Impaired Cardiac Reserve on Dobutamine Stress Echocardiography Predicts the Development of Hepatorenal Syndrome.

OBJECTIVES: Cardiac dysfunction has been implicated in the genesis of hepatorenal syndrome (HRS). It is unclear whether a low cardiac output (CO) or attenuated contractile response to hemodynamic stress can predict its occurrence. We studied cardiovascular hemodynamics in cirrhosis and assessed whether a diminished cardiac reserve with stress testing predicted the development of HRS on follow-up. METHODS: Consecutive patients undergoing liver transplant workup with dobutamine stress echocardiography (DSE) were included. CO was measured at baseline and during low-dose dobutamine infusion at 10 µg/kg/min. HRS was diagnosed using guideline-based criteria. RESULTS: A total of 560 patients underwent DSE, of whom 488 were included after preliminary assessment. There were 64 (13.1%) patients with established HRS. The HRS cohort had a higher baseline CO (8.0 ± 2 vs 6.9 ± 2 L/min; P < 0.001) and demonstrated a blunted response to low-dose dobutamine (ΔCO 29 ± 22% vs 44 ± 32%, P < 0.001) driven primarily by inotropic incompetence. Optimal cutpoint for ΔCO in patients with HRS was determined to be <25% and was used to define a low cardiac reserve. Among the 424 patients without HRS initially, 94 (22.1%) developed HRS over a mean follow-up of 1.5 years. Higher proportion with a low cardiac reserve developed HRS (52 [55.0%] vs 56 [16.9%]; hazard ratio 4.5; 95% confidence interval 3.0-6.7; P < 0.001). In a Cox multivariable model, low cardiac reserve remained the strongest predictor for the development of HRS (hazard ratio 3.9; 95% confidence interval 2.2-7.0; P < 0.001). DISCUSSION: Patients with HRS demonstrated a higher resting CO and an attenuated cardiac reserve on stress testing. On longitudinal follow-up, low cardiac reserve was an independent predictor for the development of HRS. Assessment of cardiac reserve with DSE may provide a novel noninvasive risk marker for developing HRS in patients with advanced liver disease.HRS is a life-threatening complication of liver disease. We studied whether an inability to increase cardiac contraction in response to stress can assist in the prediction of HRS. We demonstrate that patients with liver disease who exhibit cardiac dysfunction during stress testing had a 4-fold increased risk of developing HRS. This may improve our ability for early diagnosis and treatment of patients at a higher risk of developing HRS.

Permanent pacing and conduction recovery in patients undergoing cardiac surgery for active infective endocarditis in an Australian Tertiary Center.

BACKGROUND: Postoperative heart block is common among patients undergoing surgery for infective endocarditis (IE). Limited data exists allowing cardiologists to predict who will require permanent pacemaker (PPM) implantation postoperatively. We aimed to determine the rate of postoperative PPM insertion, predictors for postoperative PPM, and describe PPM utilization and rates of device-related infection during follow-up. MATERIALS AND METHODS: A retrospective analysis was performed of 191 consecutive patients from a single institution who underwent cardiac surgery for IE between 2001 and 2017. Preoperative and operative predictors for postoperative PPM were evaluated using univariate and multivariate logistic regression. RESULTS: The rate of postoperative PPM implantation was 11% (17/154). The PPM group had more preoperative prolonged PR interval alone (33% vs 12%; P = .03), coexistent prolonged PR and QRS durations (13% vs 2%; P = .01), infection beyond the valve leaflets (82% vs 41%; P = .001), aortic root debridement (65% vs 23%; P = <.001), patch repair (47% vs 20%; P = .01), postoperative prolonged PR interval (50% vs 24%; P = .01), and prolonged QRS duration (47% vs 15%; P = .001). On multivariate analysis, infection beyond the valve leaflets emerged as an independent predictor for postoperative PPM (odds ratio, 1.94, 95% confidence interval, 1.14-3.28; P = .014). A reduction in PPM utilization was observed in five patients while eight patients continued to show significant ventricular pacing with no underlying rhythm at 12 months. There were no device-related infections. CONCLUSION: Postoperative PPM was required in 11% of patients undergoing surgery for IE over a 16-year period. Infection beyond the valve leaflet was an independent predictor for postoperative PPM insertion.

Effect of haemodialysis and residual renal function on serum levels of galectin-3, B-type natriuretic peptides and cardiac troponin T.

