[Show abstract][Hide abstract] ABSTRACT: We previously reported that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy (DCM). The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python DCM model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast (MEF) model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F MEFs were depolarized and had reduced calcium uptake, with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age, and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis and activation of sterile myocardial inflammation resulting in heart failure.
[Show abstract][Hide abstract] ABSTRACT: -Whether the myocardium in non-ischemic heart failure experiences oxygen-limitation remains a long-standing controversy. We addressed this question in patients with Dilated Cardiomyopathy (DCM) using a dual approach: First, we tested the changes in myocardial oxygenation between rest and stress states, using oxygenation-sensitive CMR. Secondly, we sought to assess the functional consequences of oxygen limitation at rest by measuring myocardial energetics before and after short-term oxygen supplementation.
-Twenty six subjects (14 DCM; 12 normal) underwent cardiac MRI at 3 Tesla to assess cardiac volumes, function, oxygenation and first-pass perfusion (0.03 mmol/kg Gd-DTPA bolus) at stress and rest (4-6 minutes i.v. adenosine, 140μg/kg/min). Signal intensity change (SIΔ) and myocardial perfusion reserve index (MPRI) were measured from oxygenation and perfusion images, respectively. Furthermore, the effect of oxygen supplementation on resting myocardial energy metabolism was tested using (31)P MR spectroscopy, measuring PCr/ATP ratios in both groups at baseline and after 4 hours of oxygen via facemask in the DCM group. During stress there were equivalent rises in rate pressure product in both groups (DCM 76±15%, normal 79±9%, P=0.84). MPRI was significantly reduced in DCM (1.51 ± 0.11 vs. normal 1.86±0.10, P=0.03). However, there was no difference in oxygenation between groups: SI∆ in DCM 17±3% vs. normal 20±2% (P=0.38). Furthermore, at a LV segmental level, there was no correlation between oxygenation-sensitive SI∆ and MPRI (R=0.06, P=0.43). Resting PCr/ATP was reduced in DCM (1.66±0.07 vs normal 2.12±0.06, P=0.002). With oxygen supplementation, there was no change in PCr/ATP (1.61±0.08, P=0.58, Δ-0.04±0.05). There was also no effect of oxygen on systolic function (EF pre oxygen 34±1%, post oxygen 36±2%, P=0.46; Δ 2±1%).
-Our results demonstrate dissociation between microvascular dysfunction and oxygenation in DCM, suggesting that the impairment of perfusion is not sufficient to cause deoxygenation during stress. Cardiac energetics are unaffected by oxygen supplementation, indicating the absence of relevant myocardial hypoxia at rest. Our study suggests that novel treatments for non-ischemic heart failure should focus on efforts to directly target cardiomyocyte function and metabolism rather than oxygen delivery and microvascular function.
[Show abstract][Hide abstract] ABSTRACT: -Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF.
-We conducted a randomised, crossover study comparing selective heart rate reduction with the If blocker, ivabradine at 7.5 mg twice daily, versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise, VO2 peak, <80% predicted for age and sex). The result was compared to 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in VO2 peak. Secondary outcomes included tissue Doppler derived E/e' at echocardiography, plasma BNP and quality of life scores. Ivabradine significantly reduced peak heart rate compared to placebo in the HFpEF (107 vs. 129 bpm, P<0.0001) and Hypertensive (127 vs. 145 bpm, P=0.003) cohorts. Ivabradine, when compared to placebo, significantly worsened the change in VO2 peak in the HFpEF cohort (-2.1 vs 0.9 mL/kg/min, P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary endpoints were discernable.
-Our observations question the value of heart rate reduction, using ivabradine, for improving symptoms in a HFpEF population characterised by exercise limitation. Clinical Trial Registration Information-www.clinicaltrials.gov. Identifier: NCT02354573.
[Show abstract][Hide abstract] ABSTRACT: Introduction Heart failure (HF) is characterised by alterations in myocardial metabolism with a compensatory shift from fatty acid to glucose metabolism. This could potentially lead to myocardial lipid accumulation (steatosis). We aimed to determine if myocardial lipid is increased in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF), and assess whether it is related to cardiac structure and function.
