Extracellular matrix turnover proteins as risk markers in people with type 2 diabetes and microalbuminuria.

BACKGROUND: This post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria. METHODS: Serum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %. RESULTS: Participants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk. CONCLUSION: Elevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality.

Myocardial scarring and recurrence of ventricular arrhythmia in patients surviving an out-of-hospital cardiac arrest.

INTRODUCTION: Prediction of recurrent ventricular arrhythmia (VA) in survivors of an out-of-hospital cardiac arrest (OHCA) is important, but currently difficult. Risk of recurrence may be related to presence of myocardial scarring assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Our study aims to characterize myocardial scarring as defined by LGE-CMR in survivors of a VA-OHCA and investigate its potential role in the risk of new VA events. METHODS: Between 2015 and 2022, a total of 230 VA-OHCA patients without ST-segment elevation myocardial infarction had CMR before implantable cardioverter-defibrillator implantation for secondary prevention at Copenhagen University Hospital, Rigshospitalet, and Hospital Clínic, University of Barcelona, of which n = 170 patients had a conventional (no LGE protocol) CMR and n = 60 patients had LGE-CMR (including LGE protocol). Scar tissue including core, border zone (BZ) and BZ channels were automatically detected by specialized investigational software in patients with LGE-CMR. The primary endpoint was recurrent VA. RESULTS: After exclusion, n = 52 VA-OHCA patients with LGE-CMR and a mean left ventricular ejection fraction of 49 ± 16% were included, of which 18 (32%) patients reached the primary endpoint of VA. Patients with recurrent VA in exhibited greater scar mass, core mass, BZ mass, and presence of BZ channels compared with patients without recurrent VA. The presence of BZ channels identified patients with recurrent VA with 67% sensitivity and 85% specificity (area under the ROC curve (AUC) 0.76; 95% CI: 0.63-0.89; p < .001) and was the strongest predictor of the primary endpoint. CONCLUSIONS: The presence of BZ channels was the strongest predictor of recurrent VA in patients with an out of-hospital cardiac arrest and LGE-CMR.

Marker for kidney fibrosis is associated with inflammation and deterioration of kidney function in people with type 2 diabetes and microalbuminuria.

BACKGROUND: Diabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline. METHODS: C3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007-2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR). RESULTS: Mean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39-229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41-6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality. CONCLUSIONS: Higher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation.

Recurring episodes of bundle branch reentry ventricular tachycardia due to aortitis preceded by SARS-CoV-2 infection: a case report.

BACKGROUND: SARS-CoV-2 may trigger both vasculitis and arrhythmias as part of a multisystem inflammatory syndrome described in children as well as in adults following COVID-19 infection with only minor respiratory symptoms. The syndrome denotes a severe dysfunction of one or more extra-pulmonary organ systems, with symptom onset approximately 2-5 weeks after the COVID-19 infection. In the present case, a seemingly intractable ventricular tachycardia preceded by SARS-CoV2 infection was only managed following the diagnosis and management of aortitis. CASE PRESENTATION: A 69-year-old woman was hospitalized due to syncope, following a mild COVID-19 infection. She presented with paroxysmal atrial fibrillation and intermittent ventricular tachycardia interpreted as a septum-triggered bundle branch reentry ventricular tachycardia, unaffected by amiodaron, lidocaine and adenosine. A CT-scan revealed inflammation of the aortic arch, extending into the aortic root. In the following days, the tachycardia progressed to ventricular storm with intermittent third-degree AV block. A temporary pacemaker was implanted, and radiofrequency ablation was performed to both sides of the ventricular septum after which the ventricular tachycardia was non-inducible. Following supplemental prednisolone treatment, cardiac symptoms and arrythmia subsided, but recurred after tapering. Long-term prednisolone treatment was therefore initiated with no relapse in the following 14 months. CONCLUSION: We present a rare case of aortitis complicated with life-threatening ventricular tachycardia presided by Covid-19 infection without major respiratory symptoms. Given a known normal AV conduction prior to the COVID-19 infection, it seems likely that the ensuing aortitis in turn affected the septal myocardium, enabling the reentry tachycardia. Generally, bundle branch reentry tachycardia is best treated with radiofrequency ablation, but if it is due to aortitis with myocardial affection, long-term anti-inflammatory treatment is mandatory to prevent relapse and assure arrhythmia control. Our case highlights importance to recognize the existence of the multisystem inflammatory syndrome in adults (MIS-A) following COVID-19 infection in patients with alarming cardiovascular symptoms. The case shows that the early use of an CT-scan was crucial for both proper diagnosis and treatment option.

