Mads E. Jørgensen

Atlas of the clinical genetics of human dilated cardiomyopathy

AIM Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSION This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

Association of β-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing noncardiac surgery: a Danish nationwide cohort study.

IMPORTANCE Clinical guidelines have been criticized for encouraging the use of β-blockers in noncardiac surgery despite weak evidence. Relevant clinical trials have been small and have not convincingly demonstrated an effect of β-blockers on hard end points (ie, perioperative myocardial infarction, ischemic stroke, cardiovascular death, and all-cause death). OBJECTIVE To assess the association of β-blocker treatment with major cardiovascular adverse events (MACE) and all-cause mortality in patients with ischemic heart disease undergoing noncardiac surgery. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Individuals with ischemic heart disease with or without heart failure (HF) and with and without a history of myocardial infarction undergoing noncardiac surgery between October 24, 2004, and December 31, 2009, were identified from nationwide Danish registries. Adjusted Cox regression models were used to calculate the 30-day risks of MACE (ischemic stroke, myocardial infarction, or cardiovascular death) and all-cause mortality associated with β-blocker therapy. MAIN OUTCOMES AND MEASURES Thirty-day risk of MACE and all-cause mortality. RESULTS Of 28,263 patients with ischemic heart disease undergoing surgery, 7990 (28.3%) had HF and 20,273 (71.7%) did not. β-Blockers were used in 4262 (53.3%) with and 7419 (36.6%) without HF. Overall, use of β-blockers was associated with a hazard ratio (HR) of 0.90 (95% CI, 0.79-1.02) for MACE and 0.95 (0.85-1.06) for all-cause mortality. Among patients with HF, use of β-blockers was associated with a significantly lower risk of MACE (HR, 0.75; 95% CI, 0.70-0.87) and all-cause mortality (0.80; 0.70-0.92), whereas among patients without HF, there was no significant association of β-blocker use with MACE (1.11; 0.92-1.33) or mortality (1.15; 0.98-1.35) (P < .001 for interactions). Among patients without HF, β-blockers were also associated with a lowered risk among those with a recent myocardial infarction (<2 years), with HRs of 0.54 (95% CI, 0.37-0.78) for MACE and 0.80 (0.53-1.21) for all-cause mortality (P < .02 for interactions between β-blockers and time period after myocardial infarction), but with no significant association in the remaining patients. Results were similar in propensity score-matched analyses. CONCLUSIONS AND RELEVANCE Among patients with ischemic heart disease undergoing noncardiac surgery, use of β-blockers was associated with lower risk of 30-day MACE and mortality only among those with HF or recent myocardial infarction.

Time Elapsed After Ischemic Stroke and Risk of Adverse Cardiovascular Events and Mortality Following Elective Noncardiac Surgery

IMPORTANCE The timing of surgery in patients with recent ischemic stroke is an important and inadequately addressed issue. OBJECTIVE To assess the safety and importance of time elapsed between stroke and surgery in the risk of perioperative cardiovascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS Danish nationwide cohort study (2005-2011) including all patients aged 20 years or older undergoing elective noncardiac surgeries (n=481,183 surgeries). EXPOSURES Time elapsed between stroke and surgery in categories and as a continuous measure. MAIN OUTCOMES AND MEASURES Risk of major adverse cardiovascular events (MACE; including ischemic stroke, acute myocardial infarction, and cardiovascular mortality) and all-cause mortality up to 30 days after surgery. Odds ratios (ORs) were calculated by multivariable logistic regression models. RESULTS Crude incidence rates of MACE among patients with (n = 7137) and without (n = 474,046) prior stroke were 54.4 (95% CI, 49.1-59.9) vs 4.1 (95% CI, 3.9-4.2) per 1000 patients. Compared with patients without stroke, ORs for MACE were 14.23 (95% CI, 11.61-17.45) for stroke less than 3 months prior to surgery, 4.85 (95% CI, 3.32-7.08) for stroke 3 to less than 6 months prior, 3.04 (95% CI, 2.13-4.34) for stroke 6 to less than 12 months prior, and 2.47 (95% CI, 2.07-2.95) for stroke 12 months or more prior. MACE risks were at least as high for low-risk (OR, 9.96; 95% CI, 5.49-18.07 for stroke <3 months) and intermediate-risk (OR, 17.12; 95% CI, 13.68-21.42 for stroke <3 months) surgery compared with high-risk surgery (OR, 2.97; 95% CI, 0.98-9.01 for stroke <3 months) (P = .003 for interaction). Similar patterns were found for 30-day mortality: ORs were 3.07 (95% CI, 2.30-4.09) for stroke less than 3 months prior, 1.97 (95% CI, 1.22-3.19) for stroke 3 to less than 6 months prior, 1.45 (95% CI, 0.95-2.20) for stroke 6 to less than 12 months prior, and 1.46 (95% CI, 1.21-1.77) for stroke 12 months or more prior to surgery compared with patients without stroke. Cubic regression splines performed on the stroke subgroup supported that risk leveled off after 9 months. CONCLUSIONS AND RELEVANCE A history of stroke was associated with adverse outcomes following surgery, in particular if time between stroke and surgery was less than 9 months. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke. The time dependency of risk may warrant attention in future guidelines.

