Houman Ashrafian

Oxford University Hospitals NHS Trust, Oxford, England, United Kingdom

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Publications (68)566.92 Total impact

  • Arash Yavari, Houman Ashrafian
    Cardiovascular research. 08/2014;
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    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).
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A41-A42. · 5.01 Impact Factor
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    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.
    Journal of Cardiovascular Magnetic Resonance 04/2014; 16(1):29. · 4.44 Impact Factor
  • Andrew R. Harper, Arash Yavari, Houman Ashrafian
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    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.
    Medicine. 01/2014;
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    Journal of Cardiovascular Magnetic Resonance 01/2014; · 4.44 Impact Factor
  • Journal of Cardiovascular Magnetic Resonance 01/2014; · 4.44 Impact Factor
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    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.
    International journal of cardiology 11/2013; · 6.18 Impact Factor
  • Circulation 11/2013; · 15.20 Impact Factor
  • Thomas J Cahill, Houman Ashrafian, Hugh Watkins
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    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.
    Circulation Research 08/2013; 113(6):660-75. · 11.86 Impact Factor
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    ABSTRACT: -Aortic stenosis (AS) leads to left ventricular (LV) hypertrophy and dysfunction. We hypothesised that cardiac steatosis is involved in the pathophysiology, and also assessed whether it is reversible post aortic valve replacement (AVR). -Thirty-nine severe AS patients (symptomatic=25, asymptomatic=14) with normal left ventricular ejection fraction (LVEF) and no significant coronary artery disease and 20 age- and gender-matched healthy controls underwent cardiac 1H-magnetic resonance (MR) spectroscopy and imaging for the determination of steatosis (myocardial triglyceride content - MTC) and cardiac function including circumferential strain (measured by MR tagging). Strain was lower in both symptomatic and asymptomatic AS (-16.4±2.5% and -18.1±2.9% respectively vs. controls -20.7±2.0%, both p<0.05). Myocardial steatosis was found in both symptomatic and asymptomatic AS patients (0.89±0.42% in symptomatic AS; 0.75±0.36% in asymptomatic AS vs. controls 0.45±0.17, both p<0.05). Importantly, multivariable analysis indicated that steatosis was an independent correlate of impaired LV strain. Spectroscopic measurements of MTC correlated significantly with histological analysis of biopsies obtained during AVR. At 8.0±2.1 months after AVR, steatosis and strain had recovered towards normal. -Pronounced myocardial steatosis is present in severe AS, regardless of symptoms, and is independently associated with the degree of LV strain impairment. MTC measured by MR spectroscopy correlates with histological quantification. Steatosis and strain impairment are reversible after AVR. Our findings suggest a novel pathophysiologic mechanism in AS, myocardial steatosis, which may be amenable to treatment, thus potentially delaying onset of LV dysfunction.
    Circulation Cardiovascular Imaging 07/2013; · 5.80 Impact Factor
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    ABSTRACT: Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69 ± 5.8 % (n = 11) to 40 ± 6.5 % (n = 12), P = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n = 10, versus 61 ± 6.9 % rIPC after cyanamide, n = 10, P > 0.05). (ii) In a forearm plethysmography model of endothelial ischaemia-reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia-reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine (P = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (P = 0.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600 mg od or placebo for 48 h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18 ± 1.03 % and 4.76 ± 0.93 % P = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P = 0.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.
    Archiv für Kreislaufforschung 05/2013; 108(3):343. · 7.35 Impact Factor
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    ABSTRACT: The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
    Cell Reports 05/2013; · 7.21 Impact Factor
