Non-Cardiac Chest Pain as a Persistent Physical Symptom: Psychological Distress and Workability.

Non-Cardiac Chest Pain (NCCP) is persistent chest pain in the absence of identifiable cardiac pathology. Some NCCP cases meet criteria for Persistent Physical Symptoms (PPS), where the symptoms are both persistent and distressing/disabling. This study aimed to identify patients that might need specialist treatment for PPS by examining cases of NCCP that meet PPS criteria. We analysed data from 285 chest pain patients that had received an NCCP diagnosis after attending an emergency cardiac department. We compared NCCP patients who did and did not meet the additional criteria for heart-related PPS and hypothesised that the groups would differ in terms of psychological variables and workability. We determined that NCCP patients who meet PPS criteria were more likely than other NCCP patients to be inactive or unable to work, reported more general anxiety and anxiety about their health, were more depressed, ruminated more, and, importantly, had a higher number of other PPS. A high proportion of NCCP patients meet PPS criteria, and they are similar to other PPS patients in terms of comorbidity and disability. This highlights the importance of focusing psychological interventions for this subgroup on the interplay between the range of physical and psychological symptoms present.

[Acute myocardial infarction in young adults: incidence, risk factors and prognosis].

INTRODUCTION: The incidence of acute myocardial infarction (AMI) might not be decreasing as much among young adults as in the general population in recent years. The goal of our study was to explore incidence, risk factors and prognosis of AMI among young patients in Iceland. MATERIAL AND METHODS: This was a retrospective case control study. The data was obtained from the SCAAR-SWEDEHEART database, medical records from Landspitali University Hospital and the death register from the Directorate of Health. The epidemiology of women ≤55 years and men ≤50 years diagnosed with AMI (STEMI/NSTEMI) in Iceland in 2014-2020 was compared with older patients. RESULTS: Of all the cases (2852), 344 patients (12%) were young. No change was demonstrated in the incidence of AMI in the young patients during the study period. The proportion of STEMI was higher among young patients (52% vs. 35%, p<0.001). Smoking (50% vs. 26%, p<0.001) and obesity (BMI>30 kg/m2)(47% vs. 36%, p<0.01) were more prevalent in younger patiens compared to the older. Older patients were more likely to die in the year following the AMI, both from all-cause (7% vs. 3%, p<0.05) and cardiovascular mortality (7% vs. 3%, p<0.05). A difference in recurrent AMI between the young and older patients was not demonstrated (2% vs. 3%, p=0.3). CONCLUSION: During the research period, a change in the incidence of AMI among young patients, was not demonstrated. Younger patients with AMI have different risk factors than older patients, they have lower mortality rate but the same risk of recurrent AMI.

[Management of patients with left main stem stenosis in Iceland 2010-2020: PCI or CABG].

INTRODUCTION: Coronary artery bypass surgery (CABG) has been standard treatment for patients with left main coronary artery disease (LMCAD) but percutaneous coronary intervention (PCI) can be a good alternative. Our aim was to evaluate revascularization of LMCAD-patients in Iceland and treatment changes in recent years. We also assessed the impact of patient background factors on treatment choice and long-term survival. METHODS: This retrospective, population-based registry-study analyzed data from the SCAAR-SWEDEHEART database. Patients with significant LMCAD on coronary angiography in Iceland 2010-2020, without previous history of CABG or contraindication for surgery were enrolled. The Kaplan-Meier method was used to study long-term survival and COX-regression analysis to adjust for predictor variables. FINDINGS: Of 702 LMCAD patients, 195 were treated with PCI, 460 with CABG and 47 with medical therapy. The widest age-range was in the PCI group and the mean age was highest in the medical therapy group. Patients with LMCAD and concomitant three vessel disease or heart valve disese were mostly treated with CABG (76.1% and 84.4%). The majority of patients with LMCAD only were treated with PCI, as well as patients presenting with STEMI or in cardiogenic shock (67.1% and 70.0%). The proportion of patients treated with PCI increased from 19.8% in 2010-2015 to 42.7% in 2016-2020. There was no significant difference in survival between the PCI and CABG-groups (p=0.41). CONCLUSIONS: In patients with LMCAD the main factors determining treatment choice are age, anatomical complexity and acuteness. There has been a significant increase in LMCAD patients treated with PCI.

