Incidence of thyroid dysfunction following initiation of amiodarone treatment in patients with and without heart failure: a nationwide cohort study.

AIMS: Thyroid dysfunction is considered the most frequent complication to amiodarone treatment, but data on its occurrence outside clinical trials are sparse. The present study aimed to examine the incidence of thyroid dysfunction following initiation of amiodarone treatment in a nationwide cohort of patients with and without heart failure (HF). METHODS AND RESULTS: In Danish registries, we identified all patients with first-time amiodarone treatment during the period 2000-18, without prior thyroid disease or medication. The primary outcome was a composite of thyroid diagnoses and initiation of thyroid drugs. Outcomes were assessed at 1-year follow-up, and for patients free of events in the first year, in a landmark analysis for the subsequent 5 years. We included 43 724 patients with first-time amiodarone treatment, of whom 16 939 (38%) had HF. At 1-year follow-up, the cumulative incidence and adjusted hazard ratio (HR) of the primary outcome were 5.3% and 1.37 (95% confidence interval 1.25-1.50) in patients with a history of HF and 4.2% in those without HF (reference). In the 1-year landmark analysis, the subsequent 5-year cumulative incidences and adjusted HRs of the primary outcome were 5.3% (reference) in patients with 1-year accumulated dose <27.38 g [corresponding to average daily dose (ADD <75 mg)], 14.0% and HR 2.74 (2.46-3.05) for 27.38-45.63 g (ADD 75-125 mg), 20.0% and HR 4.16 (3.77-4.59) for 45.64-63.88 g (ADD 126-175 mg), and 24.5% and HR 5.30 (4.82-5.90) for >63.88 g (ADD >175 mg). CONCLUSION: Among patients who initiated amiodarone treatment, around 5% had thyroid dysfunction at 1-year follow-up, with a slightly higher incidence in those with HF. A dose-response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.

Add-on therapy in metformin-treated patients with type 2 diabetes at moderate cardiovascular risk: a nationwide study.

BACKGROUND: In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. METHODS: From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. RESULTS: The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF-hazard ratios (HR) were 1.11 (95% CI 0.89-1.39) for GLP-1 RA, 0.84 (0.52-1.36) for SGLT-2 inhibitors, 0.98 (0.77-1.26) for SU and 1.54 (1.25-1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5-3.6%) patients, yielding HRs of 0.82 (0.69-0.97) for GLP-1 RAs, 0.79 (0.56-1.12) for SGLT-2 inhibitors, 1.22 (1.03-1.49) for SU and 1.23 (1.07-1.47) for insulin. 1865 (3.9%, range 1.9-9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78-1.05) for GLP-1 RAs, 0.79 (0.58-1.07) for SGLT-2 inhibitors, 1.13 (0.99-1.31) for SU and 2.33 (2.08-2.61) for insulin. CONCLUSION: In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Long-term Rate of Ventricular Arrhythmia in Autoimmune Disease.

AIMS: Although selected autoimmune diseases (AIDs) have been linked to an increased risk of ventricular arrhythmias (VAs), data on the long-term rate of VAs across the spectrum of AIDs are lacking. The aim of our study was to investigate the long-term rate of VAs (a composite of ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest) in individuals with a history of 28 different AIDs. METHODS: Individuals diagnosed with an AID (2005-2018) were identified through Danish nationwide registries. Each patient with AID was matched with four individuals from the background population by age and sex. Multivariable Cox regression was used to compare the rate of VAs between the AIDs and background population, overall and according to individual AIDs. RESULTS: In total, 186,733 patients diagnosed with AIDs were matched with 746,932 individuals without AIDs (median age 55 years; 63% female; median follow-up 6.0 years). The 5-year cumulative incidence of VAs was 0.5% for patients with AIDs and 0.3% for matched individuals. Patients with any AIDs had a higher associated rate of VAs than matched individuals (HR 1.39 [95% CI, 1.29-1.49]). The highest HR was observed in patients with systemic sclerosis (3.86 [95% CI, 1.92-7.75]). The higher rate of VAs in patients with AIDs, compared with individuals from the background population, was more pronounced in patients without ischemic heart disease or heart failure/cardiomyopathy compared to those with these conditions (Pinteraction < 0.05). CONCLUSIONS: Despite a low cumulative incidence, patients with a history of AIDs had a higher relative rate of VAs than matched individuals.