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    ABSTRACT: BACKGROUND: Alterations in cardiac metabolism accompany many diseases of the heart. The advent of cardiac hyperpolarized magnetic resonance spectroscopy (MRS), via dynamic nuclear polarization (DNP), has enabled a greater understanding of the in vivo metabolic changes that occur as a consequence of myocardial infarction, hypertrophy and diabetes. However, all cardiac studies performed to date have focused on rats and larger animals, whereas more information could be gained through the study of transgenic mouse models of heart disease. Translation from the rat to the mouse is challenging, due in part to the reduced heart size (1/10th) and the increased heart rate (50 %) in the mouse compared to the rat.Methods and Results: In this study, we have investigated the in vivo metabolism of [1-13C]pyruvate in the mouse heart. To demonstrate the sensitivity of the method to detect alterations in pyruvate dehydrogenase (PDH) flux, two well characterised methods of PDH modulation were performed; overnight fasting and infusion of sodium dichloroacetate (DCA). Fasting resulted in an 85 % reduction in PDH flux, whilst DCA infusion increased PDH flux by 123 %. A comparison of three commonly used control mouse strains was performed revealing significant metabolic differences between strains. CONCLUSIONS: We have successfully demonstrated a hyperpolarized DNP protocol to investigate in vivo alterations within the diseased mouse heart. This technique offers a significant advantage over existing in vitro techniques as it reduces animal numbers and decreases biological variability. Thus [1-13C]pyruvate can be used to provide an in vivo cardiac metabolic profile of transgenic mice.
    Journal of Cardiovascular Magnetic Resonance 02/2013; 15(1):19. · 4.44 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). · 4.44 Impact Factor
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    ABSTRACT: The aim of this work was to use hyperpolarized carbon-13 ((13)C) magnetic resonance (MR) spectroscopy and cine MR imaging (MRI) to assess in vivo cardiac metabolism and function in the 15-week-old spontaneously hypertensive rat (SHR) heart. At this time point, the SHR displays hypertension and concentric hypertrophy. One of the cellular adaptations to hypertrophy is a reduction in β-oxidation, and it has previously been shown that in response to hypertrophy the SHR heart switches to a glycolytic/glucose-oxidative phenotype. Cine-MRI (magnetic resonance imaging) was used to assess cardiac function and degree of cardiac hypertrophy. Wistar rats were used as controls. SHRs displayed functional changes in stroke volume, heart rate, and late peak-diastolic filling alongside significant hypertrophy (a 56% increase in left ventricular mass). Using hyperpolarized [1-(13)C] and [2-(13)C]pyruvate, an 85% increase in (13)C label flux through pyruvate dehydrogenase (PDH) was seen in the SHR heart and (13)C label incorporation into citrate, acetylcarnitine, and glutamate pools was elevated in proportion to the increase in PDH flux. These findings were confirmed using biochemical analysis of PDH activity and protein expression of PDH regulatory enzymes. Functional and structural alterations in the SHR heart are consistent with the hypertrophied phenotype. Our in vivo work indicates a preference for glucose metabolism in the SHR heart, a move away from predominantly fatty acid oxidative metabolism. Interestingly, (13)C label flux into lactate was unchanged, indicating no switch to an anaerobic glycolytic phenotype, but rather an increased reliance on glucose oxidation in the SHR heart.
    Cardiovascular research 05/2012; 95(1):69-76. · 5.81 Impact Factor
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    ABSTRACT: AMP-activated protein kinase (AMPK) is an important regulator of energy balance and signaling in the heart. Mutations affecting the regulatory γ2 subunit have been shown to cause an essentially cardiac-restricted phenotype of hypertrophy and conduction disease, suggesting a specific role for this subunit in the heart. The γ isoforms are highly conserved at their C-termini but have unique N-terminal sequences, and we hypothesized that the N-terminus of γ2 may be involved in conferring substrate specificity or in determining intracellular localization. A yeast 2-hybrid screen of a human heart cDNA library using the N-terminal 273 residues of γ2 as bait identified cardiac troponin I (cTnI) as a putative interactor. In vitro studies showed that