[Management and revascularization of diabetics with coronary artery disease in Iceland].

BACKGROUND: The incidence of diabetes is growing, and diabetics have increased risk of atherosclerosis and diffuse coronary artery disease (CAD). Our aim was to assess the revascularization treatment of diabetics with CAD in Iceland from 2010-2020, changes in management and long-term survival of patients. METHODS: All patients in Iceland with diabetes and CAD on cardiac catheterization 2010-2020 were included in this retrospective, population-based study. We analyzed data from the SCAAR/SWEDEHEART database: patients' background information, findings of cardiac catheterization, planned treatment and results. The Kaplan-Meier method was used to estimate long-term survival and Cox-regression-analysis to adjust for predictor variables. RESULTS: Of 1905 cases (1485 patients), 1230 (65%) underwent PCI, 274 (14%) CABG and 401 (21%) had medical therapy only. The age distribution differed: The PCI group had the widest age bracket, the CABG group the narrowest, and the medical therapy group had the highest mean age. Most patients with STEMI or cardiogenic shock underwent PCI, while most patients with concomitant heart-valve disease underwent CABG. The proportion of patients undergoing CABG increased with more diffuse CAD. 41% of patients with left main- and three-vessel disease underwent CABG while only 2% of those with single-vessel disease. From 2010-2020 the proportion of patients that underwent PCI increased from 49% to 72%. There was no difference in survival between the PCI and CABG groups (p=1.00). CONCLUSION: Three quarters of patients with diabetes and obstructive CAD are now treated with PCI. The PCI and CABG groups had overall equal survival but the groups had different characteristics.

[The relationship between lack of educational attainment, cardiovascular risk factors, atherosclerosis and coronary artery disease].

INTRODUCTION: Educational attainment is related to improved health and longevity. We investigated the relationship between educational attainment and cardiovascular risk factors, subclinical atherosclerosis, and incidence of coronary artery disease. MATERIAL AND METHODS: The Reykjavik REFINE study is a population-based study recruiting 6616 subjects, 25-69 years of age from the greater Reykjavik area in 2005-2011. Baseline measurements of cardiovascular risk factors were performed, and all participants had a carotid ultrasound examination to detect subclinical atherosclerotic lesions. Clinical follow-up of cardiovascular disease during a ten-year period was performed. Educational attainment was related to clinical outcome measures. RESULTS: The study population comprised of 3251 men and 3365 women. The proportion of the study population with primary school education only was 20.1%, 31.2% had vocational training, 12.3% had high school education and 36.4% were university graduates. Traditional cardiovascular risk factors were generally higher among subjects with primary school education only. Compared to subjects with university education, the odds ratio of having severe atherosclerotic plaque was 1.84 (95% CI 1.40-2.43) among those with primary school education only and 1.49 (95% CI 1.16-1.91) among subjects with vocational training. The subjects with high school or university education were less likely to develop significant cardiovascular disease during the 10-year follow-up period. CONCLUSION: Primary school and vocational training compared to university education are associated with risk factors of atherosclerotic disease, subclinical carotid plaque, and incidence of cardiovascular disease. The reason for this disparity remains to be clarified but socioeconomic inequality related to less educational attainment might be involved.

Long-term survival of Icelandic women following acute myocardial infarction.