Cause-specific death and risk factors of 1-year mortality after implantable cardioverter-defibrillator implantation: a nationwide study.

AIMS: Current treatment guidelines recommend implantable cardioverter-defibrillators (ICDs) in eligible patients with an estimated survival beyond 1 year. There is still an unmet need to identify patients who are unlikely to benefit from an ICD. We determined cause-specific 1-year mortality after ICD implantation and identified associated risk factors. METHODS AND RESULTS: Using Danish nationwide registries (2000-2017), we identified 14 516 patients undergoing first-time ICD implantation for primary or secondary prevention. Risk factors associated with 1-year mortality were evaluated using multivariable logistic regression. The median age was 66 years, 81.3% were male, and 50.3% received an ICD for secondary prevention. The 1-year mortality rate was 4.8% (694/14 516). ICD recipients who died within 1 year were older and more comorbid compared to those who survived (72 vs. 66 years, P < 0.001). Risk factors associated with increased 1-year mortality included dialysis [odds ratio (OR): 3.26, confidence interval (CI): 2.37-4.49], chronic renal disease (OR: 2.14, CI: 1.66-2.76), cancer (OR: 1.51, CI: 1.15-1.99), age 70-79 years (OR: 1.65, CI: 1.36-2.01), and age ≥80 years (OR: 2.84, CI: 2.15-3.77). The 1-year mortality rates for the specific risk factors were: dialysis (13.8%), chronic renal disease (13.1%), cancer (8.5%), age 70-79 years (6.9%), and age ≥80 years (11.0%). Overall, the most common causes of mortality were related to cardiovascular diseases (62.5%), cancer (10.1%), and endocrine disorders (5.0%). However, the most common cause of death among patients with cancer was cancer-related (45.7%). CONCLUSION: Among ICD recipients, mortality rates were low and could be indicative of relevant patient selection. Important risk factors of increased 1-year mortality included dialysis, chronic renal disease, cancer, and advanced age.

Deep sedation as temporary bridge to definitive treatment of ventricular arrhythmia storm.

BACKGROUND: Electrical storm and incessant ventricular tachycardia (VT) are characterized by the clustering of episodes of VT or ventricular fibrillation (VF) and are associated with a poor prognosis. Autonomic nervous system activity influences VT threshold, and deep sedation may be useful for the treatment of VT emergencies. METHODS: We reviewed data from conscious patients admitted to our intensive care unit (ICU) due to monomorphic VT, polymorphic VT or VF at our tertiary center between 2010 and 2018. RESULTS: A total of 46 conscious patients with recurrent ventricular arrhythmia, refractory to initial treatment, were referred to the ICU. The majority (n = 31) were stabilized on usual care. The remaining treatment-refractory 15 patients (57 years (range 9-74), 80% males, seven with implantable cardioverter-defibrillators) with VT/VF storm (n = 11) or incessant VT (n = 4) due to ischemic heart disease (n = 10), cardiomyopathy (n = 2), primary arrhythmia (n = 2) and one patient post valve surgery, were deeply sedated and intubated. A complete resolution of VT/VF within minutes to hours was achieved in 12 patients (80%), partial resolution in two (13%) and one (7%) patient died due to ventricular free-wall rupture. One patient with recurrent VT episodes needing repeated deep sedation developed necrotic caecum. No other major complications were seen. Thirteen (87%) patients were alive after a mean follow-up of 3.7 years. CONCLUSION: Deep sedation was effective and safe for the temporary management of malignant VT/VF refractory to usual treatment. In emergencies, deep sedation may be widely accessible at both secondary and tertiary centers and a clinically useful bridge to definitive treatment of VT.