AIM: Levels of plasma markers of myocardial fibrosis (galectin-3), stretch (B-type natriuretic peptide (BNP)) and injury (high-sensitivity troponin T (hs-TnT)) are affected by haemodialysis, residual renal function (RRF) and cardiac pathology. We aimed to determine the association of RRF, urine output and haemodialysis itself on cardiac biomarkers in haemodialysis patients. METHODS: Adult haemodialysis patients underwent venesection pre- and post-haemodialysis then echocardiography and inter-dialytic urine collection to calculate RRF (mL/min per 1.73m2 ) and urine output (mL/day). Galectin-3, BNP-32, NT-ProBNP and hs-TnT levels were compared across tertiles of echocardiographic parameters, RRF and urine output using the non-parametric test for trend across ordered groups. RESULTS: Twenty-three patients (17 male) with mean age 67.7±13.8 years and median (interquartile range) dialysis duration 13.6 (9.8-19.1) months participated. Galectin-3 was substantially lower following haemodialysis: 55 ng/mL (47-70) versus 23 ng/mL (19-27, P < 0.001), but other biomarkers changed little. By increasing RRF tertile, post-dialysis galectin-3 was 32.6 ng/mL (23.7-36.6), 21.9 ng/mL (19.0-23.2) and 19.0 ng/mL (16.9-21.0, P = 0.001); NT-ProBNP was 10 192 ng/L (2303-21 504), 2037 ng/L (1224-10 795) and 1481 ng/L (172-2890, P = 0.016). Results were similar for daily urine volume, but measured echocardiographic parameters were not associated with biomarker concentrations. CONCLUSION: Plasma concentration of galectin-3 is reduced by the haemodialysis procedure. Lower RRF and urine volume are strongly associated with higher levels of galectin-3 and NT-Pro-BNP. These associations are important to the clinical interpretation of these biomarker levels in haemodialysis patients.

Does left ventricular hypertrophy affect cognition and brain structural integrity in type 2 diabetes? Study design and rationale of the Diabetes and Dementia (D2) study.

BACKGROUND: Cognitive impairment is common in type 2 diabetes mellitus, and there is a strong association between type 2 diabetes and Alzheimer's disease. However, we do not know which type 2 diabetes patients will dement or which biomarkers predict cognitive decline. Left ventricular hypertrophy (LVH) is potentially such a marker. LVH is highly prevalent in type 2 diabetes and is a strong, independent predictor of cardiovascular events. To date, no studies have investigated the association between LVH and cognitive decline in type 2 diabetes. The Diabetes and Dementia (D2) study is designed to establish whether patients with type 2 diabetes and LVH have increased rates of brain atrophy and cognitive decline. METHODS: The D2 study is a single centre, observational, longitudinal case control study that will follow 168 adult patients aged >50 years with type 2 diabetes: 50% with LVH (case) and 50% without LVH (control). It will assess change in cardiovascular risk, brain imaging and neuropsychological testing between two time-points, baseline (0 months) and 24 months. The primary outcome is brain volume change at 24 months. The co-primary outcome is the presence of cognitive decline at 24 months. The secondary outcome is change in left ventricular mass associated with brain atrophy and cognitive decline at 24 months. DISCUSSION: The D2 study will test the hypothesis that patients with type 2 diabetes and LVH will exhibit greater brain atrophy than those without LVH. An understanding of whether LVH contributes to cognitive decline, and in which patients, will allow us to identify patients at particular risk. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12616000546459 ), date registered, 28/04/2016.

Right ventricular global longitudinal strain is an independent predictor of right ventricular function: a multimodality study of cardiac magnetic resonance imaging, real time three-dimensional echocardiography and speckle tracking echocardiography.