Objective. To evaluate the impact of sex on treatment and survival after acute myocardial infarction (AMI) in Iceland. Methods. A retrospective, nationwide cohort study of patients with STEMI (2008-2018) and NSTEMI (2013-2018) and obstructive coronary artery disease. Patient and procedural information were obtained from a registry and electronic health records. Survival was estimated with Kaplan-Meier method and Cox regression analysis used to identify risk factors for long-term mortality. Excess mortality from the AMI episode was estimated by comparing the survival with age- and sex-matched population in Iceland at 30-day interval. Results. A total of 1345 STEMI-patients (24% women) and 1249 NSTEMI-patients (24% women) were evaluated. Women with STEMI (mean age: 71 ± 11 vs. 67 ± 12) and NSTEMI (mean age: 69 ± 13 vs. 62 ± 12) were older and less likely to have previous cardiovascular disease. There was neither sex difference in the extent of coronary artery disease nor treatment. Although crude one-year post-STEMI survival was lower for women (88.7% vs. 93.4%, p = .006), female sex was not an independent risk factor after adjusting for age and co-morbidities after STEMI and was protective for NSTEMI (HR 0.67, 95% CI: 0.46-0.97). There was excess 30-day mortality in both STEMI and NSTEMI for women compared with sex-, age- and inclusion year-matched Icelandic population, but thereafter the mortality rate was similar. Conclusion. Women and men with AMI in Iceland receive comparable treatment including revascularization and long-term survival appears similar. Prognosis after NSTEMI is better in women, whereas higher early mortality after STEMI may be caused by delays in presentation and diagnosis.

Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) and carotid plaque are markers of atherosclerosis and predict future coronary heart disease (CHD) events. The aim of this study was to investigate associations between CAC and carotid plaque in asymptomatic individuals, also in relation to predicted CHD-risk and incident events. A secondary aim was to compare predictive value between CAC, carotid plaque, and total carotid plaque area (TPA) as predictors for future CHD-events. METHODS: The REFINE-Reykjavik study is prospective and population-based with CAC-scoring and carotid plaque ultrasound assessment, both presence and area. A total of 948 individuals without clinical CHD were included in the study. CAC scores were categorized into 0,1-100,101-300 and > 300, and carotid plaque into none, minimal and significant. Three models were applied adjusted for age, sex, and each of the Framingham risk score (FRS), local CHD risk score and established CHD risk factors. RESULTS: Combined carotid plaque- and CAC-presence was highly prevalent, 69.5% for males and 41.7% for females (54.5% overall). TPA outperformed base models in CHD prediction, resulting in statistically significant area under the receiver operator characteristic curve (AUC) increase ranging from 0.02 to 0.05. Most CHD-events in females occurred in individuals classified as low-risk with respect to traditional risk factors but with a gradient in observed risk across carotid plaque categories. CONCLUSIONS: Carotid plaque was strongly associated with the presence and extent of CAC in asymptomatic individuals in a population-based cohort. Carotid plaque predicts incident CHD events over risk scores and may be useful for refined risk prediction in females.

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Acute gastrointestinal bleeding among patients on antiplatelet and anticoagulant therapy after percutaneous coronary intervention.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy and some require additional anticoagulation. We aimed to investigate the incidence of acute gastrointestinal bleeding (AGIB) among PCI patients receiving antiplatelet and anticoagulant therapy. METHODS: A population-based study that included all patients undergoing PCI during 2008-2016 in Iceland. Data from the Icelandic Medicines Registry were obtained on all outpatient prescriptions 1 year after first PCI. Patients receiving single or dual-antiplatelet therapy with or without anticoagulation cotherapy were analyzed. Rehospitalization for AGIB and endoscopic data were obtained within the 12-month follow-up period. RESULTS: A total of 5166 patients (male 75%) underwent PCI during the study period. The incidence of AGIB was 1% (54/5166) per year. The mean age among non-bleeders 65 (±11) years was lower than among bleeders 69 (±9) years (p = .002). The proportion of acute upper GIB (AUGIB) was 56%, whereas lower GIB occurred in 44%. Overall, 41% with AUGIB had PPIs compared to 39% of non-bleeders (NS). The incidence of AGIB among patients on single antiplatelet therapy combined with an anticoagulant was 2.5% compared to 0.9% among those on single antiplatelet treatment alone (p = .028). The number needed to harm (NNH) for treatment with single antiplatelet therapy and anticoagulant therapy compared to single antiplatelet therapy was 62 but no deaths related to AGIB. CONCLUSIONS: The 1-year incidence of AGIB was low with no mortality. Bleeding risk was found to be higher among patients on single antiplatelet therapy combined with anticoagulant therapy compared to patients on single antiplatelet therapy alone.