In a large Danish nationwide study, we examined the risk of ventricular arrhythmias, which are serious and potentially life-threatening conditions, in patients with and without a history of autoimmune diseases. Patients with a history of any autoimmune disease had a higher risk of experiencing ventricular arrhythmias compared with age- and sex-matched individuals from the background population. This association was observed for most of the autoimmune diseases when examined individually. The higher rate of ventricular arrhythmias in patients with autoimmune diseases, compared with individuals from the background population, was relatively more pronounced in patients without a history of ischemic heart disease or heart failure/cardiomyopathy compared with individuals with a history of these conditions.

Generalised arterial calcification in normoalbuminuric patients with type 1 diabetes with and without cardiovascular autonomic neuropathy.

BACKGROUND: Type 1 diabetes is associated with increased risk of cardiovascular disease and the diabetic complication cardiovascular autonomic neuropathy in itself entails increased cardiovascular risk by mechanisms not yet fully understood. Arterial calcification is an important predictor of cardiovascular events; the aim of this study was to investigate the level of generalised arterial calcification in patients with long-term, normoalbuminuric type 1 diabetes and the association with cardiovascular autonomic neuropathy, as these factors have not been investigated in type 1 diabetes. METHODS: Participants were examined for calcification of coronary and carotid arteries through non-contrast multi-detector computed tomography scans. Generalised arterial calcification was defined as the presence of calcium in both the coronary and carotid arteries. RESULTS: A total of 53 patients with type 1 diabetes were included. Coronary and carotid artery calcium scores were correlated ( r = 0.720, p < 0.0001). Cardiovascular autonomic neuropathy was associated with increased coronary ( p = 0.002) and carotid ( p = 0.001) artery calcium scores. Seventeen of 20 patients with cardiovascular autonomic neuropathy (85%) demonstrated generalised arterial calcification compared to 11 (33%) patients without cardiovascular autonomic neuropathy; patients with cardiovascular autonomic neuropathy had an odds ratio of 11.3 (95% confidence interval = 2.7-47.1, p < 0.001) for generalised arterial calcification. CONCLUSION: Cardiovascular autonomic neuropathy is associated with increased level of generalised arterial calcification in patients with normoalbuminuric, long-term type 1 diabetes.

Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality--a retrospective nationwide study.

AIMS: Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs. METHODS: Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference. RESULTS: A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005). CONCLUSION: Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

The prognostic value of left atrial peak reservoir strain in acute myocardial infarction is dependent on left ventricular longitudinal function and left atrial size.

BACKGROUND: Peak atrial longitudinal strain (PALS) during the reservoir phase has been proposed as a measure of left atrium function in a range of cardiac conditions, with the potential for added pathophysiological insight and prognostic value. However, no studies have assessed the interrelation of PALS and left ventricular longitudinal strain (global longitudinal strain) in large-scale populations in regard to prognosis. METHODS AND RESULTS: We prospectively included 843 patients (mean age 62.1±11.8; 74% male) with acute myocardial infarction and measured global longitudinal strain, left atrium volumes, and PALS within 48 hours of admission. PALS was related to a composite outcome of death and heart failure hospitalization. Reduced PALS was associated with hypertension, diabetes mellitus, and Killip class >1 (P<0.05 for all). Reduced PALS was associated with impairment of all measures of left ventricular systolic and diastolic function, and the correlation between global longitudinal strain and PALS was highly significant (P<0.001; r=-0.71). During follow-up (median 23.0 months Q1-Q3, 16.8-26.0), a total of 76 patients (9.0%) reached the composite end point of which 47 patients died (5.6%), and 29 patients were hospitalized for heart failure (3.4%). PALS was significantly associated with outcome (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.85-0.90; P<0.001); however, no independent effect of PALS (HR, 1.00; 95% CI, 0.94-1.05; P=0.87) was found when adjusting for global longitudinal strain (HR, 1.20; 95% CI, 1.09-1.33; P<0.001), maximum left atrium volume before mitral valve opening (HR, 1.02; 95% CI, 1.01-1.04; P=0.006), and age (HR, 1.06; 95% CI, 1.03-1.08; P<0.001). CONCLUSIONS: PALS provides a composite measure of left ventricular longitudinal systolic function and maximum left atrium volume before mitral valve opening, and as such contains no added information when these readily obtained measures are known.