OBJECTIVES: Accurate assessment of right ventricular (RV) systolic function is important, as it is an established predictor of mortality in cardiac and respiratory diseases. We aimed to compare speckle tracking-derived longitudinal deformation measurements with traditional two-dimensional (2D) echocardiographic parameters, as well as real time three-dimensional echocardiography (RT3DE) and cardiac magnetic resonance imaging (CMR)-derived RV volumes and ejection fraction (EF). METHOD: Subjects referred for CMR also underwent echocardiography. On both RT3DE and CMR, we measured RV volumes and EF. On 2D echocardiography, we analyzed RV fractional area change, RV internal diastolic diameter, tricuspid annular plane systolic excursion, tricuspid annular tissue Doppler-derived velocity, myocardial performance index, and RV global longitudinal strain (RV GLS). RESULTS: Sixty subjects were recruited (mean age = 45 ± 10 years; 60% male). RV GLS (R = -0.69, P < 0.001) and RT3DE RVEF (R = 0.56, P < 0.001) correlated well with CMR RVEF. RT3DE RV end-diastolic (RVEDV) and end-systolic (RVESV) volumes also correlated with CMR RV volumes: RVEDV, R = 0.74, P < 0.001 and RVESV, R = 0.84, P < 0.001. In addition, RV GLS best predicted the presence of RV dysfunction, defined as RVEF <48% on CMR (hazard ratio = 7.0 [1.5-31.7], P < 0.01). On receiver operator characteristic analysis, a RV GLS of -20% was the most sensitive and specific predictor of RV dysfunction (AUC 0.8 [0.57-1.0], P < 0.02). CONCLUSION: RVEF and volumes estimated on RT3DE were closely correlated with CMR measurements. When compared to more traditional markers of RV systolic function and RT3DE, RVGLS produced the highest correlation with CMR RVEF and was a good predictor of RV dysfunction. RV GLS should be considered a complementary modality to RT3DE and CMR in the assessment of RV systolic function.

Beta blocker use in subjects with type 2 diabetes mellitus and systolic heart failure does not worsen glycaemic control.

BACKGROUND: The prognostic benefits of beta-blockers (BB) in patients with systolic heart failure (SHF) are known but despite this, in patients with diabetes they are underutilized. The aim of this study was to assess the effect of beta-blockers (BB) on glycaemic control in patients with Type 2 Diabetes (T2DM) and systolic heart failure (SHF) stratified to beta-1 selective (Bisoprolol) vs. nonselective BB (Carvedilol). METHODS: This observational, cohort study was conducted in patients with T2DM and SHF attending an Australian tertiary teaching hospital's heart failure services. The primary endpoint was glycaemic control measured by glycosylated haemoglobin (HbA1c) at initiation and top dose of BB. Secondary endpoints included microalbuminuria, changes in lipid profile and estimated glomerular filtration rate (eGFR). RESULTS: 125 patients were assessed. Both groups were well matched for gender, NYHA class and use of guideline validated heart failure and diabetic medications. The mean treatment duration was 1.9 ± 1.1 years with carvedilol and 1.4 ± 1.0 years with bisoprolol (p = ns). The carvedilol group achieved a reduction in HbA1c (7.8 ± 0.21% to 7.3 ± 0.17%, p = 0.02) whereas the bisoprolol group showed no change in HbA1c (7.0 ± 0.20% to 6.9 ± 0.23%, p = 0.92). There was no significant difference in the change in HbA1c from baseline to peak BB dose in the carvedilol group compared to the bisoprolol group. There was a similar deterioration in eGFR, but no significant changes in lipid profile or microalbuminuria in both groups (p = ns). CONCLUSION: BB use did not worsen glycaemic control, lipid profile or albuminuria status in subjects with SHF and T2DM. Carvedilol significantly improved glycemic control in subjects with SHF and T2DM and this improvement was non significantly better than that obtained with bisoprolol. BB's should not be withheld from patients with T2DM and SHF.

The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes.

BACKGROUND: Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. METHODS: The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). RESULTS: The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. CONCLUSIONS: In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.

Pericardial tamponade: a life threatening complication of laparoscopic gastro-oesophageal surgery.

Laparoscopic surgical procedures involving the gastro-oesophageal region are commonly performed for the management of morbid obesity and refractory gastro-oesophageal reflux disease (GORD). In general, laparoscopic procedures are associated with lower morbidity and mortality in comparison with open techniques. This report highlights cases of potentially life threatening, late onset pericardial tamponade, occurring in the absence of infection or trauma, complicating laparoscopic gastro-oesophageal surgery. Possible mechanisms, clinical manifestations, diagnostic investigations and management of pericardial tamponade are reviewed.

Genesis of improved quality in imaging through a national Australian echocardiography registry.