Higher Collagen VI Formation Is Associated With All-Cause Mortality in Patients With Type 2 Diabetes and Microalbuminuria.

OBJECTIVE: Type 2 diabetes is a common risk factor for the development of chronic kidney disease (CKD). Enhanced de novo collagen type VI (COL VI) formation has been associated with renal fibrosis and CKD. We investigated the hypothesis that PRO-C6, a product specifically generated during COL VI formation, is prognostic for adverse outcomes in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: In a prospective, observational study, we measured PRO-C6 in the serum (S-PRO-C6) and urine (U-PRO-C6) of 198 patients with type 2 diabetes and microalbuminuria without symptoms of coronary artery disease. Patients were followed for a median of 6.5 years, and end points were a composite of cardiovascular events (n = 38), all-cause mortality (n = 26), and reduction of estimated glomerular filtration rate (eGFR) of >30% (disease progression [n = 42]). Cox models were unadjusted and adjusted for the conventional risk factors of sex, age, BMI, systolic blood pressure, LDL cholesterol, smoking, HbA1c, plasma creatinine, and urinary albumin excretion rate. RESULTS: Doubling of S-PRO-C6 increased hazards for cardiovascular events (hazard ratio 3.06 [95% CI 1.31-7.14]), all-cause mortality (6.91 [2.96-16.11]), and disease progression (4.81 [1.92-12.01]). Addition of S-PRO-C6 to a model containing conventional risk factors improved relative integrated discrimination by 22.5% for cardiovascular events (P = 0.02), 76.8% for all-cause mortality (P = 0.002), and 53.3% for disease progression (P = 0.004). U-PRO-C6 was not significantly associated with any of the outcomes. CONCLUSIONS: S-PRO-C6 generated during COL VI formation predicts cardiovascular events, all-cause mortality, and disease progression in patients with type 2 diabetes and microalbuminuria.

Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria.

BACKGROUND: The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown. METHODS: Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years. RESULTS: CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (ß = 0.402, p < 0.001) and eGFR (ß = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. CONCLUSION: A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers.

Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria.

BACKGROUND: To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. METHODS: 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale. RESULTS: Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality. CONCLUSION: In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.

Toe-brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria.

AIMS/HYPOTHESIS: The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria. METHODS: This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement. RESULTS: Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and all-cause mortality (1.37 [1.09, 1.57]) unadjusted and after adjustment for traditional risk factors (CVD 1.44 [1.23, 1.59] and all-cause mortality 1.39 [1.07, 1.60]). After additional adjustment for NT-proBNP and coronary artery calcification, lower TBI remained a determinant of CVD (p = 0.023). When TBI was added to traditional risk factors, the AUC increased significantly for CVD, by 0.063 (95% CI 0.012, 0.115) from 0.743 (p = 0.016), but not for all-cause mortality; adding ABI did not improve the AUC significantly. The rIDI for TBI was 46.7% (p < 0.001) for CVD and 46.0% (p = 0.002) for all-cause mortality; for ABI, the rIDI was 51.8% (p = 0.004) for CVD and 53.6% (p = 0.031) for all-cause mortality. CONCLUSIONS/INTERPRETATION: Reduced TBI and ABI were associated with increased risk of CVD and all-cause mortality, independent of traditional risk factors in type 2 diabetes, and improved prognostic accuracy.

Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate.

Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low-density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease ( n = 29) or mortality ( n = 23). Cardiac adipose tissue ( p = 0.049) and epicardial adipose tissue ( p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue ( p = 0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1-3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8.

