Preconception counselling in women of reproductive age attending cardiology clinics in Scotland.

BACKGROUND: Guidelines for the management of cardiovascular disease (CVD) recommend preconception risk stratification and counselling in all women of childbearing age. We assessed the provision of preconception counselling (PCC) among women of reproductive age attending general cardiology outpatient clinics over a 12-month period in two large health boards in Scotland. METHODS AND RESULTS: Electronic health records were reviewed and data on patient demographics, cardiac diagnoses, medication use and the content of documented discussions regarding PCC were recorded. Women were classified according to the modified WHO (mWHO) risk stratification system. Among 1650 women with a cardiac diagnosis included (1 January 2016-31 December 2016), the mean age was 32.7±8.6 years, and 1574 (95.4%) attended a consultant-led clinic. A quarter (402, 24.4%) were prescribed at least one potentially fetotoxic cardiovascular medication. PCC was documented in 10.3% of women who were not pregnant or were unable to conceive at the time of review (159/1548). The distribution of mWHO classification, and proportion of patients within each mWHO category who received any form of PCC, was 15.0% and 6.0% in mWHO class I, 20.2% and 8.7% in mWHO class II, 22.6% and 10.6% in mWHO class II-III, 9.5% and 15.7% in mWHO class III and 3.9% and 19.7% in mWHO class IV. CONCLUSION: PCC is documented infrequently in women of reproductive age with CVD in the general outpatient setting. Education relating to the risks of cardiac disease in pregnancy for clinicians and patients, and tools to support healthcare providers in delivering PCC, is important.

A novel score to predict left ventricular recovery in peripartum cardiomyopathy derived from the ESC EORP Peripartum Cardiomyopathy Registry.

BACKGROUND AND AIMS: There are no established clinical tools to predict left ventricular (LV) recovery in women with peripartum cardiomyopathy (PPCM). Using data from women enrolled in the ESC EORP PPCM Registry, the aim was to derive a prognostic model to predict LV recovery at 6 months and develop the 'ESC EORP PPCM Recovery Score'-a tool for clinicians to estimate the probability of LV recovery. METHODS: From 2012 to 2018, 752 women from 51 countries were enrolled. Eligibility included (i) a peripartum state, (ii) signs or symptoms of heart failure, (iii) LV ejection fraction (LVEF) ≤ 45%, and (iv) exclusion of alternative causes of heart failure. The model was derived using data from participants in the Registry and internally validated using bootstrap methods. The outcome was LV recovery (LVEF ≥50%) at six months. An integer score was created. RESULTS: Overall, 465 women had a 6-month echocardiogram. LV recovery occurred in 216 (46.5%). The final model included baseline LVEF, baseline LV end diastolic diameter, human development index (a summary measure of a country's social and economic development), duration of symptoms, QRS duration and pre-eclampsia. The model was well-calibrated and had good discriminatory ability (C-statistic 0.79, 95% confidence interval [CI] 0.74-0.83). The model was internally validated (optimism-corrected C-statistic 0.78, 95% CI 0.73-0.82). CONCLUSIONS: A model which accurately predicts LV recovery at 6 months in women with PPCM was derived. The corresponding ESC EORP PPCM Recovery Score can be easily applied in clinical practice to predict the probability of LV recovery for an individual in order to guide tailored counselling and treatment.

Outcomes at one year in women with peripartum cardiomyopathy: Findings from the ESC EORP PPCM Registry.

AIMS: There are few prospective reports of 1-year outcomes for women with peripartum cardiomyopathy (PPCM). We report findings from the European Society of Cardiology EURObservational Research Programme PPCM Registry. METHODS AND RESULTS: The registry enrolled women from 51 countries from 2012 to 2018. Eligibility included: (i) a peripartum state, (ii) signs or symptoms of heart failure, (iii) left ventricular (LV) ejection fraction ≤45%, (iv) exclusion of alternative causes of heart failure. We report mortality, thromboembolism, stroke, rehospitalization, LV recovery and remodelling at 1 year. Differences between regions were compared. One-year mortality data were available in 535 (71%) women and follow-up differed across regions. At 1 year, death from any cause occurred in 8.4% of women, with regional variation (Europe 4.9%, Africa 6.5%, Asia-Pacific 9.2%, Middle East 18.9%; p < 0.001). The frequencies of thromboembolism and stroke were 6.3% and 2.5%, respectively, and were similar across regions. A total of 14.0% of women had at least one rehospitalization and 3.5% had recurrent rehospitalizations (i.e. two or more). Overall, 66.1% of women had recovery of LV function (22% between 6 months and 1 year), with a mean LV ejection fraction increase from baseline of 21.2% (±13.6). Recovery occurred most frequently in Asia-Pacific (77.5%) and least frequently in the Middle East (32.7%). There were significant regional differences in the use of heart failure pharmacotherapies. CONCLUSIONS: Approximately 1 in 12 women with PPCM had died by 1 year and thromboembolism and stroke occurred in 6.3% and 2.5%, respectively. Around 1 in 7 women had been rehospitalized and, in 1 in 3, LV recovery had not occurred. PPCM is associated with substantial mortality and morbidity globally.