BACKGROUND: Despite rapid technological advances and growth, quality in imaging has not received the focus seen elsewhere in cardiovascular medicine, resulting in significant gaps between guidelines and practice. Contemporary echocardiography practice requires comprehensive real-time data collection to allow dynamic auditing and benchmarking of key performance indices. The American College of Cardiology (ACC) proposed additional data standardisation, structured reporting identifying key data elements and imaging registries. In the absence of an Australian echocardiography registry, we developed a national clinical quality registry (GenesisCare Cardiovascular Outcomes Echo Registry). We hypothesised that measurement and local reporting of data would improve compliance of echo studies with quality guidelines and hence their clinical value. METHODS AND RESULTS: We prospectively collected data on 4 099 281 echocardiographic studies entered directly into a central electronic database from 63 laboratories across four Australian states between 2010 and 2021. Real-time auditing of key data elements and introduction of quality improvement pathways were performed to maximise completeness and uniformity of data acquisition and reporting. We compared completeness of key data element acquisition (AV peak velocity, left ventricular ejection fraction, E/e', LA area, rhythm, RVSP) by time and state using de-identified data. Key performance outcomes benchmarked against the aggregated study cohort and international standards were reported to individual sites to drive quality improvement. Between 2010 and 2014 there were significant improvements in data completeness (72.0%+/-26.8% vs 86.8%+/-13.5%, p=0.02), which were maintained to 2020. In addition, interstate variability fell for both EF and E/e' (p<0.002). CONCLUSIONS: This large-scale collaboration provides a platform for the development of major quality improvement initiatives in echocardiography. Introduction of local quality assurance programmes via a unified national data set significantly improved the completeness of reporting of key echo quality measures. This in turn significantly improved the quality of, and reduced the interstate variability of, echo data. Developing a centralised database allowed rapid adoption nationally of local quality improvements.

Advanced glycation urinary protein-bound biomarkers and severity of diabetic nephropathy in man.

BACKGROUND/AIMS: The formation of advanced glycation end products (AGEs) is accelerated in patients with diabetic nephropathy. The aim of this study was to ascertain if the urinary excretion of proteins modified by advanced glycation can be used as biomarkers for albuminuria in individuals with type 1 or type 2 diabetes. METHODS: Community-based patients with type 1 (n = 68) or type 2 diabetes (n = 216) attending a diabetes clinic of a tertiary referral hospital were classified as having normoalbuminuria (Normo, albumin excretion rate (AER) <20 µg/min), microalbuminuria (Micro, AER 20-200 µg/min) or macroalbuminuria (Macro, AER ≥200 µg/min). Serum and urine AGE-modified proteins were measured. RESULTS: In patients with both type 1 diabetes and type 2 diabetes, there was a clear association between the degree of albuminuria and urinary AGE-modified proteins (p < 0.0001). Exclusive to patients with type 1 diabetes, urinary excretion of the AGE carboxymethyllysine correlated with AER, whereas patients with type 2 diabetes and macroalbuminuria had an increase in urinary methylglyoxal, an AGE intermediate. These changes were independent of isotopic glomerular filtration rate levels. Serum concentrations of AGEs or soluble receptor for AGEs were not consistently associated with albuminuria in either type 1 or type 2 diabetes. CONCLUSIONS: Urinary excretion of proteins modified by AGEs may be useful biomarkers of albuminuria in individuals with type 1 and type 2 diabetes, warranting prospective investigation in larger diabetic cohorts.

Validation of rapid automated tissue synchronization imaging for the assessment of cardiac dyssynchrony in sinus and non-sinus rhythm.

AIMS: Cardiac resynchronization therapy is showing benefits for an increasing number of indications but fails to predict response in up to 20-30% of subjects. Echocardiographically assessed dyssynchrony has been proposed as a potential stratifier but current methods are time-consuming and suffer poor reproducibility, thus limiting their clinical utility. This study compared the accuracy, time efficiency, and reproducibility of automated tissue synchronization imaging (Auto TSI) vs. established manual tissue velocity imaging (TVI) techniques for the assessment of intra-ventricular dyssynchrony in sinus and non-sinus rhythm. METHODS AND RESULTS: Fifty consecutive stable systolic heart failure patients on optimal guideline-based medical therapy underwent intra-ventricular dyssynchrony assessment [time to peak velocity (Ts), septal to lateral delay (SLD), and dyssynchrony index (DI)] with TVI and Auto TSI techniques, enabling the assessment of agreement, time efficiency, and reproducibility. Statistical analyses included Pearson's correlation, Bland-Altman's statistics, and coefficient of reproducibility. There was excellent agreement between Auto TSI and TVI for the measurement of Ts [r=0.92, P<0.001, limits of agreement (LOA): -27.3 to 56.5 ms], SLD (r=0.94, P<0.001, LOA: -41 to 49 ms), and DI (r=0.89, P<0.001, LOA: -12.2 to 12.6 ms) which persisted irrespective of cardiac rhythm [Ts: sinus (n=32) r=0.93, P<0.001; non-sinus (n=18) r=0.91, P<0.001]. Automated TSI was more time efficient (3±1 vs. 14±2 min, P<0.001) and demonstrated superior reproducibility: intra-observer (5.5 vs. 9.6%) and inter-observer variability (9.5 vs. 13.4%). CONCLUSION: Automated TSI enables rapid, reproducible intra-ventricular dyssynchrony assessment and overcomes some of the limitations of conventional techniques in sinus and non-sinus rhythm.