Cost-effectiveness of Intensive Blood Pressure Management

Importance Among high-risk patients with hypertension, targeting a systolic blood pressure of 120 mm Hg reduces cardiovascular morbidity and mortality compared with a higher target. However, intensive blood pressure management incurs additional costs from treatment and from adverse events. Objective To evaluate the incremental cost-effectiveness of intensive blood pressure management compared with standard management. Design, Setting, and Participants This cost-effectiveness analysis conducted from September 2015 to August 2016 used a Markov cohort model to estimate cost-effectiveness of intensive blood pressure management among 68-year-old high-risk adults with hypertension but not diabetes. We used the Systolic Blood Pressure Intervention Trial (SPRINT) to estimate treatment effects and adverse event rates. We used Centers for Disease Control and Prevention Life Tables to project age- and cause-specific mortality, calibrated to rates reported in SPRINT. We also used population-based observational data to model development of heart failure, myocardial infarction, stroke, and subsequent mortality. Costs were based on published sources, Medicare data, and the National Inpatient Sample. Interventions Treatment of hypertension to a systolic blood pressure goal of 120 mm Hg (intensive management) or 140 mm Hg (standard management). Main Outcomes and Measures Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results Standard management yielded 9.6 QALYs and accrued

Age-Specific Performance of the Revised Cardiac Risk Index for Predicting Cardiovascular Risk in Elective Noncardiac Surgery

155 261 in lifetime costs, while intensive management yielded 10.5 QALYs and accrued

Danish trends in pharmacotherapy, comorbidities, and demographics in patients referred for coronary angiography - what changed during a decade?

176 584 in costs. Intensive blood pressure management cost

Association between serum bilirubin and cardiovascular disease in an overweight high risk population from the SCOUT trial

23 777 per QALY gained. In a sensitivity analysis, serious adverse events would need to occur at 3 times the rate observed in SPRINT and be 3 times more common in the intensive management arm to prefer standard management. Conclusions and Relevance Intensive blood pressure management is cost-effective at typical thresholds for value in health care and remains so even with substantially higher adverse event rates.

Noncardiac surgery in patients with aortic stenosis: a contemporary study on outcomes in a matched sample from the Danish health care system.