Methods 71 subjects (25 HFrEF due to dilated cardiomyopathy-DCM, 18 HFpEF and 28 normal volunteers were prospectively recruited). HFpEF was defined by left ventricular (LV) ejection fraction (EF) >50%, abnormal diastolic function, maximum oxygen consumption < 80% predicted for age, height and gender, with a cardiac limitation in exercise. All subjects underwent cardiovascular magnetic (MR) resonance at 3T for the determination of LV volumes and function and 1H-MR spectroscopy (MRS) to quantify myocardial lipid/water (%).
Results All subjects were matched for gender, body mass index, blood glucose, free fatty acids and lipid profile. As expected HFrEF patients had significantly increased LV volumes and reduced EF, whilst HFpEF patients had significantly increased LV mass to end-diastolic volume ratio (LV mass/EDV). Importantly, cardiac lipid was increased in both HFrEF and HFpEF when compared to normal controls (cardiac lipid/water 0.67 ± 0.42% in HFrEF; 1.06 ± 0.83% in HFpEF vs. normal controls 0.44 ± 0.17, all p < 0.05), with HFpEF having the highest level of cardiac lipid (Table 1, Figure 1). In HFrEF patients, cardiac lipid negatively correlated with LVEF and positively correlated with LV size. In HFpEF, cardiac lipid positively correlated with age and LV mass/EDV. Although HFpEF patients were significantly older, multiple regression analysis showed that age was not an independent predictor of cardiac lipid.
Conclusions Myocardial steatosis occurs in both HFrEF and HFpEF and is related to parameters of LV remodelling. This suggests that myocardial lipid may play a role in the pathophysiological processes of LV remodelling in both HFrEF and HFpEF. Cardiac lipid accumulation may be a potential therapeutic target in these conditions.
No preview · Article · Jun 2015 · Heart (British Cardiac Society)
[Show abstract][Hide abstract] ABSTRACT: Heart failure (HF) is characterised by alterations in fatty acid and glucose metabolism. We aimed to determine if myocardial lipid is increased in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF), and assess whether it is related to cardiac structure and function.
Full-text · Article · Feb 2015 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: Energy depletion has been highlighted as an important contributor to the pathology of hypertrophic cardiomyopathy (HCM), a common inherited cardiac disease. Pharmacological reversal of energy depletion appears an attractive approach and the use of perhexiline has been proposed as it is thought to shift myocardial metabolism from fatty acid to glucose utilisation, increasing ATP production and myocardial efficiency. We used the Mybpc3-targeted knock-in mouse model of HCM to investigate changes in the cardiac metabolome following perhexiline treatment. Echocardiography indicated that perhexiline induced partial improvement of some, but not all hypertrophic parameters after six weeks. Non-targeted metabolomics, applying ultra-high performance liquid chromatography-mass spectrometry, described a phenotypic modification of the cardiac metabolome with 272 unique metabolites showing a statistically significant change (p<0.05). Changes in fatty acids and acyl carnitines indicate altered fatty acid transport into mitochondria, implying reduction in fatty acid beta-oxidation. Increased glucose utilisation is indirectly implied through changes in the glycolytic, glycerol, pentose phosphate, tricarboxylic acid and pantothenate pathways. Depleted reduced glutathione and increased production of NADPH suggest reduction in oxidative stress. These data delineate the metabolic changes occurring during improvement of the HCM phenotype and indicate the requirements for further targeted interventions.
Full-text · Article · Nov 2014 · Molecular BioSystems
[Show abstract][Hide abstract] ABSTRACT: Myocardial T1 relaxation times have been reported to be markedly abnormal in diverse myocardial pathologies, ascribed to interstitial changes, evaluated by T1 mapping and calculation of extracellular volume (ECV). T1 mapping is sensitive to myocardial water content of both intra- and extracellular in origin, but the effect of intravascular compartment changes on T1 has been largely neglected. We aimed to assess the role of intravascular compartment on native (pre-contrast) T1 values by studying the effect of adenosine-induced vasodilatation in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR).
