Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study.

BACKGROUND & AIMS: It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. METHODS: In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. RESULTS: Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). CONCLUSIONS: We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups.

Non-invasive hepatic biomarkers (ELF and CK18) in people with type 2 diabetes: the Edinburgh type 2 diabetes study.

BACKGROUND & AIMS: Type 2 diabetes is an established risk factor for the presence and progression of fatty liver. Little is known about the distributions and correlates of hepatic non-invasive biomarkers in community-based populations with diabetes, unselected for liver disease. We aimed to identify the distribution of, and metabolic risk factors associated with serum cytokeratin-18 (CK18) and the Enhanced Liver Fibrosis score (ELF), in a large, representative cohort of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study, ET2DS). METHODS: Nine hundred and thirty-nine ET2DS participants, aged 60-74 years underwent physical examination including ultrasound for assessment of liver fat. Representative subgroups were assessed for markers of chronic liver disease (CK18 and ELF). RESULTS: CK18 values ranged from 29-993 U/L (median 102, IQR 76-137 U/L) and ELF scores ranged from 6.9-11.6 (mean 8.9, SD 0.8). Statistically significant associations were found between both biomarkers and a number of metabolic risk factors. Neither CK18 nor ELF was consistently or strongly associated with established hepatic risk factors (alcohol excess, hepatotoxic medication use and positive immunology titres). CONCLUSIONS: We identified the distribution of CK18 and ELF in a large cohort of older people with type 2 diabetes and showed that these markers are associated with an adverse metabolic risk factor profile, although much of the variation in biomarkers remained unexplained. Prospective studies are required to determine the extent to which CK18 and/or ELF predict the development of symptomatic liver disease and to identify additional risk factors which may influence the development of advanced liver disease in people with type 2 diabetes.

Hypertrophy of neurons within cardiac ganglia in human, canine, and rat heart failure: the potential role of nerve growth factor.

BACKGROUND: Autonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hypertrophied in human, canine, and rat heart failure and that nerve growth factor, which we hypothesize is elevated in the failing heart, contributes to this neuronal hypertrophy. METHODS AND RESULTS: Somal morphology of neurons from human (579.54±14.34 versus 327.45±9.17 µm(2); P<0.01) and canine hearts (767.80±18.37 versus 650.23±9.84 µm(2); P<0.01) failing secondary to ischemia and neurons from spontaneously hypertensive rat hearts (327.98±3.15 versus 271.29±2.79 µm(2); P<0.01) failing secondary to hypertension reveal significant hypertrophy of neurons in cardiac ganglia compared with controls. Western blot analysis shows that nerve growth factor levels in the explanted, failing human heart are 250% greater than levels in healthy donor hearts. Neurons from cardiac ganglia cultured with nerve growth factor are significantly larger and have greater dendritic arborization than neurons in control cultures. CONCLUSIONS: Hypertrophied neurons are significantly less excitable than smaller ones; thus, hypertrophy of vagal postganglionic neurons in cardiac ganglia would help to explain the parasympathetic withdrawal that accompanies heart failure. Furthermore, our observations suggest that nerve growth factor, which is elevated in the failing human heart, causes hypertrophy of neurons in cardiac ganglia.

Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes. RESEARCH DESIGN AND METHODS: Eight hundred thirty-one men and women (aged 60-75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change. RESULTS: Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized ß, -0.12) and of subclinical markers with actual 4-year decline (standardized ß, -0.12, 0.12, and -0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors. CONCLUSIONS: Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.

Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: Type 2 diabetes is an established risk factor for development of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and clinical correlates of these conditions in a large cohort of people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 939 participants, aged 61-76 years, from the Edinburgh Type 2 Diabetes Study (ET2DS)-a large, randomly selected population of people with type 2 diabetes-underwent liver ultrasonography. Ultrasound gradings of steatosis were compared with magnetic resonance spectroscopy in a subgroup. NAFLD was defined as hepatic steatosis in the absence of a secondary cause (screened by questionnaire assessing alcohol and hepatotoxic medication use, plasma hepatitis serology, autoantibodies and ferritin, and record linkage to determine prior diagnoses of liver disease). Binary logistic regression was used to analyze independent associations of characteristics with NAFLD. RESULTS: Hepatic steatosis was present in 56.9% of participants. After excluding those with a secondary cause for steatosis, the prevalence of NAFLD in the study population was 42.6%. Independent predictors of NAFLD were BMI, lesser duration of diabetes, HbA(1c), triglycerides, and metformin use. These remained unchanged after exclusion of participants with evidence of hepatic fibrosis from the group with no hepatic steatosis. CONCLUSIONS: Prevalences of hepatic steatosis and NAFLD were high in this unselected population of older people with type 2 diabetes, but lower than in studies in which ultrasound gradings were not compared with a gold standard. Associations with features of the metabolic syndrome could be used to target screening for this condition.