Is modification of the VVI backup mode in implantable cardioverter-defibrillators from St Jude medical required due to increased risk of inappropriate shocks?

Inappropriate implantable cardioverter-defibrillator (ICD) shock therapy is painful, stressful, and typically occurs unexpected in conscious patients and may be related to a less favourable prognosis. In our institution, we have observed four cases of multiple inappropriate ICD shocks during reset to VVI backup mode. All four patients were implanted with a St Jude Medical ICD since 2010. The reset to VVI backup mode happens as a 'safety' response when the ICD encounters errors in the software or hardware often due to electromagnetic interference. The ICD then operates in a simple mode, with only a ventricular fibrillation (VF) zone starting at 146 b.p.m., with shock therapy only and changes in sensitivity settings making the ICD more sensitive. In all cases, the reason for the multiple inappropriate shocks was that the VF zone was reached due to exercise-induced sinus tachycardia or due to oversensing during sinus rhythm. The VVI backup mode has to balance between protection from failure of ICD therapy during life-threatening ventricular arrhythmias and from inappropriate shocks. It seems the non-programmable parameters in VVI backup mode of St Jude Medical ICDs carry an unacceptable high risk of inappropriate shocks during normal rhythm as illustrated by our four cases. A higher VF zone comparable with the zones chosen by the other manufacturer would give a better balance, since it is very unlikely that a patient will need shock therapy urgently for slow ventricular tachycardia.

Urinary biomarkers are associated with incident cardiovascular disease, all-cause mortality and deterioration of kidney function in type 2 diabetic patients with microalbuminuria.

AIMS/HYPOTHESIS: We evaluated two urinary biomarkers reflecting different aspects of renal pathophysiology as potential determinants of incident cardiovascular disease (CVD), all-cause mortality and a reduced estimated GFR (eGFR) in patients with type 2 diabetes and microalbuminuria but without clinical features of coronary artery disease. METHODS: In a prospective study of 200 patients, all received multifactorial treatment. Baseline measurements of urinary hepatocyte growth factor (HGF) and adiponectin were available for 191 patients. Cox models were adjusted for sex, age, LDL-cholesterol, smoking, HbA1c, plasma creatinine, systolic BP and urinary AER (UAER). The pre-defined endpoint of chronic kidney disease progression was a decline in the eGFR of >30% during follow-up. HRs per 1 SD increment of log-transformed values are presented. RESULTS: Patients had a mean ± SD age of 59 ± 9 years with a median (interquartile range) UAER of 103 (39-230) mg/24 h. During a median 6.1 years of follow-up, there were 40 incident CVD events, 26 deaths and 42 patients reached the pre-defined chronic kidney disease progression endpoint after 4.9 years (median). Higher urinary HGF was a determinant of CVD in unadjusted (HR 1.9 [95% CI 1.3, 2.8], p = 0.001) and adjusted (HR 2.0 [95% CI 1.2, 3.2], p = 0.004) models, and of all-cause mortality in unadjusted (HR 2.3 [95% CI 1.3, 3.9], p = 0.003) and adjusted (HR 2.5 [95% CI 1.3, 4.8], p = 0.005) models. A higher adiponectin level was associated with CVD in unadjusted (HR 1.4 [95% CI 1.0, 1.9], p = 0.04) and adjusted (HR 1.4 [95% CI 1.1, 2.3], p = 0.013) models, and with a decline in the eGFR of >30% in unadjusted (HR 1.6 [95% CI 1.2, 2.2], p = 0.008) and adjusted (HR 1.5 [95% CI 1.1, 2.2], p = 0.007) models. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes and microalbuminuria receiving multifactorial treatment, higher urinary HGF was associated with incident CVD and all-cause mortality, and higher adiponectin was associated with CVD and deterioration in renal function.

Optimal Cardiac Resynchronization Therapy Pacing Rate in Non-Ischemic Heart Failure Patients: A Randomized Crossover Pilot Trial.