Copeptin is associated with mortality in elderly people.

BACKGROUND: Elevated copeptin, a marker for vasopressin release, has been associated with impaired prognosis in acute myocardial infarction (MI). The aim was to investigate whether this association extends beyond the acute phase and whether it is related to markers of stress (cortisol) and heart failure (NTproBNP). METHODS: Copeptin, cortisol and NTproBNP were measured in 926 participants (age: 76.0; male: 48.5%) in the ICELAND MI study whereof 246 had a previous MI (91 recognizable (RMI) and 155 previously unrecognizable (UMI) detected by cardiac magnetic resonance imaging). The primary endpoint was cardiovascular events (CVEs), and secondary endpoints were total mortality, heart failure and MI (median follow-up was 9.1 years). The relation between copeptin and prognosis was assessed with the Cox proportional hazard regression (unadjusted, adjusted for cortisol and NTproBNP, respectively, and a multiple model: copeptin, cortisol, NTproBNP, age, sex, serum creatinine, heart failure). RESULTS: Copeptin was higher in participants with MI (8.9 vs. 6.4 pmol/L; P < .01), with no difference between RMI vs. UMI. Increased copeptin correlated with evening cortisol (r = .11; P < .01) and NTproBNP (r = .07; P = .04). Copeptin was associated with CVE and total mortality after adjusting for cortisol and NTproBNP separately, and remained significantly associated with total mortality in the multiple model. CONCLUSIONS: Copeptin was higher in subjects with previous MI regardless whether previously recognized or not. Copeptin correlated weakly with cortisol and NTproBNP, and was independently associated with total mortality. This indicates that the prognostic implications of copeptin are not only mediated by heart failure or stress, supporting the assumption that copeptin is a marker of general vulnerability.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR.

BACKGROUND: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. METHODS: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. RESULTS: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. CONCLUSIONS: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Gastric Outlet Obstruction as the Initial Presentation of Upper Tract Urothelial Carcinoma.

GOO is often the first sign of advanced upper gastrointestinal neoplasms. The most common neoplasms associated with GOO include gastric, pancreatic, and biliary tract cancers. Urinary tract urothelial carcinoma has been a rarely documented cause of GOO.

Long-term outcomes after coronary artery bypass surgery in patients with diabetes.

OBJECTIVES: Our aim was to investigate the outcome of patients with diabetes undergoing coronary artery bypass grafting (CABG) surgery in a whole population with main focus on long-term mortality and complications. METHODS: This was a nationwide retrospective analysis of all patients who underwent isolated primary CABG in Iceland between 2001 and 2016. Overall survival together with the composite end point of major adverse cardiac and cerebrovascular events was compared between patients with diabetes and patients without diabetes during a median follow-up of 8.5 years. Multivariable regression analyses were used to evaluate the impact of diabetes on both short- and long-term outcomes. RESULTS: Of a total of 2060 patients, 356 (17%) patients had diabetes. Patients with diabetes had a higher body mass index (29.9 vs 27.9 kg/m2) and more often had hypertension (83% vs 62%) and chronic kidney disease (estimated glomerular filtration rate ≤60 ml/min/1.73 m2, 21% vs 14%). Patients with diabetes had an increased risk of operative mortality [odds ratio 2.52, 95% confidence interval (CI) 1.27-4.80] when adjusted for confounders. 5-Year overall survival (85% vs 91%, P < 0.001) and 5-year freedom from major adverse cardiac and cerebrovascular events were also inferior for patients with diabetes (77% vs 82%, P < 0.001). Cox regression analysis adjusting for potential confounders showed that the diagnosis of diabetes significantly predicted all-cause mortality [hazard ratio (HR) 1.87, 95% CI 1.53-2.29] and increased risk of major adverse cardiac and cerebrovascular events (HR 1.47, 95% CI 1.23-1.75). CONCLUSIONS: Patients with diabetes have significantly lower survival after CABG, both within 30 days and during long-term follow-up.