Circulating high-molecular-weight RAGE ligands activate pathways implicated in the development of diabetic nephropathy.

The accumulation of advanced glycation end products is thought to be a key factor in the initiation and progression of diabetic nephropathy. Here we determined whether the size of the ligands for the receptor for advanced glycation end products (RAGEs) that were present in the serum of patients with type 2 diabetes modulates their pathogenic potential. Serum was collected from control subjects and patients with type 2 diabetes with varying degrees of renal disease (normo-, micro-, or macroalbuminuria). The titers of the RAGE ligands N-carboxymethyllysine (CML), S100A, S100B, and high-mobility group box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay in serum as well as in pooled size-fractionated serum. We also measured cellular binding of serum fractions to mesangial cells transfected with RAGE and examined the downstream signaling pathways. Circulating CML was increased in patients with type 2 diabetes, whereas HMGB1 was decreased. S100A8, S100BA9, and soluble RAGE were unchanged. The high-molecular-weight (over 50 kDa) serum fraction contained the greatest proportion of RAGE ligands, with all immunoreactivity and cellular binding observed only with serum fractions over 30 kDa. High-molecular-weight serum from macroalbuminuric patients showed greater RAGE binding capacity, modulation of cell-surface RAGE expression, increased phospho-protein kinase C-alpha, and p65 nuclear factor kappaB DNA-binding activity, which were competitively inhibited by soluble RAGE or CML neutralizing antibodies. These data show that ligands that activate RAGE present in the circulation of patients with type 2 diabetes and nephropathy are predominantly of high molecular weight.

Thrombus entrapped in a patent foramen ovale: a potential source of pulmonary and systemic embolism.

Patent foramen ovale (PFO) occurs in up to 30% of the population, making it the most common site for intra-cardiac shunting. The passage of thrombus across a PFO is typically transient, thus is rarely proven. We describe a rare case of a 79-year-old man with thrombus entrapped across a PFO providing a source for ongoing pulmonary and systemic thromboembolism, despite systemic anticoagulation. There is a paucity of literature to guide primary management of this condition. Management options include surgical thrombectomy with PFO closure, thrombolysis and systemic anticoagulation. The role of percutaneous PFO closure devices for secondary prevention of thromboembolic complications is currently under investigation.

Plasma ACE2 Activity Predicts Mortality in Aortic Stenosis and Is Associated With Severe Myocardial Fibrosis.

OBJECTIVES: This study investigated the relationship between plasma angiotensin-converting enzyme 2 (ACE2) activity levels and the severity of stenosis and myocardial remodeling in patients with aortic stenosis (AS) and determined if plasma ACE2 levels offered incremental prognostic usefulness to predict all-cause mortality. BACKGROUND: ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of cardiovascular disease. METHODS: Plasma ACE2 activity was measured in 127 patients with AS; a subgroup had myocardial tissue collected at the time of aortic valve replacement. RESULTS: The median plasma ACE2 activity was 34.0 pmol/ml/min, and levels correlated with increased valvular calcification (p = 0.023) and the left ventricular (LV) mass index (r = 0.34; p < 0.001). Patients with above-median plasma ACE2 had higher LV end-diastolic volume (57 ml/m2 vs. 48 ml/m2; p = 0.021). Over a median follow-up of 5 years, elevated plasma ACE2 activity was an independent predictor of all-cause mortality after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06; p = 0.042), including brain natriuretic peptide activation (integrated discrimination improvement: 0.08; p < 0.001). In 22 patients with plasma and tissue, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression (0.7-fold; p = 0.033) and severe myocardial fibrosis (p = 0.027). CONCLUSIONS: In patients with AS, elevated plasma ACE2 was a marker of myocardial structural abnormalities and an independent predictor of mortality with incremental value over traditional prognostic markers. Loss of ACE2 from the myocardium was associated with increased fibrosis and higher circulating ACE2 levels.

