On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-ß-hydroxybutyrate (ßHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on ßHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]glucose and/or 4 mM [14 C]ßHB to measure glycolytic rates or ßHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reaction, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi ) concentrations were measured using 31 P-nuclear magnetic resonance spectroscopy. Rates of ßHB oxidation in LG hearts were half that in HG hearts, with ßHB oxidation directly proportional to glycogen content. ßHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with ßHB alone was twice that of hearts perfused with ßHB and glucose, which had significantly higher levels of the glycolytic intermediates fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. ßHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total NADP/H pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although ßHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. ßHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac ßHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (d-ß-hydroxybutyrate, acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Krebs cycle intermediates; therefore their utilisation requires anaplerotic supplementation, and intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. It is demonstrated here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate ß-hydroxybutyrate oxidation in isolated perfused rat heart, and this contribution was quantified using a novel pulse-chase metabolic approach. Further, using metabolomics and 31 P-MR, it was shown that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise ßHB, and ßHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis.

Takotsubo Syndrome: Finally Emerging From the Shadows?

It is now 30 years since Japanese investigators first described Takotsubo Syndrome (TTS) as a disorder occurring mainly in ageing women, ascribing it to the impact of multivessel coronary artery spasm. During the intervening period, it has become clear that TTS involves relatively transient vascular injury, followed by prolonged myocardial inflammatory and eventually fibrotic changes. Hence symptomatic recovery is generally slow, currently an under-recognised issue. It appears that TTS is induced by aberrant post-ß2-adrenoceptor signalling in the setting of "surge" release of catecholamines. Resultant activation of nitric oxide synthases and increased inflammatory vascular permeation lead to prolonged myocardial infiltration with macrophages and associated oedema formation. Initially, the diagnosis of TTS was made via exclusion of relevant coronary artery stenoses, plus the presence of regional left ventricular hypokinesis. However, detection of extensive myocardial oedema on cardiac MRI imaging offers a specific basis for diagnosis. No adequate methods are yet available for definitive diagnosis of TTS at hospital presentation. Other major challenges remaining in this area include understanding of the recently demonstrated association between TTS and antecedent cancer, the development of effective treatments to reduce risk of short-term (generally due to shock) and long-term mortality, and also to accelerate symptomatic recovery.

Assessing the optimal preparation strategy to minimize the variability of cardiac pyruvate dehydrogenase flux measurements with hyperpolarized MRS.

Hyperpolarized [1-13 C] pyruvate MRS can measure cardiac pyruvate dehydrogenase (PDH) flux in vivo through 13 C-label incorporation into bicarbonate. Using this technology, substrate availability as well as pathology have been shown to modulate PDH flux. Clinical protocols attempt to standardize PDH flux with oral glucose loading prior to scanning, while rodents in preclinical studies are usually scanned in the fed state. We aimed to establish which strategy was optimal to maximize PDH flux and minimize its variability in both control and Type II diabetic rats, without affecting the pathological variation being assessed. We found similar variances in the bicarbonate to pyruvate ratio, reflecting PDH flux, in fed and fasted/glucose-loaded animals, which showed no statistically significant differences. Furthermore, fasting/glucose loading did not alter the low PDH flux seen in Type II diabetic rats. Overall this suggests that preclinical cardiac hyperpolarized magnetic resonance studies could be performed either in the fed or in the fasted/glucose-loaded state. Centres planning to start new clinical studies with cardiac hyperpolarized magnetic resonance in man may find it beneficial to run small proof-of-concept trials to determine whether metabolic standardizations by oral or intravenous glucose load are beneficial compared with scanning patients in the fed state.

Emerging drugs for the treatment of angina pectoris.