cTnI is a good AMPK substrate and that Ser150 is the principal residue phosphorylated. Furthermore, on AMPK activation during ischemia, Ser150 is phosphorylated in whole hearts. Using phosphomimics, measurements of actomyosin ATPase in vitro and force generation in demembraneated trabeculae showed that modification at Ser150 resulted in increased Ca(2+) sensitivity of contractile regulation. Treatment of cardiomyocytes with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) resulted in increased myocyte contractility without changing the amplitude of Ca(2+) transient and prolonged relaxation despite shortening the time constant of Ca(2+) transient decay (tau). Compound C prevented the effect of AICAR on myocyte function. These results suggest that AMPK activation increases myocyte contraction and prolongs relaxation by increasing myofilament Ca(2+) sensitivity. We conclude that cTnI phosphorylation by AMPK may represent a novel mechanism of regulation of cardiac function.
    Circulation Research 03/2012; 110(9):1192-201. · 11.86 Impact Factor
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    ABSTRACT: The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.
    Cell metabolism 03/2012; 15(3):361-71. · 17.35 Impact Factor
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    ABSTRACT: The ratio of myocardial phosphocreatine (PCr)/ATP reflects the balance of energy consumption and energy supply in the heart. It is reduced in a range of important physiological conditions including during and after acute hypoxia, after a prolonged visit to high-altitude, and in those suffering from both type 2 diabetes mellitus and various forms of heart failure. Yet despite its significance, the factors underlying the reduced PCr/ATP ratio seen in heart failure remain poorly understood. Given that oxidative phosphorylation is the only viable steady-state provider of ATP in the heart, the argument has been put forward that the observed reduction in myocardial PCr/ATP in all these conditions can be accounted for by some form of mitochondrial insufficiency. Thus we used a computer model of oxidative phosphorylation, coupled with creatine kinase, to study the effects of hypoxia and mitochondrial dysfunction on myocardial PCr/ATP. In physiological normoxia, all oxidative phosphorylation complexes, NADH supply and proton leak exerted comparable (of the same order of magnitude) control over PCr/ATP, as defined within Metabolic Control Analysis (MCA). Under hypoxia, the control increased considerably for all components of the system, especially for cytochrome oxidase and mitochondrial proton leak. Hypoxia alone, without any changes in other factors, exerted a pronounced effect on PCr/ATP. Our simulations support three important ideas: First, that mitochondrial abnormalities can contribute considerably to a blunted PCr/ATP; second, that hypoxia and mitochondrial dysfunction can interact in important ways to determine the energy status of the failing heart; and third, that hypoxia alone can account for significant decreases in cardiac PCr/ATP.
    Molecular BioSystems 12/2011; 7(12):3335-42. · 3.35 Impact Factor
  • Houman Ashrafian, William J McKenna, Hugh Watkins
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    ABSTRACT: As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca(2+) sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca(2+) handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.
    Circulation Research 06/2011; 109(1):86-96. · 11.86 Impact Factor

Publication Stats

2k Citations
566.92 Total Impact Points

Institutions

  • 2005–2014
    • Oxford University Hospitals NHS Trust
      • Department of Cardiovascular Medicine
      Oxford, England, United Kingdom
    • University of Nottingham
      • Centre for Sports Medicine
      Nottingham, ENG, United Kingdom
  • 2003–2012
    • University of Oxford
      • Department of Cardiovascular Medicine
      Oxford, ENG, United Kingdom
  • 2010
    • University of Aberdeen
      • School of Medicine and Dentistry
      Aberdeen, SCT, United Kingdom
  • 2007–2009
    • University of Birmingham
      • School of Clinical and Experimental Medicine
      Birmingham, England, United Kingdom
    • Royal Brompton and Harefield NHS Foundation Trust
      Harefield, England, United Kingdom
  • 2008
    • The University of Warwick
      • Warwick Medical School (WMS)
      Warwick, ENG, United Kingdom
  • 2004
    • Ealing Hospital NHS Trust
      Londinium, England, United Kingdom