Association between intrarenal arterial resistance and diastolic dysfunction in type 2 diabetes.

BACKGROUND: In comparison to the well established changes in compliance that occur at the large vessel level in diabetes, much less is known about the changes in compliance of the cardiovascular system at the end-organ level. The aim of this study was therefore to examine whether there was a correlation between resistance of the intrarenal arteries of the kidney and compliance of the left ventricle, as estimated by measurements of diastolic function, in subjects with type 2 diabetes. METHODS: We studied 167 unselected clinic patients with type 2 diabetes with a kidney duplex scan to estimate intrarenal vascular resistance, i.e. the resistance index (RI = peak systolic velocity-minimum diastolic velocity/peak systolic velocity) and a transthoracic echocardiogram (TTE) employing tissue doppler studies to document diastolic and systolic ventricular function. RESULTS: Renal RI was significantly higher in subjects with diastolic dysfunction (0.72 +/- 0.05) when compared with those who had a normal TTE examination (0.66 +/- 0.06, p < 0.01). Renal RI values were correlated with markers of diastolic dysfunction including the E/Vp ratio (r = 0.41, p < 0.001), left atrial area (r = 0.36, p < 0.001), the E/A ratio (r = 0.36, p < 0.001) and the E/E' ratio (r = 0.31, p < 0.001). These associations were independent of systolic function, hypertension, the presence and severity of chronic kidney disease, the use of renin-angiotensin inhibitors and other potentially confounding variables. CONCLUSION: Increasing vascular resistance of the intrarenal arteries was associated with markers of diastolic dysfunction in subjects with type 2 diabetes. These findings are consistent with the hypothesis that vascular and cardiac stiffening in diabetes are manifestations of common pathophysiological mechanisms.

Prevalence and predictors of cardiac hypertrophy and dysfunction in patients with Type 2 diabetes.

The aim of the present study was to determine the prevalence and predictors of an abnormal echocardiogram in patients with Type 2 diabetes. Cardiac function and structure were rigorously assessed by comprehensive transthoracic echocardiographic techniques in 229 patients with Type 2 diabetes. Cardiovascular risk factors and diabetic complications were assessed, and predictors of an abnormal echocardiogram were identified using multivariate logistic regression analysis. An abnormal echocardiogram was present in 166 patients (72%). LVH (left ventricular hypertrophy) occurred in 116 patients (51%), and cardiac dysfunction was found in 146 patients (64%), of whom 109 had diastolic dysfunction alone and 37 had systolic+/-diastolic dysfunction. Independent predictors of an abnormal echocardiogram were obesity, age, the number of antihypertensive drugs used (all P<0.001) and creatinine clearance (P<0.05). The risk of an abnormal echocardiogram increased by 9% for each year over 50 years of age {OR (odds ratio), 1.09 [95% CI (confidence interval), 1.04-1.15]}, 3-fold if obesity was present [BMI (body mass index) >30; OR, 4.2 (95% CI, 1.9-9.0)] and by 80% for each antihypertensive agent used [OR, 1.8 (95% CI, 1.3-2.4) per agent]. In conclusion, an abnormal cardiac echocardiogram is common in patients with Type 2 diabetes. Importantly, although cardiac abnormalities can be predicted by traditional risk factors, such as age, obesity and renal function, the absence of micro- or macro-vascular complications does not predict a normal echocardiogram. We suggest that an echocardiogram identifies those with Type 2 diabetes at increased cardiovascular risk due to occult LVH and diastolic dysfunction, and this information may lead to more aggressive management of known risk factors in the clinic.

Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) is an endogenous regulator of the renin angiotensin system. Increased circulating ACE2 predicts adverse outcomes in patients with heart failure (HF), but it is unknown if elevated plasma ACE2 activity predicts major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD). METHODS: We prospectively recruited patients with obstructive CAD (defined as ≥50% stenosis of the left main coronary artery and/or ≥70% stenosis in ≥ 1 other major epicardial vessel on invasive coronary angiography) and measured plasma ACE2 activity. Patients were followed up to determine if circulating ACE2 activity levels predicted the primary endpoint of MACE (cardiovascular mortality, HF or myocardial infarction). RESULTS: We recruited 79 patients with obstructive coronary artery disease. The median (IQR) plasma ACE2 activity was 29.3 pmol/ml/min [21.2-41.2]. Over a median follow up of 10.5 years [9.6-10.8years], MACE occurred in 46% of patients (36 events). On Kaplan-Meier analysis, above-median plasma ACE2 activity was associated with MACE (log-rank test, p = 0.035) and HF hospitalisation (p = 0.01). After Cox multivariable adjustment, log ACE2 activity remained an independent predictor of MACE (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24-4.72, p = 0.009) and HF hospitalisation (HR: 4.03, 95% CI: 1.42-11.5, p = 0.009). CONCLUSIONS: Plasma ACE2 activity independently increased the hazard of adverse long-term cardiovascular outcomes in patients with obstructive CAD.

Genetic Variation in Kruppel like Factor 15 Is Associated with Left Ventricular Hypertrophy in Patients with Type 2 Diabetes: Discovery and Replication Cohorts.

Left ventricular (LV) hypertrophy (LVH) is a heritable trait that is common in type 2 diabetes and is associated with the development of heart failure. The transcriptional factor Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy in experimental models. This study investigated if KLF15 gene variants were associated with LVH in type 2 diabetes. In stage 1 of a 2-stage approach, patients with type 2 diabetes and no known cardiac disease were prospectively recruited for a transthoracic echocardiographic assessment (Melbourne Diabetes Heart Cohort) (n=318) and genotyping of two KLF15 single nucleotide polymorphisms (SNPs) (rs9838915, rs6796325). In stage 2, the association of KLF15 SNPs with LVH was investigated in the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) type 2 diabetes cohort (n=5631). The KLF15 SNP rs9838915 A allele was associated in a dominant manner with LV mass before (P=0.003) and after (P=0.001) adjustment for age, gender, body mass index (BMI) and hypertension, and with adjusted septal (P<0.0001) and posterior (P=0.004) wall thickness. LVH was present in 35% of patients. Over a median follow up of 5.6years, there were 22 (7%) first heart failure hospitalizations. The adjusted risk of heart failure hospitalization was 5.5-fold greater in those with LVH and the rs9838915 A allele compared to those without LVH and the GG genotype (hazard ratio (HR) 5.5 (1.6-18.6), P=0.006). The association of rs9838915 A allele with LVH was replicated in the Go-DARTS cohort. We have identified the KLF15 SNP rs9838915 A allele as a marker of LVH in patients with type 2 diabetes, and replicated these findings in a large independent cohort. Studies are needed to characterize the functional importance of these results, and to determine if the SNP rs9838915 A allele is associated with LVH in other high risk patient cohorts.

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.

The Receptor for Advanced Glycation End Products (RAGE) Is Associated with Persistent Atrial Fibrillation.

OBJECTIVE: Upregulation of the receptor for advanced glycation end products (RAGE) has been proposed as a pathophysiological mechanism underlying the development of atrial fibrillation (AF). We sought to investigate if soluble RAGE levels are associated with AF in Caucasian patients. METHODS: Patients (n = 587) were prospectively recruited and serum levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) measured. The patients included 527 with sinus rhythm, 32 with persistent AF (duration >7 days, n = 32) and 28 with paroxysmal AF (duration <7 days, n = 28). RESULTS: Patients with AF were older and had a greater prevalence of heart failure than patients in sinus rhythm. Circulating RAGE levels were higher in patients with persistent AF [median sRAGE 1190 (724-2041) pg/ml and median esRAGE 452 (288-932) pg/ml] compared with paroxysmal AF [sRAGE 799 (583-1033) pg/ml and esRAGE 279 (201-433) pg/ml, p ≤ 0.01] or sinus rhythm [sRAGE 782 (576-1039) pg/ml and esRAGE 289 (192-412) pg/ml, p < 0.001]. In multivariable logistic regression analysis, independent predictors of persistent AF were age, heart failure, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% confidence interval (CI) 1.0-1.1, p = 0.001] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.1-1.4, p < 0.001]. Heart failure and age were the only independent predictors of paroxysmal AF. In AF patients, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% CI 1.1-1.2, p = 0.007] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.0-1.5, p = 0.017] independently predicted persistent compared with paroxysmal AF. CONCLUSIONS: Soluble RAGE is elevated in Caucasian patients with AF, and both sRAGE and esRAGE predict the presence of persistent AF.