Phenotype clustering of hospitalized high-risk patients with COVID-19 - a machine learning approach within the multicentre, multinational PCHF-COVICAV registry.

IMTRODUCTION: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV). MATERIAL AND METHODS: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm). RESULTS: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk. CONCLUSIONS: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Heart disease in pregnancy and risk of pre-eclampsia: a Swedish register-based study.

BACKGROUND AND AIMS: Pre-eclampsia complicates 3-5% of pregnancies worldwide and is associated with adverse outcomes for the mother and the offspring. Pre-eclampsia and heart failure have common risk factors, including hypertension, obesity and diabetes. It is not known whether heart failure increases the risk of pre-eclampsia. This study examines whether pregestational heart failure increases the risk of pre-eclampsia. METHODS: In a registry-based case-cohort study that included all pregnancies in Sweden (n=3 125 527) between 1990 and 2019, all pregnancies with pre-eclampsia (n=90 354) were identified and up to five control pregnancies (n=451 466) for each case were chosen, matched on the mother's birth year. Multiple logistic regression analysis was used to evaluate the impact of heart failure on the risk of pre-eclampsia, with adjustment for established risk factors and other cardiovascular diseases. RESULTS: Women with heart failure had no increased risk for pre-eclampsia, OR 1.02 (95% CI 0.69 to 1.50). Women with valvular heart disease had an increased OR of preterm pre-eclampsia, with an adjusted OR of 1.78 (95% CI 1.04 to 3.06). Hypertension and diabetes were independent risk factors for pre-eclampsia. Obesity, multifetal pregnancies, in vitro fertilisation, older age, Nordic origin and nulliparity were more common among women who developed pre-eclampsia compared with controls. CONCLUSION: Women with heart failure do not have an increased risk of pre-eclampsia. However, women with valvular heart disease prior to pregnancy have an increased risk of developing preterm pre-eclampsia independent of other known risk factors.

Heart failure outcomes in low-risk patients with atrial fibrillation: a case-control study of 680 523 Swedish individuals.

AIMS: Knowledge of long-term outcomes in patients with atrial fibrillation (AF) remains limited. We sought to evaluate the risk of new-onset heart failure (HF) in patients with AF and a low cardiovascular risk profile. METHODS AND RESULTS: Data from the Swedish National Patient Register were used to identify all patients with a first-time diagnosis of AF without underlying cardiovascular disease at baseline between 1987 and 2018. Each patient was compared with two controls without AF from the National Total Population Register. In total, 227 811 patients and 452 712 controls were included. During a mean follow-up of 9.1 (standard deviation 7.0) years, the hazard ratio (HR) for new-onset HF was 3.55 [95% confidence interval (CI) 3.51-3.60] in patients compared with controls. Women with AF (18-34 years) had HR for HF onset 24.6 (95% CI 7.59-80.0) and men HR 9.86 (95% CI 6.81-14.27). The highest risk was within 1 year in patients 18-34 years, HR 103.9 (95% CI 46.3-233.1). The incidence rate within 1 year increased from 6.2 (95% CI 4.5-8.6) per 1000 person-years in young patients (18-34 years) to 142.8 (95% CI 139.4-146.3) per 1000 person-years among older patients (>80 years). CONCLUSIONS: Patients studied had a three-fold higher risk of developing HF compared with controls. Young patients, particularly women, carry up to 100-fold increased risk to develop HF within 1 year after AF. Further studies in patients with AF and low cardiovascular risk profile are needed to prevent serious complications such as HF.

Hyperkalaemia as a cause of undertreatment with mineralocorticoid receptor antagonists in heart failure.