FLUORESCENCE LIFETIME IMAGING OPHTHALMOSCOPY (FLIO) PATTERNS IN CLINICALLY UNAFFECTED CHILDREN OF MACULAR TELANGIECTASIA TYPE 2 (MACTEL) PATIENTS.

PURPOSE: Macular telangiectasia Type 2 (MacTel) is an inherited retinal disease following an autosomal dominant pattern with late onset and reduced penetrance. Fluorescence lifetime imaging ophthalmoscopy (FLIO) enhances diagnosis by showing distinct changes in MacTel. This study investigates FLIO-associated changes in clinically unaffected family members. METHODS: Eighty-one patients with MacTel (61 ± 12 years), 33 clinically healthy children under age 40 years of these MacTel patients (MacTel-C; 31 ± 6 years), 27 other family members (children over age 40 years, siblings, and parents) and 30 controls were investigated with the Heidelberg FLIO. All subjects underwent multimodal conventional imaging, including optical coherence tomography, blue-light reflectance, fluorescein angiography, and macular pigment imaging. RESULTS: All 81 patients with MacTel showed typical FLIO patterns. Of the 33 investigated MacTel-C with completely normal eye examinations and conventional imaging, 12 (36%) show FLIO patterns consistent with early MacTel. CONCLUSION: Prolonged FLIO lifetimes in the parafoveal area within the short spectral channel, especially temporally, are MacTel-specific. Fluorescence lifetime imaging ophthalmoscopy detects these lifetime patterns in over one-third of clinically unaffected MacTel-C. Although further studies will be necessary to determine the specificity of FLIO, it may help diagnose MacTel before conventional imaging modalities show changes or patients experience visual disturbances. Early detection may facilitate future gene discovery studies and interventional trials.

The prognostic effect of known and newly detected type 2 diabetes in patients with acute coronary syndrome.

BACKGROUND: Dysglycemia is a well-established risk factor of coronary artery disease. Less is known of the prognostic effect of dysglycemia in acute coronary syndromes (ACSs). The aim of this study was to evaluate the long-term outcome of patients with ACSs according to glucometabolic categories. METHODS: Patients with ACSs were consecutively included in the study. Among those with no previous history of type 2 diabetes (T2DM) glucose metabolism was evaluated with fasting glucose in plasma, glycated hemoglobin and a standard 2-h oral glucose tolerance test. Patients were classified having normal glucose metabolism, prediabetes, newly detected T2DM (nT2DM) and previously known T2DM (kT2DM). The clinical outcome parameters were death or myocardial infarction and other major adverse cardiac events (MACEs). RESULTS: A total of 372 ACS patients (male 75.8%, 65.1 years (SD: 11.8)) constituted the study population. The proportion diagnosed with normal glucose metabolism, prediabetes, nT2DM and kT2DM was 20.7%, 46.5%, 6.2% and 26.6%, respectively. The mean follow-up period was 2.9 years. Patients with prediabetes, nT2DM and kT2DM had a hazard ratio of 5.8 (95% confidence interval (CI) 0.8-44.6), 10.9 (95% CI 1.2-98.3) and 14.9 (95% CI 2.0-113.7), respectively, for death/myocardial infarction and 1.4 (95% CI 0.6-3.1), 2.9 (95% CI 1.1-8.0) and 3.3 (95% CI 1.5-7.6), respectively, for a composite of MACEs. CONCLUSION: Patients with ACS and nT2DM or kT2DM were at increased risk of death/myocardial infarction and MACE compared with patients with normal glucose metabolism after approximately three years of follow-up.

Association of Genetically Predicted Lipid Levels With the Extent of Coronary Atherosclerosis in Icelandic Adults.