Socio-economic factors determine maternal and neonatal outcomes in women with peripartum cardiomyopathy: A study of the ESC EORP PPCM registry.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes. METHODS: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI]). RESULTS: 739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of diagnosis. However, baseline LV ejection fraction did not differ according to sociodemographic factors. Countries with low HE prescribed guideline-directed heart failure therapy less frequently. Six-month mortality was higher in countries with low HE; and LV non-recovery in those with low HDI, low HE and lower levels of education. Maternal outcome (death, re-hospitalization, or persistent LV dysfunction) was independently associated with income. Neonatal death was significantly more common in countries with low HE and low HDI, but was not influenced by maternal income or education attainment. CONCLUSIONS: Maternal and neonatal outcomes depend on country-specific socioeconomic characteristics. Attempts should therefore be made to allocate adequate resources to health and education, to improve maternal and fetal outcomes in PPCM.

Effects of the First Year of the COVID-19 Pandemic on Utilization of Emergency Medical Services in Maryland.

BACKGROUND: The opioid epidemic in the United States has devastated the lives of individuals and imposed decades-long opportunity costs on the community. METHODS: We analyzed Emergency Medical Services (EMS) data from the Maryland Department of Health installation of the Electronic Surveillance System for Early Notification of Community-Based Epidemics (ESSENCE) to assess the impact of COVID-19 on EMS call volume and how COVID-19 impacted patients' decisions whether to accept transport to a hospital following an EMS call. RESULTS: The rate of patients accepting transportation via EMS to a hospital emergency department (ED) declined for both opioid-related and non-opioid-related calls from prepandemic (before April 2020) to mid-pandemic (mid-March 2020 to mid-April 2020). The opioid-related call volume increased more from pre- to mid-pandemic for male patients than for female patients, and this "gender gap" had not returned to prepandemic levels by April 2021. CONCLUSION: Consistent with reports from other states, the pandemic worsened the opioid crisis in Maryland, impacting some populations more than others while also decreasing the likelihood that individuals experiencing an opioid-related overdose would seek further medical care following an EMS call.

A 20-year population study of peripartum cardiomyopathy.

BACKGROUND AND AIMS: The epidemiology of peripartum cardiomyopathy (PPCM) in Europe is poorly understood and data on long-term outcomes are lacking. A retrospective, observational, population-level study of validated cases of PPCM in Scotland from 1998 to 2017 was conducted. METHODS: Women hospitalized with presumed de novo left ventricular systolic dysfunction around the time of pregnancy and no clear alternative cause were included. Each case was matched to 10 controls. Incidence and risk factors were identified. Morbidity and mortality were examined in mothers and children. RESULTS: The incidence of PPCM was 1 in 4950 deliveries. Among 225 women with PPCM, obesity, gestational hypertensive disorders, and multi-gestation were found to be associated with having the condition. Over a median of 8.3 years (9.7 years for echocardiographic outcomes), 8% of women with PPCM died and 75% were rehospitalized for any cause at least once. Mortality and rehospitalization rates in women with PPCM were ∼12- and ∼3-times that of controls, respectively. The composite of all-cause death, mechanical circulatory support, or cardiac transplantation occurred in 14%. LV recovery occurred in 76% and, of those who recovered, 13% went on to have a decline in LV systolic function despite initial recovery. The mortality rate for children born to women with PPCM was ∼5-times that of children born to controls and they had an ∼3-times greater incidence of cardiovascular disease over a median of 8.8 years. CONCLUSIONS: PPCM affected 1 in 4950 women around the time of pregnancy. The condition is associated with considerable morbidity and mortality for the mother and child. There should be a low threshold for investigating at-risk women. Long term follow-up, despite apparent recovery, should be considered.