Long-term survival using intra-aortic balloon pump and percutaneous right ventricular assist device for biventricular mechanical support of cardiogenic shock.

Right ventricular (RV) involvement in acute inferior left ventricular (LV) myocardial infarction increases the risks of cardiogenic shock and in-hospital mortality. Acutely impaired RV performance results in reduced LV preload and, in combination with impaired LV contractility, causes severely reduced LV stroke volume and cardiac output. Here we report long-term patient survival after acute biventricular myocardial infarction (MI) using simultaneous RV support with a TandemHeart percutaneous ventricular assist device (Cardiac Assist Technologies, Pittsburgh, Pennsylvania) and LV support with an intra-aortic balloon pump. Further evaluation of completely percutaneous biventricular support in acute MI is warranted.

Percutaneous revascularization of subclavian artery chronic occlusion with dual cerebral artery protection.

Percutaneous intervention for symptomatic subclavian artery chronic occlusion is an occasionally performed, minimally invasive alternative to surgical bypass. Potential complications include stroke, perforation, and recanalization failure. We discuss a case of successful percutaneous revascularization of symptomatic subclavian artery chronic occlusion using coronary devices and dual cerebral embolic protection.

Delayed complete heart block secondary to jailed first septal perforator.

Partial or total occlusion of septal perforator branches can occur during stenting of the proximal and mid portion of the left anterior descending artery, secondary to plaque snow plowing and/or stent "jailing". Flow compromise in a sizeable septal branch can result in a myocardial infarction or in atrioventricular conduction abnormalities. Complete heart block has been described at the time of the procedure, and though it is usually transient, it may require temporary pacing. We report a case of delayed, symptomatic and permanent complete atrio-ventricular block that occurred 2 days after the index procedure, requiring implantation of a permanent pacemaker.

Transient left ventricular apical ballooning: a review of the literature.

Transient left ventricular apical ballooning is a newly defined syndrome characterized by sudden onset of chest symptoms, electrocardiographic changes characteristic of myocardial ischemia, transient left ventricular dysfunction-particularly in the apical region, low-grade troponin elevation, and no significant coronary stenosis by angiogram. This syndrome is also referred to as Takotsubo cardiomyopathy, "Ampulla" cardiomyopathy, Human Stress cardiomyopathy, and Broken Heart Syndrome. Emergency physicians, family physicians, general internists, and cardiologists may all encounter this syndrome at the point of contact. The similarity to acute coronary syndrome requires all clinicians who may potentially care for these patients to familiarize themselves with this newly recognized disease. We provide a recent case and review the current literature surrounding this syndrome.

A comparison of arterial closure devices to manual compression in liver transplantation candidates undergoing coronary angiography.

Whether arterial closure devices can be used safely in a coagulopathic population undergoing cardiac catheterization and at high risk for groin complications, such as liver transplant candidates, is unknown. In this prospective, non-randomized consecutive series of 80 liver transplant candidates undergoing coronary angiography, manual compression and arterial closure devices were compared. Ilio-femoral angiography was performed to determine suitability for use of the closure device. Bleeding and vascular complications were recorded along with time to ambulation. Arterial closure devices were used in 31 patients (39%), whereas manual compression was used in 49 patients (50 procedures) (61%). There were no significant differences between the two groups with respect to age, sex, cardiac risk factors, peripheral vascular disease, baseline platelet count or baseline INR. There were 10 total vascular complications out of 50 procedures (20%) in the manual compression group compared to 2 vascular complications out of 31 procedures in the arterial closure device group (6%; p = 0.12). The time to ambulation was significantly less in the group receiving arterial closure devices versus manual compression (4.2 1.8 hours versus 6.6 3.7 hours, respectively; p = 0.0003). In coagulopathic patients at higher risk for groin complications, arterial closure devices can be safely used and decrease time to ambulation compared to manual compression.