AIMS: To determine the incidence of hyperkalaemia in patients with heart failure with reduced ejection fraction (HFrEF) during up-titration of guideline-directed medical therapy (GDMT) in real-world settings. METHODS: A retrospective review of medical records of all patients hospitalized for newly onset HFrEF at Sahlgrenska University Hospital, Sweden, between 1 January 2016 and 31 December 2019. Based on mineralocorticoid receptor antagonist (MRA) treatment within the first 6 months, patients were divided into four groups: (i) never received MRA, (ii) needed MRA dose reduction, (iii) needed discontinuation of MRA, and (iv) stable MRA treatment. Potassium levels were assessed at baseline and has the highest potassium level during the 6 months of up-titration. RESULTS: Of 3456 patients hospitalized for heart failure, 630 (18%) were eligible (68.4% men, 66.8 years, mean EF of 29.4%). After up-titration of GDMT 48.4% of patients received MRAs. Patients without MRA treatment were older (P < 0.0001), had lower EF (P = 0.022), had higher NTproBNP (P = 0.017), had lower eGFR (P = 0.001), and were more often treated with angiotensin receptor inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitors (all P < 0.0001). In overall study population, hyperkalaemia increased from 5.9 to 24.4% after 6 months of up-titration of GDMT (P < 0.0001). Among four groups, the incidence of hyperkalaemia throughout up-titration of GDMT increased from 6.8 to 54.5% in patients with dose reduction of MRA, from 8.8 to 50.9% in those with discontinuation of MRA, from 5 to 10% in patients with stable MRA treatment, and from 6 to 28% in patients who were MRA naive (all P < 0.0001). In the MRA-naive group, normokalaemia/hypokalaemia occurred in 87.5% at baseline, and after 6 months of up-titration of GDMT, normokalaemia/hypokalaemia remained in 47.8%, whereas mild, moderate, and severe hyperkalaemia occurred in 22.4%, 5.7%, and 0.9%, respectively. CONCLUSIONS: Hyperkalaemia increased significantly during up-titration of GDMT but with varying magnitudes in different clinical phenotypes, which might explain why physicians refrain from prescribing MRAs to patients with HFrEF.

Treatment response in recent-onset heart failure with reduced ejection fraction: non-ischaemic vs. ischaemic aetiology.

AIMS: In heart failure (HF) with reduced left ventricular ejection fraction (HFrEF), the prognosis appears better in non-ischaemic than in ischaemic aetiology. Infrequent diagnostic work-up for ischaemic heart disease (IHD) in HF is reported. In this study, we compared short-term response to initiated guideline-directed medical treatment (GDMT) in recent-onset HFrEF of non-ischaemic (non-IHF) vs. ischaemic (IHF) aetiology and evaluated the frequency of coronary investigation. METHODS AND RESULTS: Patients hospitalized with recent-onset HFrEF [left ventricular ejection fraction (LVEF) < 40%] between 1 January 2016 and 31 December 2019 were included. Treatment response was determined by use of a hierarchical clinical composite outcome classifying each patient as worsened, improved, or unchanged based on hard outcomes (mortality, heart transplantation, and HF hospitalization) and soft outcomes (± ≥10 unit change in LVEF, ± ≥30% change in N-terminal pro-B-type natriuretic peptide, and ± ≥1 point change in New York Heart Association functional class) during 28 weeks of follow-up. The associations between baseline characteristics and composite changes were analysed with multiple logistic regression. Among the 364 patients analysed, 47 were not investigated for IHD. Comparing non-IHF (n = 203) vs. IHF (n = 114), patients were younger (mean age 61.0 vs. 69.4 years, P < 0.001) with lower mean LVEF (26% vs. 31%, P < 0.001), but with similar male predominance (70.4% vs. 75.4%, P = 0.363). For non-IHF vs. IHF, the composite outcomes were worsened (19.1% vs. 43.9%, P < 0.001) and improved (74.2% vs. 43.9%, P < 0.001). After multivariable adjustments, IHF was associated with increased odds for worsening [odds ratio (OR) 2.94; 95% confidence interval (CI) 1.51-5.74; P = 0.002] and decreased odds for improvement (OR 0.35; 95% CI 0.18-0.65; P < 0.001). In cases without previous IHD or new-onset myocardial infarction (n = 261), a decision for coronary investigation was made in 69.0%. CONCLUSIONS: In recent-onset HFrEF, patients with non-IHF responded better to GDMT than patients with IHF. Almost one-third of patients selected for follow-up at HF clinics were never investigated for IHD.

Trends in survival of Swedish men and women with heart failure from 1987 to 2014: a population-based case-control study.