Prediction of all-cause mortality and heart failure admissions from global left ventricular longitudinal strain in patients with acute myocardial infarction and preserved left ventricular ejection fraction.

OBJECTIVES: This study sought to test the hypothesis that semiautomated calculation of left ventricular global longitudinal strain (GLS) can identify high-risk subjects among patients with myocardial infarctions (MIs) with left ventricular ejection fractions (LVEFs) >40%. BACKGROUND: LVEF is a key determinant in decision making after acute MI, yet it is relatively indiscriminant within the normal range. Novel echocardiographic deformation parameters may be of particular clinical relevance in patients with relatively preserved LVEFs. METHODS: Patients with MIs and LVEFs >40% within 48 h of admission for coronary angiography were prospectively included. All patients underwent echocardiography with semiautomated measurement of GLS. The primary composite endpoint (all-cause mortality and hospitalization for heart failure) was analyzed using Cox regression analyses. The secondary endpoints were cardiac death and heart failure hospitalization. RESULTS: A total of 849 patients (mean age 61.9 ± 12.0 years, 73% men) were included, and 57 (6.7%) reached the primary endpoint (median follow-up 30 months). Significant prognostic value was found for GLS (hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.10 to 1.32; p < 0.001). GLS > -14% was associated with a 3-fold increase in risk for the combined endpoint (HR: 3.21; 95% CI: 1.82 to 5.67; p < 0.001). After adjustment for other variables, GLS remained independently related to the combined endpoint (HR: 1.14; 95% CI: 1.04 to 1.26; p = 0.007). For the secondary endpoints, GLS > -14% was significantly associated with cardiovascular death (HR: 12.7; 95% CI: 3.0 to 54.6; p < 0.001) and heart failure hospitalization (HR: 5.31; 95% CI: 1.50 to 18.82; p < 0.001). CONCLUSIONS: Assessment of GLS using a semiautomated algorithm provides important prognostic information in patients with LVEFs >40% above and beyond traditional indexes of high-risk MI.

Relationship between left ventricular longitudinal deformation and clinical heart failure during admission for acute myocardial infarction: a two-dimensional speckle-tracking study.

BACKGROUND: Heart failure (HF) complicating acute myocardial infarction (MI) is an ominous prognostic sign frequently caused by left ventricular (LV) systolic dysfunction. However, many patients develop HF despite preserved LV ejection fractions. The aim of this study was to test the hypothesis that LV longitudinal function is a stronger marker of in-hospital HF than traditional echocardiographic indices. METHODS: A total of 548 patients with acute MIs were evaluated (mean age, 63.2 ± 11.7 years; 71.6% men). Within 48 hours of admission, comprehensive echocardiography with assessment of global longitudinal strain (GLS) was performed, along with measurements of N-terminal pro-brain natriuretic peptide. RESULTS: A total 89 patients (16.2%) had in-hospital HF assessed by Killip class > 1 in whom GLS was significantly impaired compared with patients without in-hospital HF (Killip class 1) (-14.6 ± 3.3% vs -10.1 ± 3.5%, P < .0001). In stepwise multiple logistic regression analysis including age, known HF, three-vessel disease, involvement of the left anterior descending coronary artery, episodes of atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, troponin T level, LV ejection fraction, wall motion score index, and diastolic dysfunction indices, GLS emerged as the strongest marker of clinical HF (odds ratio, 1.47; 95% confidence interval [CI], 1.33-1.62; P < .0001). GLS remained independently associated with in-hospital HF in patients with LV ejection fractions > 40% (odds ratio, 1.33; 95% CI, 1.14-1.54; P < .05) and improved the C-statistic over other important covariates significantly (0.87 [95% CI, 0.82-0.91] vs 0.82 [95% CI, 0.76-0.89], P = .02). CONCLUSIONS: Global longitudinal function assessed by GLS is significantly impaired in patients with MIs with in-hospital HF, and multivariate analysis suggests that reduced GLS is the single most powerful marker of manifest LV hemodynamic deterioration in the acute phase of MI.

