Uric acid in advanced heart failure: relation to central haemodynamics and outcome.

OBJECTIVE: The role of hyperuricaemia as a prognostic maker has been established in chronic heart failure (HF) but limited information on the association between plasma uric acid (UA) levels and central haemodynamic measurements is available. METHODS: A retrospective study on patients with advanced HF referred for right heart catherisation. Regression analyses were constructed to investigate the association between UA and haemodynamic variables. Cox models were created to investigate if UA was a significant predictor of adverse outcome where log1.1(UA) was used to estimate the effect on outcome associated with a 10% increase in UA levels. RESULTS: A total of 228 patients were included (77% males, age 49±12 years, mean left ventricular ejection fraction (LVEF) of 17%±8%). Median UA was 0.48 (0.39-0.61) mmol/L. UA level was associated to pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) in univariable (both p<0.001) and multivariable regression analysis (p<0.004 and p=0.025 for PCWP and CI). When constructing multivariable Cox models including PCWP, CI, central venous pressure, age, estimated glomerular filtration rate (eGFR), use of loop diuretics and LVEF, log1.1(UA) independently predicted the combined endpoint (left ventricular assist device, total artificial heart implantation, heart transplantation or all-cause mortality) (hazard ratio (HR): 1.10 (1.03-1.17), p=0.004) as well as all-cause mortality (HR: 1.15 (1.06-1.25), p=0.001). CONCLUSIONS: Elevated UA is associated with greater haemodynamic impairment in advanced HF. In adjusted Cox models (age, eGFR, LVEF and haemodynamics), UA predicts the combined endpoint and all-cause mortality in long-term follow-up.

The effect of empagliflozin on contractile reserve in heart failure: Prespecified sub-study of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.

Infective endocarditis in right ventricular outflow tract conduits: a register-based comparison of homografts, Contegra grafts and Melody transcatheter valves.

OBJECTIVES: The aim was to investigate the incidence of infective endocarditis (IE) in right ventricle-to-pulmonary artery conduits implanted at a Danish tertiary centre. METHODS: Cases of IE in patients with homografts, Contegra grafts and Melody transcatheter valves were evaluated retrospectively with regard to the likeliness of the diagnosis using the modified Duke criteria and the likeliness of conduit involvement. Incidence rates for IE were calculated 1 and 5 years after valve implantation for all 3 conduits, and separately for Melody subgroups depending on which conduit served as landing zone. Cox regression with time-dependent covariates was used to model the impact of the conduit type on the incidence of IE. RESULTS: Annualized incidence rates of IE in homografts, Contegra grafts and Melody valves were 0.40% (0.40 cases per 100 patient-years), 0.97% and 6.96% 1 year and 0.27%, 1.12% and 2.89% 5 years after valve implantation. Hazard ratios (HRs) were 3.20 [95% confidence interval (CI) 0.91-11.17, P = 0.069] for Contegra grafts and 11.89 (95% CI 2.91-48.48, P < 0.001) for Melody valves compared to homografts. CONCLUSIONS: Bovine pulmonary conduits were more prone to endocarditis, with Melody valves being the most frequently infected. HRs for the risk of suffering from endocarditis were substantially higher for Melody valves and Contegra grafts compared to homografts, although this finding was only statistically significant for Melody valves and not for Contegra grafts.

Prognostic value of multi-detector computed tomography in asymptomatic aortic valve stenosis.

BACKGROUND: Multi-Detector Computed Tomography (MDCT) is a high-resolution imaging technique with potential additive value in the evaluation of patients with aortic valve stenosis (AS). We aimed to assess the prognostic value of MDCT in asymptomatic patients with AS compared to conventional transthoracic echocardiography (TTE). METHODS: 116 patients with asymptomatic AS (Vmax>2.5m/s assessed by clinical screening TTE, LVEF>50%) were examined with TTE (Vivid e9) and MDCT (Aquilion 320) on the same day. The treating physician was blinded for research protocol defined imaging results. Outcome was defined as indication for aortic valve replacement (AVR) determined by the treating physician or sudden cardiac death. RESULTS: The mean age was 72 (8) years, 27% were women, mean AVA by TTE was 1.01 (0.30) cm(2). Median follow up time was 27 (IQR 19-44) months. Forty seven patients (41%) developed indication for AVR. No patients suffered a sudden cardiac death. AVA and aortic valve calcification were significant univariable predictors of AVR when measured by both TTE and MDCT, whereas left ventricular mass was only significant measured by MDCT. Significant coronary artery disease by MDCT tended to predict future indication for AVR, but this did not reach statistical significance (HR: 1.79 (95% CI 0.96-3.44), p=0.08). CONCLUSION: MDCT derived AVA can be of use as an alternative to TTE derived AVA in patients with asymptomatic AS to predict future clinical indication for AVR.