Background— The revised cardiac risk index (RCRI) holds a central role in preoperative cardiac risk stratification in noncardiac surgery. Its performance in unselected populations, including different age groups, has, however, not been systematically investigated. We assessed the relationship of RCRI with major adverse cardiovascular events in an unselected cohort of patients undergoing elective, noncardiac surgery overall and in different age groups. Methods and Results— We followed up all individuals ≥25 years who underwent major elective noncardiac surgery in Denmark (January 1, 2005, to November 30, 2011) for the 30-day risk of major adverse cardiovascular events (ischemic stroke, myocardial infarction, or cardiovascular death). There were 742 of 357 396 (0.2%), 755 of 74 889 (1.0%), 521 of 11 921 (4%), and 257 of 3146 (8%) major adverse cardiovascular events occurring in RCRI classes I, II, III, and IV. Multivariable odds ratio estimates were as follows: ischemic heart disease 3.30 (95% confidence interval, 2.96–3.69), high-risk surgery 2.70 (2.46–2.96), congestive heart failure 2.65 (2.29–3.06), cerebrovascular disease 10.02 (9.08–11.05), insulin therapy 1.62 (1.37–1.93), and kidney disease 1.45 (1.33–1.59). Modeling RCRI classes as a continuous variable, C statistic was highest among age group 56 to 65 years (0.772) and lowest for those aged >85 years (0.683). Sensitivity of RCRI class >I (ie, having ≥1 risk factor) for capturing major adverse cardiovascular events was 59%, 71%, 64%, 66%, and 67% in patients aged ⩽55, 56 to 65, 66 to 75, 76 to 85, and >85 years, respectively; the negative predictive values were >98% across all age groups. Conclusions— In a nationwide unselected cohort, the performance of the RCRI was similar to that of the original cohort. Having ≥1 risk factor was of moderate sensitivity, but high negative predictive value for all ages.

Perioperative stroke: a question of timing?

AIMS Coronary angiography holds a central role in the diagnosis of coronary heart disease. We studied temporal trends in referral patterns 2000-09. METHODS AND RESULTS We identified 156 496 first-time coronary angiographies in 2000-09 in nationwide registries. Trends were analyzed in 2-year intervals. Numbers of acute (5943-10 707) and elective (17 294-25 550) procedures increased between 2000-01 and 2008-09. Mean age increased from 61.8 to 63.9 years (P < 0.001) and the proportion of females increased from 33 to 37% (P < 0.001). An increase in the number of patients with prior chronic heart failure (2866 vs. 3197), cerebrovascular disease (1790 vs. 2906), diabetes (2527 vs. 4593), and arrhythmias (2985 vs. 4733) was observed. The proportion of acute patients examined the same day as hospitalized increased from 56.6 to 83.1%. Odds ratios (95% confidence interval) for treatment with statins [3.42(3.27;3.57)], RAS-inhibitors [1.85(1.77;1.93)], and acetylsalicylic acid [1.43(1.37;1.49)] at the time of coronary angiography increased towards 2008-09. Elective patients received medical treatment more often than acute patients (P < 0.001). CONCLUSION During a 10-year period, there was an increase in the mean age of patients and the proportion of female patients, and a 56% increase in number of coronary angiographies performed. The use of prophylactic cardiovascular drugs among these high-risk patients increased during our study period.

Noncardiac surgery in patients with aortic stenosis

BACKGROUND AND AIMS An inverse relationship between (serum) total bilirubin and risk of cardiovascular disease has been reported previously, but longitudinal data on overweight and obese patients are lacking. We have investigated the relationship between total bilirubin and cardiovascular adverse events in a large group of patients with risk factors for cardiovascular disease who were enrolled in a large weight loss trial. METHODS AND RESULTS Data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial, including almost 10.000 overweight/obese high cardiovascular risk patients, were used. The relationship between total bilirubin level at screening and the primary outcome (i.e. non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death) for the entire study period was investigated using Cox proportional hazards models. The population was divided into four groups based on total bilirubin levels (normal range 5-25 μmol/L). Time-dependent Cox analyses were also performed to adjust for weight loss over time. Initial analyses adjusted for sex, age and treatment allocation showed significantly reduced hazard ratios of 0.80 (95% confidence interval 0.68-0.94), 0.73 (0.62-0.86) and 0.77 (0.65-0.91), for the three higher total bilirubin groups: >8 and ≤10 μmol/L, >10 and ≤13 μmol/L and >13 μmol/L (5-95 interpercentile range for total bilirubin at screening; 6-19 μmol/L), compared to the lowest total bilirubin group ≤8 μmol/L. When adjusting for classical cardiovascular risk factors, estimates increased towards unity. Additional adjustment for indicators of liver function did not alter the results. A time-dependent Cox model, adjusted for weight loss, demonstrated a similar trend. CONCLUSION Bilirubin was not a risk-factor independent from other traditional cardiovascular risk-factors in our population.