Cardiovascular autonomic neuropathy and subclinical cardiovascular disease in normoalbuminuric type 1 diabetic patients.

Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (-) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with -CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with -CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.

Global left ventricular longitudinal strain is closely associated with increased neurohormonal activation after acute myocardial infarction in patients with both reduced and preserved ejection fraction: a two-dimensional speckle tracking study.

AIMS: N-terminal pro brain natriuretic peptide (NT-proBNP) is released in response to increased myocardial wall stress and is associated with adverse outcome in acute myocardial infarction. However, little is known about the relationship between longitudinal deformation indices and NT-proBNP. METHODS AND RESULTS: We prospectively included 611 patients with acute myocardial infarction admitted to a tertiary centre and performed echocardiography within 48 h of admission. Global longitudinal myocardial function was assessed by two-dimensional speckle tracking simultaneously with measurement of plasma NT-proBNP. A significant linear relationship between NT-proBNP and global longitudinal strain (GLS) was found (P < 0.0001, r = 0.62). Weaker correlation was found between NT-proBNP and left ventricular ejection fraction (LVEF; P < 0.0001, r = - 0.44). GLS emerged on multivariable analysis including age, sex, estimated glomerular filtration rate, Killip class ≥2, diabetes, hypertension, presence of ST segment elevation, anterior infarction, troponin level, left atrial volume index, mitral valve deceleration time, and E/e' as the strongest predictor of log(NT-proBNP) (P < 0.0001). In patients with preserved systolic function (LVEF >45%), GLS remained strongly correlated with NT-proBNP (P < 0.0001, r = 0.50). The C-statistic associated with prediction of upper vs. lower quartiles of NT-proBNP was significantly higher for GLS compared with LVEF (0.76 vs. 0.56; P < 0.0001). CONCLUSION: Left ventricular longitudinal function assessed by GLS exhibits a stronger association with NT-proBNP levels in acute myocardial infarction compared with LVEF. In patients with apparently preserved systolic function, GLS is superior to LVEF in identifying increased neurohormonal activation.

Clinical characteristics and major comorbidities in heart failure patients more than 85 years of age compared with younger age groups.

AIMS: Heart failure (HF) is increasingly prevalent among the growing number of elderly people, but not well studied. We sought to evaluate disease pattern and importance of prognostic factors among very elderly patients with HF. METHODS AND RESULTS: Among 8507 patients screened for entry into two studies on HF, we analysed the clinical characteristics, major comorbidities and prognostic factors in 825 patients older than 85 years (very elderly) compared with younger age groups. Adjusted hazard ratios [HR (95% confidence intervals)] of long-term mortality were calculated using Cox models. The very elderly were more often female (60 vs. 26%) and had a higher prevalence of preserved ejection fraction (53 vs. 36%) compared with patients younger than 65 years (P< 0.001). The prevalence of cardiovascular comorbidities increased with advancing age only until the seventh decade and then declined, resulting in the lowest prevalence of diabetes (12 vs. 16%, P< 0.001), hypertension (20 vs. 26%, P< 0.001), ischaemic heart disease (42 vs. 53%, P< 0.001), and peripheral artery disease (4 vs. 6%, P= 0.017) among the very elderly compared with patients aged <85 years. Non-cardiovascular comorbidities generally increased linearly with age. Long-term mortality was associated with atrial fibrillation [HR = 1.30 (1.06-1.60), P= 0.013] with greater prognostic importance in the very elderly, while ejection fraction, diabetes [HR = 1.31 (1.01-1.61), P= 0.04], and renal insufficiency [HR = 1.36 (1.13-0.63), P< 0.0001] had less prognostic importance than in younger patients (P for interactions <0.003). CONCLUSION: The prevalence of cardiovascular comorbidities is lower in very elderly HF patients and has different prognostic importance.