INTRODUCTION: Angina pectoris, or symptomatic myocardial ischaemia, reflects an impairment of coronary blood flow, and usually a deficiency of available myocardial energetics. Treatment options vary with the precise cause, which may vary with regards to the roles of increased myocardial oxygen demand versus reduced supply. Traditionally, organic nitrates, ß-adrenoceptor antagonists, and non-dihydropyridine calcium antagonists were the only commonly used prophylactic anti-anginal agents. However, many patients failed to respond adequately to such therapy, and/or were unsuitable for their use. Areas covered: A number of 'new' agents have been shown to represent ancillary forms of prophylactic anti-anginal therapy and are particularly useful in patients who are relatively unsuitable for either percutaneous or surgical revascularisation. These include modulators of myocardial metabolic efficiency, such as perhexiline, trimetazidine and ranolazine, as well as high dose allopurinol, nicorandil and ivabradine. The advantages and disadvantages of these various agents are summarized. Expert opinion: 'Optimal' medical treatment of angina pectoris now includes use of agents primarily intended to reduce risk of infarction (e.g. statins, aspirin, ACE inhibitors). In patients whose angina persists despite the use of 'standard' anti-anginal therapy, and who are not ideal for invasive revascularization options, a number of emerging drugs offer prospects of symptomatic relief.

Can Perhexiline Be Utilized Without Long-Term Toxicity? A Clinical Practice Audit.

BACKGROUND: Perhexiline, originally used as a first-line prophylactic antianginal agent, is now regarded primarily as a treatment for otherwise refractory myocardial ischemia. Recent studies have also demonstrated its short-term utility in heart failure, hypertrophic cardiomyopathy, and inoperable aortic stenosis. Its benefits on myocardial energetics state are potentially counter-balanced by risk of hepatotoxicity and peripheral neuropathy during long-term treatment if drug accumulation occurs. Since perhexiline exhibits complex pharmacokinetics with wide inter-individual variability, its long-term use requires regular plasma concentration monitoring. In this study, the risk of neuro- and hepato-toxicity during long-term perhexiline therapy in relation to the intensity of therapeutic drug monitoring was investigated. Furthermore, determinants of mortality during perhexiline treatment were evaluated. METHODS: In 170 patients treated with perhexiline for a median of 50 months (interquartile range: 31-94 months), outcomes and relationship to plasma drug concentrations were documented. RESULTS: Rationale for treatment with perhexiline included myocardial ischemia in 88% and severe systolic heart failure in 38%. Plasma concentrations were within the therapeutic range of 150-600 ng/mL on 65% of assay occasions and toxic levels accounted for 8.8% of measurements. No patient developed hepatotoxicity attributable to perhexiline while 3 developed peripheral neuropathy possibly induced by treatment. Actuarial 5-year survival rate was 83% overall, and 76.3% in patients with associated systolic heart failure. CONCLUSIONS: This first audit of a large population treated long-term perhexiline demonstrates the following: (1) Although the frequency of monitoring is less than ideal, therapeutic drug monitoring effectively limits occurrence of toxic drug concentrations and virtually eliminates long-term hepato- and neuro-toxicity and (2) Mortality rates during long-term therapy, notably for patients with concomitant heart failure, are surprisingly low.

Drugs that Affect Cardiac Metabolism: Focus on Perhexiline.

Approaches to the pharmacotherapy of angina pectoris have previously centred on the concept that a transient imbalance between myocardial oxygen "demand" and supply within the myocardium can best be addressed by reducing demand (for example, with ß-adrenoceptor antagonist) or by increasing availability of blood (via coronary vasomotor reactivity adjustment or coronary revascularization). However, this principle is potentially challenged by the emergence of cases of angina unsuitable for such therapies (for example because of concomitant severe systolic heart failure) and by the recognition that impaired myocardial energetics may precipitate angina in the absence of fixed or variable coronary obstruction (for example in hypertrophic cardiomyopathy). The past 20 years have seen the re-emergence of a class of anti-anginal agents which act primarily by improving efficiency of myocardial oxygen utilization, and thus can correct impaired energetics, simultaneously treating angina and heart failure symptoms. We review the principles underlying the safe use of such agents, beginning with the prototype drug perhexiline maleate, which despite complex pharmacokinetics and potential hepato- or neuro-toxicity has emerged as an attractive management option in many "complicated" cases of angina pectoris.

Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium.

PURPOSE: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. METHOD: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. RESULTS: Myocardial uptake of both (+) and (-) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (-) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (-) perhexiline were the plasma concentrations [(+) perhexiline: ß = -0.256, p = 0.015; (-) perhexiline: ß = -0.347, p = 0.001] and patients' age [(+) perhexiline: ß = 0.300, p = 0.004; (-) perhexiline: ß = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (ß = 0.228, p = 0.025), while atrial uptake of (-) perhexiline varied inversely with simultaneous heart rate (ß = -0.240, p = 0.015). CONCLUSION: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (-) perhexiline may selectively modulate heart rate reduction.