Importance: Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary atherosclerosis. Objective: To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis. Design, Setting, and Participants: This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait. Exposures: Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides. Main Outcomes and Measures: The extent of angiographic CAD and coronary artery calcium quantity. Results: A total of 12 460 adults (mean [SD] age, 65.1 [10.7] years; 8383 men [67.3%]) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) was associated with greater odds of obstructive CAD (odds ratio [OR], 1.83 [95% CI, 1.63-2.07]; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 [95% CI, 1.11-1.44]; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 [95% CI, 1.26-1.72]; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 [95% CI, 1.70-2.44]; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 [95% CI, 0.53-0.87]; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol. Conclusions and Relevance: In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.

Sequence variants with large effects on cardiac electrophysiology and disease.

Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease.

Nature of Cardiac Rehabilitation Around the Globe.

BACKGROUND: Cardiac rehabilitation (CR) is a clinically-effective but complex model of care. The purpose of this study was to characterize the nature of CR programs around the world, in relation to guideline recommendations, and compare this by World Health Organization (WHO) region. METHODS: In this cross-sectional study, a piloted survey was administered online to CR programs globally. Cardiac associations and local champions facilitated program identification. Quality (benchmark of ≥ 75% of programs in a given country meeting each of 20 indicators) was ranked. Results were compared by WHO region using generalized linear mixed models. FINDINGS: 111/203 (54.7%) countries in the world offer CR; data were collected in 93 (83.8%; N = 1082 surveys, 32.1% program response rate). The most commonly-accepted indications were: myocardial infarction (n = 832, 97.4%), percutaneous coronary intervention (n = 820, 96.1%; 0.10), and coronary artery bypass surgery (n = 817, 95.8%). Most programs were led by physicians (n = 680; 69.1%). The most common CR providers (mean = 5.9 ±â€¯2.8/program) were: nurses (n = 816, 88.1%; low in Africa, p < 0.001), dietitians (n = 739, 80.2%), and physiotherapists (n = 733, 79.3%). The most commonly-offered core components (mean = 8.7 ±â€¯1.9 program) were: initial assessment (n = 939, 98.8%; most commonly for hypertension, tobacco, and physical inactivity), risk factor management (n = 928, 98.2%), patient education (n = 895, 96.9%), and exercise (n = 898, 94.3%; lower in Western Pacific, p < 0.01). All regions met ≥ 16/20 quality indicators, but quality was < 75% for tobacco cessation and return-to-work counseling (lower in Americas, p = < 0.05). INTERPRETATION: This first-ever survey of CR around the globe suggests CR quality is high. However, there is significant regional variation, which could impact patient outcomes.

Cardiac Rehabilitation Availability and Density around the Globe.

BACKGROUND: Despite the epidemic of cardiovascular disease and the benefits of cardiac rehabilitation (CR), availability is known to be insufficient, although this is not quantified. This study ascertained CR availability, volumes and its drivers, and density. METHODS: A survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Factors associated with volumes were assessed using generalized linear mixed models, and compared by World Health Organization region. Density (i.e. annual ischemic heart disease [IHD] incidence estimate from Global Burden of Disease study divided by national CR capacity) was computed. FINDINGS: CR was available in 111/203 (54.7%) countries; data were collected in 93 (83.8% country response; N = 1082 surveys, 32.1% program response rate). Availability by region ranged from 80.7% of countries in Europe, to 17.0% in Africa (p < .001). There were 5753 programs globally that could serve 1,655,083 patients/year, despite an estimated 20,279,651 incident IHD cases globally/year. Volume was significantly greater where patients were systematically referred (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.35-1.38) and programs offered alternative models (OR = 1.05, 95%CI = 1.04-1.06), and significantly lower with private (OR = .92, 95%CI = .91-.93) or public (OR = .83, 95%CI = .82-84) funding compared to hybrid sources.Median capacity (i.e., number of patients a program could serve annually) was 246/program (Q25-Q75 = 150-390). The absolute density was one CR spot per 11 IHD cases in countries with CR, and 12 globally. INTERPRETATION: CR is available in only half of countries globally. Where offered, capacity is grossly insufficient, such that most patients will not derive the benefits associated with participation.