AIMS: To compare trends in short-term and long-term survival of patients with heart failure (HF) compared with controls from the general population. METHODS AND RESULTS: We used data from the Swedish National Inpatient Registry to identify all patients aged ≥18 years with a first recorded diagnosis of HF between 1 January 1987 and 31 December 2014 and compared them with controls matched on age and sex from the Total Population Register. We included 702 485 patients with HF and 1 306 183 controls. In patients with HF aged 18-64 years, short-term (29 days to 6 months) and long-term mortality (>11 years) decreased from 166 and 76.6 per 1000 person-years in 1987 to 2000 to 99.6 and 49.4 per 1000 person-years, respectively, in 2001 to 2014. During the same period, mortality improved marginally, in those aged ≥65 years: short-time mortality from 368.8 to 326.2 per 1000 person-years and long-term mortality from 219.6 to 193.9 per 1000 person-years. In 1987-2000, patients aged <65 years had more than three times higher risk of dying at 29 days to 6 months, with an hazard ratio (HR) of 3.66 [95% confidence interval (CI) 3.46-3.87], compared with controls (P < 0.0001) but substantially higher in 2001-2014 with an HR of 11.3 (95% CI 9.99-12.7, P < 0.0001). HRs for long-term mortality (6-10 and >11 years) increased moderately from 2.49 (95% CI 2.41-2.57) and 3.16 (95% CI 3.07-3.24) in 1987-2000 to 4.35 (95% CI 4.09-4.63) and 4.11 (95% CI 3.49-4.85) in 2001-2014, largely because survival among controls improved more than that among patients with HF (P < 0.0001). CONCLUSIONS: Absolute survival improved in HF patients aged <65 years, but only marginally so in those aged ≥65 years. Compared with controls, both short-term and long-term relative risk of dying increased, especially in younger patients with HF.

Increased arterial stiffness and reduced left ventricular long-axis function in patients recovered from peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is idiopathic pregnancy-associated heart failure (HF) with reduced left ventricular ejection fraction (LVEF). We aimed to assess arterial stiffness and left ventricular (LV) function in women recovered from PPCM compared with controls. METHODS: Twenty-two PPCM patients were compared with 15 age-matched controls with previous uncomplicated pregnancies. Eleven of the patients were at inclusion in the study recovered and off medication since at least 6 months and still free from cardiovascular symptoms with normal LVEF and normal NT-proBNP. All underwent echocardiography, including LV strain, left atrial (LA) reservoir strain and tissue Doppler early diastolic velocity (e´) and non-invasive assessment for arterial stiffness and central aortic systolic blood pressure (AoBP) at rest and immediately postexercise. RESULTS: The patients off medication showed alterations compared with controls. AoBP was higher (120 ± 9 mm Hg vs. 104 ± 13 mm Hg; p = .001), a difference which persisted postexercise. The arterial elastance was higher (1.9 ± 0.4 mm Hg/ml vs. 1.3 ± 0.2 mm Hg/ml; p < .001), while there were lower e´ septal (8.9 ± 1.7 cm/s vs. 11.0 ± 1.1 cm/s; p = 0. 002), LV global strain (18.7 ± 3.9% vs. 23.1 ± 1.6%; p = .004) and LA reservoir strain (24.8 ± 9.1% vs. 37.7 ± 6.3%; p = .002). CONCLUSIONS: Compared with healthy controls, PPCM patients considered recovered and off medication had increased arterial stiffness, decreased LV longitudinal function and reduced LA function.

Young patients with heart failure: clinical characteristics and outcomes. Data from the Swedish Heart Failure, National Patient, Population and Cause of Death Registers.

AIMS: The prevalence and hospitalizations of patients with heart failure (HF) aged <55 years have increased in Sweden during the last decades. We aimed to compare characteristics of younger and older patients with HF, and examine survival in patients <55 years compared with matched controls. METHODS AND RESULTS: All patients ≥18 years in the Swedish Heart Failure Register from 2003 to 2014 were included. Data were merged with National Patient and Cause of Death Registers. Among 60 962 patients, 3752 (6.2%) were <55 years, and were compared with 7425 controls from the Population Register. Compared with patients ≥55 years, patients <55 years more frequently had registered diagnoses of obesity, dilated cardiomyopathy, congenital heart disease, and an ejection fraction <40% (9.8% vs. 4.7%, 27.2% vs. 5.5%, 3.7% vs. 0.8%, 67.9% vs. 45.1%, respectively; all P < 0.001). One-year all-cause mortality was 21.2%, 4.2%, and 0.3% in patients ≥55 years, patients <55 years, and controls <55 years, respectively (all P < 0.001). Patients <55 years had a five times higher mortality risk compared with controls [hazard ratio (HR) 5.48, 95% confidence interval (CI) 4.45-6.74]; the highest HR was in patients 18-34 years (HR 38.3, 95% CI 8.70-169; both P < 0.001). At the age of 20, the estimated life-years lost was up to 36 years for 50% of patients, with declining estimates with increasing age. CONCLUSION: Patients with HF <55 years had different comorbidities than patients ≥55 years. The highest mortality risk relative to that of controls was among the youngest patients.