BACKGROUND: The optimal pacing rate during cardiac resynchronization therapy (CRT) is unknown. Therefore, we investigated the impact of changing basal pacing frequencies on autonomic nerve function, cardiopulmonary exercise capacity and self-perceived quality of life (QoL). METHODS: Twelve CRT patients with non-ischemic heart failure (NYHA class II-III) were enrolled in a randomized, double-blind, crossover trial, in which the basal pacing rate was set at DDD-60 and DDD-80 for 3 months (DDD-R for 2 patients). At baseline, 3 months and 6 months, we assessed sympathetic nerve activity by microneurography (MSNA), peak oxygen consumption (pVO2), N-terminal pro-brain natriuretic peptide (p-NT-proBNP), echocardiography and QoL. RESULTS: DDD-80 pacing for 3 months increased the mean heart rate from 77.3 to 86.1 (p = 0.001) and reduced sympathetic activity compared to DDD-60 (51±14 bursts/100 cardiac cycles vs. 64±14 bursts/100 cardiac cycles, p<0.05). The mean pVO2 increased non-significantly from 15.6±6 mL/min/kg during DDD-60 to 16.7±6 mL/min/kg during DDD-80, and p-NT-proBNP remained unchanged. The QoL score indicated that DDD-60 was better tolerated. CONCLUSION: In CRT patients with non-ischemic heart failure, 3 months of DDD-80 pacing decreased sympathetic outflow (burst incidence only) compared to DDD-60 pacing. However, Qol scores were better during the lower pacing rate. Further and larger scale investigations are indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT02258061.

Plasma NT-proBNP and white matter hyperintensities in type 2 diabetic patients.

UNLABELLED: Elevated plasma N-terminal (NT)-proBNP from the heart as well as white matter hyperintensities (WMH) in the brain predict cardiovascular (CV) mortality in the general population. The cause of poor prognosis associated with elevated P-NT-proBNP is not known but WMH precede strokes in high risk populations. We assessed the association between P-NT-proBNP and WMH or brain atrophy measured with magnetic resonance imaging (MRI) in type 2 diabetic patients, and age-matched controls. METHODS AND RESULTS: We measured P-NT-proBNP(ng/l) in 20 diabetic patients without prior stroke but with(n=10) or without(n=10) asymptomatic coronary artery disease(CAD) in order to include patients with a wide-ranging CV risk profile. All patients and 26 controls had a 3D MRI and brain volumes(ml) with WMH and brain parenchymal fraction(BPF), an indicator of brain atrophy, were determined.P-NT-proBNP was associated with WMH in linear regression analysis adjusted for CV risk factors(r=0.94, p=0.001) and with BPF in univariate analysis(r=0.57, p=0.009). Patients divided into groups of increased P-NT-proBNP levels were paralleled with increased WMH volumes(geometric mean[SD];(2.86[5.11] ml and 0.76[2.49] ml compared to patients with low P-NT-proBNP 0.20[2.28] ml, p=0.003)) and also when adjusted for age, sex and presence of CAD(p=0.017). The association was strengthened by CV risk factors and we did not find a common heart or brain specific driver of both P-NT-proBNP and WMH. Patients and particular patients with CAD had higher WMH, however no longer after adjustment for age and sex. CONCLUSION: P-NT-proBNP was associated with WMH in type 2 diabetic patients, suggesting a linkage between heart and brain disease.

Voltage-guided ablation technique for cavotricuspid isthmus-dependent atrial flutter: refining the continuous line.