Aging of platelet nitric oxide signaling: pathogenesis, clinical implications, and therapeutics.

The nitric oxide (NO)/soluble guanylate cyclase (sGC) system is fundamental to endothelial control of vascular tone, but also plays a major role in the negative modulation of platelet aggregation. The phenomenon of platelet NO resistance, or decreased antiaggregatory response to NO, occurs increasingly with advanced age, as well as in the context of cardiovascular disease states such as heart failure, ischemic heart disease, and aortic valve disease. The central causes of NO resistance are "scavenging" of NO and dysfunction of sGC. In the current review, we discuss the roles of several modulators of NO synthesis and of the NO/sGC cascade on changes in platelet physiology with aging, together with potential therapeutic options to reduce associated thrombotic risk.

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

AIM: Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. METHODS: Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. RESULTS: Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12-0.44), the median atrial concentration was 6.02 mg kg⁻¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg kg⁻¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1-27.1), ventricular : plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84). CONCLUSIONS: This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.

Thioredoxin-interacting protein: pathophysiology and emerging pharmacotherapeutics in cardiovascular disease and diabetes.

The thioredoxin system, which consists of thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), has emerged as a major anti-oxidant involved in the maintenance of cellular physiology and survival. Dysregulation in this system has been associated with metabolic, cardiovascular, and malignant disorders. Thioredoxin-interacting protein (TXNIP), also known as vitamin D-upregulated protein or thioredoxin-binding-protein-2, functions as a physiological inhibitor of Trx, and pathological suppression of Trx by TXNIP has been demonstrated in diabetes and cardiovascular diseases. Furthermore, TXNIP effects are partially Trx-independent; these include direct activation of inflammation and inhibition of glucose uptake. Many of the effects of TXNIP are initiated by its dissociation from intra-nuclear binding with Trx or other SH-containing proteins: these effects include its migration to cytoplasm, modulating stress responses in mitochondria and endoplasmic reticulum, and also potentially activating apoptotic pathways. TXNIP also interacts with the nitric oxide (NO) signaling system, with apparent suppression of NO effect. TXNIP production is modulated by redox stress, glucose levels, hypoxia and several inflammatory activators. In recent studies, it has been shown that therapeutic agents including insulin, metformin, angiotensin converting enzyme inhibitors and calcium channel blockers reduce TXNIP expression, although it is uncertain to what extent TXNIP suppression contributes to their clinical efficacy. This review addresses the role of TXNIP in health and in cardiovascular and metabolic disorders. Finally, the potential advantages (and disadvantages) of pharmacological suppression of TXNIP in cardiovascular disease and diabetes are summarized.

Dissociation of early shock in takotsubo cardiomyopathy from either right or left ventricular systolic dysfunction.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS). METHODS: We evaluated 102 consecutive TTC patients with acute transthoracic echocardiography (TTE) to detect RV hypokinesis. Correlates of hypotension, shock and PHS were identified by univariate and multivariate analyses. RESULTS: Of the 102 patients evaluated, 33% had RV hypokinesis but only 9% had extensive RV involvement. Within the first 24 hours of admission, severe hypotension (systolic blood pressure (SBP) ≤ 90 mmHg) occurred in 21% of the patients and shock (hypotension + peripheral organ hypo-perfusion) in 16.6% of cases. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in PHS. On the other hand, RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction. CONCLUSIONS: In TTC, RV hypokinesis occurs in approximately 33% of cases and correlates with more severe LV wall motion abnormality but not with development of hypotension or shock. These data therefore reinforce previous findings that hypotension/shock in TTC are not purely by impaired cardiac output.

Occurrence of Tako-Tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors.

Tako-Tsubo cardiomyopathy (TTC) occurs particularly in post-menopausal women, being precipitated in many cases by severe emotional stress. We describe six patients in whom TTC occurred in association with therapeutic ingestion or overdose of the serotonin/noradrenaline reuptake inhibitor venlafaxine, or its metabolite desvenlafaxine. Importantly, two of the six cases were not post-menopausal women. An increased risk of TTC may account for some of the reported cardiovascular adverse effects of venlafaxine and similar agents.

Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling.

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = -0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients.

Therapeutic Potential of Ketone Bodies for Patients With Cardiovascular Disease: JACC State-of-the-Art Review.

Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remodeling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies.

Prolonged suppression of the anti-oxidant/anti-inflammatory effects of BNP post-Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) episodes are primarily initiated by 'pulse' release of catecholamines inducing neutrophil infiltration and myocardial inflammation in susceptible individuals (largely ageing women). Evidence of myocardial inflammation and associated energetic impairment persists for ≥ 3 months post-acute TTS episodes, suggesting the existence of additional 'perpetuating' mechanisms. The effects of B-type natriuretic peptide (BNP) in suppressing superoxide (O2- ) release from neutrophils are transiently impaired in acute heart failure. We also evaluated the extent and duration of BNP-induced suppression of O2- release post-TTS. METHODS AND RESULTS: TTS patients were studied acutely (n = 34) and 3 months thereafter (n = 13) and compared with control subjects (n = 25). O2- generation from neutrophils, triggered by N-formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate, and its suppression by BNP, were measured in vitro. Determinants of variability in BNP effect were sought via univariate and multivariate analyses. Relative to control subjects, in TTS patients, BNP suppression of both phorbol myristate acetate and N-formyl-methionyl-leucyl-phenylalanine-induced O2- release was impaired acutely (P < 0.05 for both); this did not improve over the 3-month recovery period, despite treatment with conventional anti-failure medication in 85% of patients. No significant correlates of BNP effect (other than TTS) were identified. CONCLUSIONS: (1) While TTS is associated with marked and prolonged release of BNP, there is virtually total loss of the ability of BNP to suppress neutrophil O2- release and its impact on tissue inflammation. (2) BNP responses do not recover for at least 3 months post-attacks, suggesting that this might contribute to perpetuation of myocardial inflammation in TTS patients.

Cardioplegia in paediatric cardiac surgery: a systematic review of randomized controlled trials.

OBJECTIVES: Cardioplegia is the primary method for myocardial protection during cardiac surgery. We conducted a systematic review of randomized controlled trials of cardioplegia in children to evaluate the current evidence base. METHODS: We searched MEDLINE, CENTRAL and LILACS and manually screened retrieved references and systematic reviews to identify all randomized controlled trials comparing cardioplegia solutions or additives in children undergoing cardiac surgery published in any language; secondary publications and those reporting inseparable adult data were excluded. Two or more reviewers independently screened studies for eligibility and extracted data; the Cochrane Risk of Bias tool was used to assess for potential biases. RESULTS: We identified 26 trials randomizing 1596 children undergoing surgery; all were single-centre, Phase II trials, recruiting few patients (median 48, interquartile range 30-99). The most frequent comparison was blood versus crystalloid in 10 (38.5%) trials, and the most common end points were biomarkers of myocardial injury (17, 65.4%), inotrope requirements (15, 57.7%) and length of stay in the intensive care unit (11, 42.3%). However, the heterogeneity of patients, interventions and reported outcome measures prohibited meta-analysis. Overall risk of bias was high in 3 (11.5%) trials, unclear in 23 (88.5%) and low in none. CONCLUSIONS: The current literature on cardioplegia in children contains no late phase trials. The small size, inconsistent use of end points and low quality of reported trials provide a limited evidence base to inform practice. A core outcome set of clinically important, standardized, validated end points for assessing myocardial protection in children should be developed to facilitate the conduct of high-quality, multicentre trials. PROSPERO registration: CRD42017080205.

Randomized controlled trials in children's heart surgery in the 21st century: a systematic review.