Prevalence and risk factors of aortic stenosis and aortic sclerosis: a 21-year follow-up of middle-aged men.

Introduction. There is limited knowledge about factors associated with the development of aortic stenosis. This study aimed to examine the prevalence of aortic sclerosis or stenosis in 71-years-old men and determine which risk factors at 50 years of age predict the development of aortic sclerosis or aortic stenosis. Methods. A random sample of Swedish men from the general population, born in 1943 (n = 798) were followed for 21 years. Data on clinical characteristics and laboratory values were collected in 1993. An echocardiography was performed in 2014. We used logistic regression to examine the association between baseline data and the outcome. Results. Echocardiography was performed in 535 men, and aortic sclerosis or aortic stenosis was diagnosed in 27 (5.0%). 14 persons developed aortic stenosis (2.6%). Among men with aortic sclerosis or aortic stenosis, 29.6% were obese. In multivariable stepwise regression model, body mass index (odds ratio per unit increase 1.23 (95% CI 1.10-1.38; p = .0003)) and hypercholesterolemia, combined with high sensitive C-reactive protein (odds ratio versus all other 2.66 (1.18-6.00; p = .019)) were significantly associated with increased risk of developing aortic sclerosis or aortic stenosis. Body mass index was the only factor significantly associated with a higher risk of developing aortic stenosis. Conclusion. The prevalence of either aortic sclerosis or aortic stenosis was 5% and of aortic stenosis 2.6%. Obesity and hypercholesterolemia combined with elevated high sensitive C-reactive protein at the age of 50 predicted the development of degenerative aortic sclerosis or stenosis, whilst only obesity was correlated with the occurrence of aortic stenosis.

High validity of cardiomyopathy diagnoses in western Sweden (1989-2009).

AIM: Hospital discharges with a diagnosis of cardiomyopathy have more than doubled in Sweden since 1987. We validated the cardiomyopathy diagnoses over this time period to investigate that the increase was real and not a result of improved recognition of the diagnosis and better diagnostic methods. METHODS AND RESULTS: Every fifth year from 1989 to 2009, records for all patients with a cardiomyopathy diagnosis were identified by searching the local registers in three hospitals in Västra Götaland, Sweden. The diagnoses were validated according to criteria defined by the European Society of Cardiology from 2008. The population comprised 611 cases with cardiomyopathy diagnoses [mean age 58.9 (SD 15.5) years, 68.2% male], divided into three major groups: dilated, hypertrophic, and other cardiomyopathies. Hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy were analysed as a group. Cardiomyopathies for which there were few cases, such as restrictive, arrhythmogenic right ventricular, left ventricular non-compaction, takotsubo, and peripartum cardiomyopathies, were analysed together and defined as 'other cardiomyopathies'. Relevant co-morbidities were registered. The use of echocardiography was 99.7%, of which 94.6% was complete echocardiography reports. The accuracy rates of the diagnoses dilated cardiomyopathy, hypertrophic cardiomyopathy, and other cardiomyopathies were 85.5%, 87.5%, and 100%, respectively, with no differences between the three hospitals or years studied; nor did the prevalence of co-morbidities differ. CONCLUSIONS: The accuracy rate of the cardiomyopathy diagnoses from in-hospital records from >600 patients in western Sweden during a 20 year period was 86.6%, with no significant trend over time, strengthening epidemiological findings that this is likely due to an actual increase in cardiomyopathy diagnoses rather than changes in coding practices. The use of echocardiography was high, and there was no significant difference in co-morbidities during the study period. The accuracy rate of the cardiomyopathy diagnoses during the 20 year period was high. The use of diagnostic tools did not increase under the study period, and once cardiomyopathy diagnoses were suspected, echocardiography was performed in almost all cases. In this study, the occurrence of cardiomyopathy was increasing over time without significant increase of co-morbidity, supporting that an actual increase of cardiomyopathy has occurred.