1.5T, 1.7-fold at 3T, and 1.4-fold at 7T, respectively. CONCLUSION: The 7T provides a new tool to explore aortic 4D flow, yielding higher SNR that can be used to push the boundaries of acceleration and resolution. Field strength and contrast enhancement at all fields provide significant improvements in SNR.

Structural and Metabolic Effects of Obesity on the Myocardium and the Aorta.

Obesity per se is a recognized risk factor for cardiovascular disease exerting independent adverse effects on the cardiovascular system. Despite this well documented link, the mechanisms by which obesity modulates cardiovascular risk are not well understood. Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end stage systolic heart failure. In addition, obesity causes changes in cardiac metabolism that make ATP production and utilization less efficient producing functional consequences that are linked to the increased rate of heart failure in this population. This review focuses on the cardiovascular structural and metabolic remodelling that occurs in obesity with and without co-morbidities and the potential links to increased mortality in this population. © 2014 S. Karger GmbH, Freiburg.