42 subjects (26 patients with severe AS without obstructive coronary artery disease and 16 controls) underwent cardiovascular magnetic resonance at 3 T for native T1-mapping (ShMOLLI), first-pass perfusion (myocardial perfusion reserve index-MPRI) at rest and during adenosine stress, and late gadolinium enhancement (LGE).
AS patients had increased resting myocardial T1 (1196 ± 47 ms vs. 1168 ± 27 ms, p = 0.037), reduced MPRI (0.92 ± 0.31 vs. 1.74 ± 0.32, p < 0.001), and increased left ventricular mass index (LVMI) and LGE volume compared to controls. During adenosine stress, T1 in AS was similar to controls (1240 ± 51 ms vs. 1238 ± 54 ms, p = 0.88), possibly reflecting a similar level of maximal coronary vasodilatation in both groups. Conversely, the T1 response to stress was blunted in AS (ΔT1 3.7 ± 2.7% vs. 6.0 ± 4.2% in controls, p = 0.013). Seven months after AVR (n = 16) myocardial T1 and response to adenosine stress recovered towards normal. Native T1 values correlated with reduced MPRI, aortic valve area, and increased LVMI.
Our study suggests that native myocardial T1 values are not only influenced by interstitial and intracellular water changes, but also by changes in the intravascular compartment. Performing T1 mapping during or soon after vasodilator stress may affect ECV measurements given that hyperemia alone appears to substantially alter T1 values.
Full-text · Article · Nov 2014 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: This editorial refers to 'Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling' by K.M.S. Gomes et al., pp. 498-508, this issue.
Preview · Article · Aug 2014 · Cardiovascular Research
[Show abstract][Hide abstract] ABSTRACT: The advent of molecular genetics – fuelled by the progress in DNA sequencing technologies and publication of the landmark Human Genome Project over a decade ago – has had a major impact on our understanding of the architecture of disease, opening up the prospect of personalized medicine based upon knowledge of an individual's genetic variants. Current management of patients with inherited cardiomyopathies is starting to integrate knowledge of an individual's genomic profile together with advancements in cardiovascular imaging. This has enhanced surveillance potential for high-risk individuals and has begun to facilitate diagnosis and, to a lesser extent, appropriate risk stratification and prognostication. This review introduces the reader to the inherited cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy and dilated cardiomyopathy) – representing the first cardiac disorders to be accurately delineated at a molecular genetic level – and provides an insight into their molecular genetic and clinical complexity.
[Show abstract][Hide abstract] ABSTRACT: High-risk percutaneous coronary intervention (PCI) procedures are being performed in greater numbers, in older patients with multiple comorbidities, and increasingly in the setting of acute coronary syndromes. Estimating inpatient PCI mortality and MACE risk (mortality, Q-wave myocardial infarction, urgent coronary artery bypass grafting and stroke) is essential in informing decision-making, consent, and operator and institutional benchmarking. There are a number of currently available risk scores that are often applied interchangeably. We investigated if there was concordance between contemporary risk scoring systems for inpatient mortality and MACE following PCI in patients at low, moderate or high-risk in a 'real life' cohort, depending upon method of presentation (elective, urgent, emergency).
No preview · Article · Jun 2014 · Heart (British Cardiac Society)
[Show abstract][Hide abstract] ABSTRACT: Left ventricular (LV) hypertrophy in aortic stenosis (AS) is characterized by reduced myocardial perfusion reserve due to coronary microvascular dysfunction. However, whether this hypoperfusion leads to tissue deoxygenation is unknown. We aimed to assess myocardial oxygenation in severe AS without obstructive coronary artery disease, and to investigate its association with myocardial energetics and function.
Twenty-eight patients with isolated severe AS and 15 controls underwent cardiovascular magnetic resonance (CMR) for assessment of perfusion (myocardial perfusion reserve index-MPRI) and oxygenation (blood-oxygen level dependent-BOLD signal intensity-SI change) during adenosine stress. LV circumferential strain and phosphocreatine/ adenosine triphosphate (PCr/ATP) ratios were assessed using tagging CMR and 31P MR spectroscopy, respectively.