OBJECTIVES: Randomized controlled trials are the gold standard for evaluating health care interventions, yet are uncommon in children's heart surgery. We conducted a systematic review of clinical trials in paediatric cardiac surgery to evaluate the scope and quality of the current international literature. METHODS: We searched MEDLINE, CENTRAL and LILACS, and manually screened retrieved references and systematic reviews to identify all randomized controlled trials reporting the effect of any intervention on the conduct or outcomes of heart surgery in children published in any language since January 2000; secondary publications and those reporting inseparable adult data were excluded. Two reviewers independently screened studies for eligibility and extracted data; the Cochrane Risk of Bias tool was used to assess for potential biases. RESULTS: We identified 333 trials from 34 countries randomizing 23 902 children. Most were early phase (313, 94.0%), recruiting few patients (median 45, interquartile range 28-82), and only 11 (3.3%) directly evaluated a surgical intervention. One hundred and nine (32.7%) trials calculated a sample size, 52 (15.6%) reported a CONSORT diagram, 51 (15.3%) were publicly registered and 25 (7.5%) had a Data Monitoring Committee. The overall risk of bias was low in 22 (6.6%), high in 69 (20.7%) and unclear in 242 (72.7%). CONCLUSIONS: The recent literature in children's heart surgery contains few late-phase clinical trials. Most trials did not conform to the accepted standards of reporting, and the overall risk of bias was low in few studies. There is a need for high-quality, multicentre clinical trials to provide a robust evidence base for contemporary paediatric cardiac surgical practice.

Does cardiac resynchronization therapy restore peripheral circulatory homeostasis?

AIMS: To evaluate whether peripheral circulatory 'remodelling' as measured by changes in vascular compliance and in markers of nitric oxide signalling contributes to patient response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Effects of CRT were evaluated in 33 patients pre-procedure and 6 months post-procedure. Peak oxygen consumption, 6 min walk distance, New York Heart Association class, and quality of life score were evaluated. Augmentation index and its interactions with nitric oxide (NO) were evaluated by applanation tonometry. Platelet NO responsiveness and content of thioredoxin-interacting protein were assessed. Plasma concentrations of N-terminal proBNP, asymmetric and symmetric dimethylarginine (SDMA), high sensitivity C-reactive protein, catecholamines, and matrix metalloproteinases-2 and -9 were assessed. Despite significant improvement in 6 min walk distance (P = 0.005), New York Heart Association class (P < 0.001), quality of life (P = 0.001), and all echocardiographic parameters post-CRT, there were no significant changes in augmentation index measurements, thioredoxin-interacting protein content, and platelet NO response. Significant falls in N-terminal proBNP (P = 0.008) and SDMA (P = 0.013; independent of renal function) occurred. Falls in SDMA predicted reduction in high-sensitivity C-reactive protein (P = 0.04) and increases in peak oxygen consumption (P = 0.04). There were no correlations between changes in echocardiographic parameters and those in vascular function. CONCLUSIONS: These data suggest that the beneficial effects of CRT over 6 months are independent of any change in peripheral NO-related signalling. However, there is evidence that suppression of inflammation occurs, and its magnitude predicts extent of clinical improvement.

Metabolic Remodeling in Diabetic Cardiomyopathy.

Diabetes is a risk factor for heart failure and cardiovascular mortality with specific changes to myocardial metabolism, energetics, structure, and function. The gradual impairment of insulin production and signalling in diabetes is associated with elevated plasma fatty acids and increased myocardial free fatty acid uptake and activation of the transcription factor PPARα. The increased free fatty acid uptake results in accumulation of toxic metabolites, such as ceramide and diacylglycerol, activation of protein kinase C, and elevation of uncoupling protein-3. Insulin signalling and glucose uptake/oxidation become further impaired, and mitochondrial function and ATP production become compromised. Increased oxidative stress also impairs mitochondrial function and disrupts metabolic pathways. The diabetic heart relies on free fatty acids (FFA) as the major substrate for oxidative phosphorylation and is unable to increase glucose oxidation during ischaemia or hypoxia, thereby increasing myocardial injury, especially in ageing female diabetic animals. Pharmacological activation of PPARγ in adipose tissue may lower plasma FFA and improve recovery from myocardial ischaemic injury in diabetes. Not only is the diabetic heart energetically-impaired, it also has early diastolic dysfunction and concentric remodelling. The contractile function of the diabetic myocardium negatively correlates with epicardial adipose tissue, which secretes proinflammatory cytokines, resulting in interstitial fibrosis. Novel pharmacological strategies targeting oxidative stress seem promising in preventing progression of diabetic cardiomyopathy, although clinical evidence is lacking. Metabolic agents that lower plasma FFA or glucose, including PPARγ agonism and SGLT2 inhibition, may therefore be promising options.