High prevalence of cardiac involvement in patients with myotonic dystrophy type 1: a cross-sectional study.

BACKGROUND: Patients with myotonic dystrophy type 1 (DM1) have a three-fold higher risk of sudden cardiac death (SCD) than age-matched healthy controls. Despite numerous attempts to define the cardiac phenotype and natural history, existing literature suffers from low power, selection-bias and lack of controls. Thus, the optimal strategy for assessing cardiac involvement in DM1 is unclear. METHOD: In this large single-centre study, we evaluated 129 unselected DM1 patients (49.6% men), mean (SD) age 44 (14.7) years with family history, physical examination, electrocardiogram (ECG), echocardiography, Holter-monitoring and muscle strength testing. RESULTS: Cardiac involvement was found in 71 patients (55%) and included: 1) Conduction abnormalities: atrio-ventricular block grade I (AVB grade I) (23.6%), AVB grade II (5.6%), right/left bundle branch block (5.5/3.2%) and prolonged QTc (7.2%); 2) arrhythmias: atrial fibrillation/flutter (4.1%), other supraventricular tachyarrhythmia (7.3%) and non-sustained ventricular tachycardia (4.1%); and 3) structural abnormalities: left ventricular systolic dysfunction (20.6%) and reduced global longitudinal strain (21.7%). A normal ECG was not significantly associated with normal findings on Holter-monitoring or echocardiography. Patients with abnormal cardiac findings had weaker muscle strength than those with normal cardiac findings: ankle dorsal flexion (median (range) 4.5 (0-5) vs. 5.0 (2.5-5), p=0.004) and handgrip (median 4.0 (0-5) vs. 4.50 (2-5), p=0.02). CONCLUSION: The cardiac phenotype of DM1 includes a high prevalence of conduction disorders, arrhythmias and risk factors of SCD. Systematic cardiac screening with ECG, Holter-monitoring and echocardiography is needed in order to make a proper characterization of cardiac involvement in DM1.

Left ventricular global longitudinal strain in acute myocardial infarction--with special reference to neurohormonal activation, in-hospital heart failure and prognosis.

BACKGROUND: Systolic dysfunction, clinical heart failure and elevated levels of neurohormonal peptides are major predictors of adverse outcome after acute myocardial infarction (MI). In the present thesis we evaluated global longitudinal strain (GLS) in patients with acute MI in relation to neurohormonal activation, in-hospital heart failure and prognosis with specific attention to the group of patients with preserved LVEF that currently do not meet the criteria for anti remodeling therapies. RESULTS: GLS was found to be significantly associated with neurohormonal activation as assessed by NT-proBNP levels and that this association was present also in patients with preserved LVEF. Patients with clinical HF during hospitalization for acute MI had significantly poorer GLS compared to controls and this relationship was robust when adjusting for known factors associated with elevated LV filling pressure such as left atrial volume and E/e' ratio. Furthermore, measurement of GLS attenuated the value of NT-proBNP in relation to in-hospital HF in patients with preserved LVEF. Finally, GLS was related to outcome in the largest ever echocardiographic deformation study of patients with acute MI and relatively preserved LVEF. We found that GLS predicted mortality and heart failure admissions and that the effect on mortality was driven by a significantly increased risk of cardiac death in patients with impaired GLS. CONCLUSIONS: In conclusion, the results of this thesis demonstrate that GLS as a measure of LV systolic function is significantly related to elevated neurohormonal activation, early hemodynamic deterioration and predict adverse outcome in a low risk population without indications for anti remodeling therapies. Early measurement of GLS in this population could be used as a risk stratification tool for added monitoring and clinical trials.

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy.

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.