AS patients had reduced MPRI (1.1 +/- 0.3 vs. controls 1.7 +/- 0.3, p < 0.001) and BOLD SI change during stress (5.1 +/- 8.9% vs. controls 18.2 +/- 10.1%, p = 0.001), as well as reduced PCr/ATP (1.45 +/- 0.21 vs. 2.00 +/- 0.25, p < 0.001) and LV strain (-16.4 +/- 2.7% vs. controls -21.3 +/- 1.9%, p < 0.001). Both perfusion reserve and oxygenation showed positive correlations with energetics and LV strain. Furthermore, impaired energetics correlated with reduced strain. Eight months post aortic valve replacement (AVR) (n = 14), perfusion (MPRI 1.6 +/- 0.5), oxygenation (BOLD SI change 15.6 +/- 7.0%), energetics (PCr/ATP 1.86 +/- 0.48) and circumferential strain (-19.4 +/- 2.5%) improved significantly.
Severe AS is characterized by impaired perfusion reserve and oxygenation which are related to the degree of derangement in energetics and associated LV dysfunction. These changes are reversible on relief of pressure overload and hypertrophy regression. Strategies aimed at improving oxygen demand-supply balance to preserve myocardial energetics and LV function are promising future therapies.
Full-text · Article · Apr 2014 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: Mutations in the GFPT1 and DPAGT1 genes, which encode enzymes associated with roles in protein N-linked glycosylation, have been recently identified in a rare subgroup of patients with congenital myasthenic syndromes (CMSs). Aberrant glycosylation is implicated in the development of cardiomyopathies in the congenital disorders of glycosylation. We investigated whether patients with CMS and GFPT1 or DPAGT1 mutations also had evidence of a cardiac phenotype. Cardiovascular magnetic resonance and echocardiography were used to evaluate cardiac structure and function in patients with GFPT1 (n=2) and DPAGT1 (n=2) mutations. Electrocardiography was abnormal in all, with abnormal repolarization and deep S waves (n=3) or left ventricular hypertrophy by voltage criteria (n=1). Despite normal biventricular size and systolic function, GFPT1/DPAGT1 patients demonstrated late gadolinium enhancement suggestive of myocardial fibrosis (n=4), diastolic dysfunction (n=3) and impaired phosphocreatine to adenosine triphosphate ratio (an indicator of myocardial energetic state), assessed using 31P magnetic resonance spectroscopy (n=2). These findings may reflect incipient cardiomyopathy due to aberrant cardiac glycoprotein function and reinforce the need for cardiac surveillance in patients with disorders due to glycosylation pathway defects.
Full-text · Article · Jan 2014 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: While remote ischemic preconditioning (rIPC) protects the mature heart against ischemia-reperfusion (IR) injury, the effect on the neonatal heart is not known. The neonatal heart relies almost solely on carbohydrate metabolism, which is modified by rIPC in the mature heart. We hypothesized that rIPC combined with metabolic support with glucose-insulin (GI) infusion improves cardiac function and reduces infarct size after IR injury in neonatal piglets in-vivo.
32 newborn piglets were randomized into 4 groups: control, GI, GI+rIPC and rIPC. GI and GI+rIPC groups received GI infusion continuously from 40min prior to ischemia. rIPC and GI+rIPC groups underwent four cycles of 5min limb ischemia. Myocardial IR injury was induced by 40min occlusion of the left anterior descending artery followed by 2h reperfusion. Myocardial lactate concentrations were assessed in microdialysis samples analyzed by mass spectrometry. Infarct size was measured using triphenyltetrazolium chloride staining. Systolic recovery (dP/dtmax as % of baseline) after 2h reperfusion was 68.5±13.8% in control, 53.7±11.2% in rIPC (p<0.05), and improved in GI (83.6±18.8%, p<0.05) and GI+rIPC (87.0±15.7%, p<0.01).
rIPC+GI protects the neonatal porcine heart against IR injury in-vivo. rIPC alone has detrimental metabolic and functional effects that are abrogated by simultaneous GI infusion.
No preview · Article · Nov 2013 · International journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: Despite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high. There is increasing evidence that the risk and course of HF depend on genetic predisposition; however, the genetic contribution to HF is heterogeneous and complex. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation.
Full-text · Article · Aug 2013 · Circulation Research