Ben Mercer

Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology

Background: It is unclear whether diabetes mellitus (DM) is an adverse prognostic factor in chronic heart failure (CHF) of ischaemic and non-ischaemic aetiology managed with contemporary evidence-based care. Methods: In total, 1091 outpatients with CHF with reduced ejection fraction were prospectively observed for a mean of 960 days. Total and cardiovascular mortality was quantified after accounting for potential confounders. Results: In total, 25.7% of patients had DM; this group was more likely to have CHF of ischaemic aetiology and was more symptomatic. Patients with DM received comparable medical- and device-based therapies, except for greater doses of loop diuretic. DM was associated with approximately doubled crude and adjusted risk of total and cardiovascular mortality. The association of diabetes with these outcomes in patients with ischaemic and non-ischaemic cardiomyopathies was of similar magnitude. Conclusions: In spite of advances in the management of CHF, DM remains a major adverse prognostic feature, irrespective of ischaemic/non-ischaemic aetiology.

Diabetes mellitus and the heart

Diabetes mellitus is a risk factor for the development of coronary artery disease and chronic heart failure. When carefully screened for, diabetes or prediabetic disorders, are present in the majority of patients with clinically manifest ischaemic heart disease, and confer a major adverse impact upon morbidity and mortality. Important therapeutic modifications are required in the management of coronary artery disease and chronic heart failure associated with diabetes, and vice versa. However, despite optimal management, aided by recent landmark trials solely recruiting patients with diabetes, outcomes for patients with diabetes and heart disease remain poor. This review outlines the epidemiology, pathogenesis and management of diabetic heart disease, along with highlighting the many gaps in the evidence‐base and suggesting future research priorities.

Association of diabetes with increased all-cause mortality following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction in the contemporary era

Background: We investigated the association between diabetes mellitus (DM) and all-cause mortality in a large cohort of consecutive patients treated with primary percutaneous coronary intervention (PPCI) in the contemporary era. Methods: We conducted a retrospective analysis of a single-centre registry of patients undergoing PPCI for ST-segment elevation myocardial infarction (STEMI) at a large regional PCI centre between 2005 and 2009. All-cause mortality in relation to patient and procedural characteristics was compared between patients with and without DM. Results: Of 2586 patients undergoing PPCI, 310 (12%) had DM. Patients with DM had a higher prevalence of multi-vessel coronary disease (p<0.001) and prior myocardial infarction (p<0.001). Patients with DM were less commonly admitted directly to the interventional centre (p=0.002). Symptom-to-balloon (p<0.001) and door-to-balloon time (p=0.002) were longer in patients with DM. Final infarct-related-artery TIMI-flow grade was lower in patients with DM (p=0.031). All-cause mortality at 30 days (p=0.0025) and 1 year (p<0.0001) was higher in patients with DM. DM was independently associated with increased mortality after multivariate adjustment for potential confounders. Conclusions: Mortality remains substantially higher in patients with DM following reperfusion for STEMI in comparison with those without diabetes, despite contemporary management with PPCI. Greater co-morbidity, delayed presentation, longer times-to-reperfusion, and less optimal reperfusion may contribute to adverse outcomes.

Prospective development and validation of a model to predict heart failure hospitalisation

Objective Acute heart failure syndrome (AHFS) is a major cause of hospitalisation and imparts a substantial burden on patients and healthcare systems. Tools to define risk of AHFS hospitalisation are lacking. Methods A prospective cohort study (n=628) of patients with stable chronic heart failure (CHF) secondary to left ventricular systolic dysfunction was used to derive an AHFS prediction model which was then assessed in a prospectively recruited validation cohort (n=462). Results Within the derivation cohort, 44 (7%) patients were hospitalised as a result of AHFS during 1 year of follow-up. Predictors of AHFS hospitalisation included furosemide equivalent dose, the presence of type 2 diabetes mellitus, AHFS hospitalisation within the previous year and pulmonary congestion on chest radiograph, all assessed at baseline. A multivariable model containing these four variables exhibited good calibration (Hosmer–Lemeshow p=0.38) and discrimination (C-statistic 0.77; 95% CI 0.71 to 0.84). Using a 2.5% risk cut-off for predicted AHFS, the model defined 38.5% of patients as low risk, with negative predictive value of 99.1%; this low risk cohort exhibited <1% excess all-cause mortality per annum when compared with contemporaneous actuarial data. Within the validation cohort, an identically applied model derived comparable performance parameters (C-statistic 0.81 (95% CI 0.74 to 0.87), Hosmer–Lemeshow p=0.15, negative predictive value 100%). Conclusions A prospectively derived and validated model using simply obtained clinical data can identify patients with CHF at low risk of hospitalisation due to AHFS in the year following assessment. This may guide the design of future strategies allocating resources to the management of CHF.

Importance of insulin resistance to vascular repair and regeneration.