Ablation of the cavotricuspid isthmus has become first-line therapy for "isthmus-dependent" atrial flutter. The goal of ablation is to produce bidirectional cavotricuspid isthmus block. Traditionally, this has been obtained by creation of a complete ablation line across the isthmus from the ventricular end to the inferior vena cava. This article describes an alternative method used in our laboratory. There is substantial evidence that conduction across the isthmus occurs preferentially over discrete separate bundles of tissue. Consequently, voltage-guided ablation targeting only these bundles with large amplitude atrial electrograms results in a highly efficient alternate method for the interruption of conduction across the cavotricuspid isthmus. Understanding the bundle structure of conduction over the isthmus facilitates more flexible approaches to its ablation and targeting maximum voltages in our hands has resulted in reduction of ablation time and fewer recurrences.

Tubular markers are associated with decline in kidney function in proteinuric type 2 diabetic patients.

UNLABELLED: Our aim was to investigate u-NGAL, u-KIM1 and p-FGF23 and prediction of decline in kidney function in type 2 diabetic patients with proteinuria. METHODS: We performed a follow-up study, follow-up median (range) 3.5 (1-5) years. At baseline u-NGAL, u-KIM1 and p-FGF23 (ELISA) was measured and patients were followed yearly with estimated(e)-GFR (MDRD) and u-albumin. RESULTS: We included 177 patients (44 women), mean age (SD) 59 (9) years. eGFR 90 (24) ml/min/1.73 m(2) at baseline, u-albumin: median (interquartile range) 104 (39-238) mg/24 h. Patients with levels of u-KIM1 in the highest quartile had a greater decline in eGFR than patients with the lowest quartile 6.0 (5.4) versus 3.2 (5.5) ml/min/1.73 m(2) per year (p=0.02). u-NGAL in the highest versus lowest quartile eGFR decline: 5.1 (4.7) and 2.8 (7.1)ml/min/1.73 m(2) per year (p=0.07). Higher values of u-NGAL and u-KIM1 were associated with enhanced decline in eGFR (R=0.16 and R=0.19, p<0.05), however not after adjustment for progression promoters. p-FGF23 was not predictive of decline in eGFR. CONCLUSION: Higher levels of markers of tubular damage are associated with a faster decline in eGFR. However, since this is not independent of known progression promoters, measurement of tubular markers does not give additional prognostic information.

NT-proBNP, echocardiographic abnormalities and subclinical coronary artery disease in high risk type 2 diabetic patients.

BACKGROUND: Intensive multifactorial treatment aimed at prevention of cardiovascular (CV) disease may reduce left ventricular (LV) echocardiographic abnormalities in diabetic subjects. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the association between P-NT-proBNP and the putative residual abnormalities in such patients are not well described. This study examined echocardiographic measurements of LV hypertrophy, atrial dilatation and LV dysfunction and their relation to P-NT-proBNP levels or subclinical coronary artery disease (CAD) in type 2 diabetic patients with microalbuminuria receiving intensive multifactorial treatment. METHODS: Echocardiography including tissue Doppler imaging and P-NT-proBNP measurements were performed in 200 patients without prior CAD. Patients with P-NT-proBNP > 45.2 ng/L and/or coronary calcium score ≥ 400 were stratified as high risk patients for CAD(n = 133) and examined for significant CAD by myocardial perfusion imaging and/or CT-angiography and/or coronary angiography. RESULTS: LV mass index was 41.2 ± 10.9 g/m2.7 and 48 (24%) patients had LV hypertrophy. LA and RA dilatation were found in 54(27%) and 45(23%) patients, respectively, and LV diastolic dysfunction was found in 109(55%) patients. Patients with increased P-NT-proBNP levels did not have more major echocardiographic abnormalities. In 70(53%) of 133 high risk patients significant CAD was demonstrated and patients with LV hypertrophy had increased risk of significant CAD(adjusted odd ratio[CI] was 4.53[1.14-18.06]). CONCLUSION: Among asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment, P-NT-proBNP levels is not associated with echocardiographic abnormalities. LV diastolic dysfunction was frequently observed, whereas LV hypertrophy was less frequent but associated with significant CAD.

Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate.

OBJECTIVE: Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02-7.66, P = 0.047). CONCLUSIONS: In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.