Metabolic insulin resistance is apparent across a spectrum of clinical disorders, including obesity and diabetes, and is characterized by an adverse clustering of cardiovascular risk factors related to abnormal cellular responses to insulin. These disorders are becoming increasingly prevalent and represent a major global public health concern because of their association with significant increases in atherosclerosis-related mortality. Endogenous repair mechanisms are thought to retard the development of vascular disease, and a growing evidence base supports the adverse impact of the insulin-resistant phenotype upon indices of vascular repair. Beyond the impact of systemic metabolic changes, emerging data from murine studies also provide support for abnormal insulin signaling at the level of vascular cells in retarding vascular repair. Interrelated pathophysiological factors, including reduced nitric oxide bioavailability, oxidative stress, altered growth factor activity, and abnormal intracellular signaling, are likely to act in conjunction to impede vascular repair while also driving vascular damage. Understanding of these processes is shaping novel therapeutic paradigms that aim to promote vascular repair and regeneration, either by recruiting endogenous mechanisms or by the administration of cell-based therapies.

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell‐based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire‐induced femoral artery injury augmented re‐endothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re‐endothelialization of wire‐injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC‐mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men. Stem Cells 2014;32:2714–2723

Early Repolarization Syndrome; Mechanistic Theories and Clinical Correlates

The early repolarization (ER) pattern on the 12-lead electrocardiogram is characterized by J point elevation in the inferior and/or lateral leads. The ER pattern is associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Based on studies in animal models and genetic studies, it has been proposed that J point elevation in ER is a manifestation of augmented dispersion of repolarization which creates a substrate for ventricular arrhythmia. A competing theory regarding early repolarization syndrome (ERS) proposes that the syndrome arises as a consequence of abnormal depolarization. In recent years, multiple clinical studies have described the characteristics of ER patients with VF in more detail. The majority of these studies have provided evidence to support basic science observations. However, not all clinical observations correlate with basic science findings. This review will provide an overview of basic science and genetic research in ER and correlate basic science evidence with the clinical phenotype.

Insulinlike growth factor – binding protein-1 improves vascular endothelial repair in male mice in the setting of insulin resistance

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor-binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance.

A Gene-based restoration of Akt activity in endothelial progenitor cells from human subjects at high cardiovascular risk rescues vascular reparative capacity

Introduction Late-outgrowth endothelial progenitor cells (LEPC) are putative mediators of endogenous vascular repair, and represent an attractive tool for future cell-based cardiovascular repair strategies. However, progenitor function may be impaired in high cardiovascular risk populations, such as those of South Asian (SA) ethnicity, in whom cell based therapies are likely to offer most benefit. Methods Detailed analysis of in vitro LEPC function (abundance, proliferation, migration, angiogenesis and senescence) was performed in 12 SA men and 12 matched White European (WE) controls. Molecular abnormalities within the Akt/eNOS signalling axis were analysed with PCR and western blotting. LEPC were transfused into immunodeficient mice subsequent to femoral artery injury to assess in vivo reparative function. In vitro and in vivo studies were repeated after lentiviral gene delivery of constitutively active Akt1 (E17K) or control (EGFP) to SA LEPC; augmented Akt activity was confirmed using a Glycogen Synthase Kinase phosphorylation assay. Data are expressed as mean [SEM] and compared with t tests as appropriate; statistical significance is defined as p<0.05 (denoted by *). Results The two groups were matched for age and cardiovascular risk factors, although the SA group was comparatively insulin resistant (HOMA-IR 1.2 [0.2] vs 0.5 [0.1] au*). SA LEPC exhibited impaired colony formation (0.06 [0.02] vs 0.19 [0.03] colonies/ml blood*), migration to vascular endothelial growth factor (5 [0.7] vs 10 [1.7] cells/microscopic field*) and in vitro angiogenesis (1.9 [0.6] vs 3.8 [0.5] tubular structures/microscopic field*), associated with markedly decreased abundance of the phosphorylated forms of the pro-angiogenic molecules S473-Akt (0.14 [0.05] vs 0.81 [0.2] au*) and S1177-eNOS (0.05 [0.02] vs 0.15 [0.01] au*). Transfusion of WE LEPC into immunodeficient mice after wire-induced femoral artery luminal injury augmented re-endothelialisation; however, neither SA LEPC, nor vehicle, augmented re-endothelialisation (WE: 54.2 [6.4], SA: 36.9 [3.4], vehicle: 31.1 [2.4] % re-endothelialised; WE vs SA*; SA vs vehicle p=0.2). Lentiviral gene delivery of a E17K, but not EGFP control, to SA LEPC was associated with augmented Akt1 activity and rescue of in vivo re-endothelialisation capacity (E17K: 55.2 [4.4] vs EGFP 24.1 [1.3] % re-endothelialised; E17K vs EGFP*; E17K vs WE non-transduced cells p=0.9). Conclusions These data provide proof of principle for human LEPC based vascular repair therapy, and demonstrate a mechanism by which to rescue marked progenitor dysfunction in a group at high risk of cardiovascular events, whom are likely to benefit from cardiovascular repair therapies.

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice

Abstract Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell–specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.