Proteomic Profiling in Patients With Peripartum Cardiomyopathy: A Biomarker Study of the ESC EORP PPCM Registry.

BACKGROUND: Peripartum cardiomyopathy (PPCM) remains an important cause of maternal morbidity and mortality globally. The pathophysiology remains incompletely understood, and the diagnosis is often missed or delayed. OBJECTIVES: This study explored the serum proteome profile of patients with newly diagnosed PPCM, as compared with matched healthy postpartum mothers, to unravel novel protein biomarkers that would further an understanding of the pathogenesis of PPCM and improve diagnostic precision. METHODS: Study investigators performed untargeted serum proteome profiling using data-independent acquisition-based label-free quantitative liquid chromatography-tandem mass spectrometry on 84 patients with PPCM, as compared with 29 postpartum healthy controls (HCs). Significant changes in protein intensities were determined with nonpaired Student's t-tests and were further classified by using the Boruta algorithm. The proteins' diagnostic performance was evaluated by area under the curve (AUC) and validated using the 10-fold cross-validation. RESULTS: Patients with PPCM presented with a mean left ventricular ejection fraction of 33.5% ± 9.3% vs 57.0% ± 8.8% in HCs (P < 0.001). Study investigators identified 15 differentially up-regulated and 14 down-regulated proteins in patients with PPCM compared with HCs. Seven of these proteins were recognized as significant by the Boruta algorithm. The combination of adiponectin, quiescin sulfhydryl oxidase 1, inter-α-trypsin inhibitor heavy chain, and N-terminal pro-B-type natriuretic peptide had the best diagnostic precision (AUC: 0.90; 95% CI: 0.84-0.96) to distinguish patients with PPCM from HCs. CONCLUSIONS: Salient biologic themes related to immune response proteins, inflammation, fibrosis, angiogenesis, apoptosis, and coagulation were predominant in patients with PPCM compared with HCs. These newly identified proteins warrant further evaluation to establish their role in the pathogenesis of PPCM and potential use as diagnostic markers.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKß deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Declining risk of heart failure hospitalization following first acute myocardial infarction in Scotland between 1991-2016.

AIM: Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapies have improved. In light of these competing influences, we examined long-term trends in the risk of HF hospitalization (HFH) following a first AMI occurring in Scotland over 25 years. METHODS AND RESULTS: All patients in Scotland discharged alive after a first AMI between 1991 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow-up 1 year, maximum 26 years). A total of 175 672 people with no prior history of HF were discharged alive after a first AMI during the period of study. A total of 21 445 (12.2%) patients had a first HFH during a median follow-up of 6.7 years. Incidence of HFH (per 1000 person-years) at 1 year following discharge from a first AMI decreased from 59.3 (95% confidence interval [CI] 54.2-64.7) in 1991 to 31.3 (95% CI 27.3-35.8) in 2015, with consistent trends seen for HF occurring within 5 and 10 years. Accounting for the competing risk of death, the adjusted risk of HFH at 1 year after discharge decreased by 53% (95% CI 45-60%), with similar decreases at 5 and 10 years. CONCLUSION: The incidence of HFH following AMI in Scotland has decreased since 1991. These trends suggest that better treatment of AMI and secondary prevention are having an impact on the risk of HF at a population level.

Apparent Treatment-Resistant Hypertension Across the Spectrum of Heart Failure Phenotypes in the Swedish HF Registry.

BACKGROUND: Hypertension is common in patients with heart failure (HF), but less is known about resistant hypertension. OBJECTIVES: This study sought to investigate apparent treatment-resistant hypertension (aTRH) in patients with HF in the SwedeHF (Swedish Heart Failure Registry), across the spectrum of HF phenotypes (heart failure with reduced ejection fraction [HFrEF], heart failure with mildly reduced ejection fraction [HFmrEF], and heart failure with preserved ejection fraction [HFpEF]). METHODS: aTRH was defined as systolic blood pressure ≥140 mm Hg (≥135 mm Hg in diabetes) despite treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or sacubitril-valsartan, as well as a calcium-channel blocker and a diuretic; non-treatment-resistant hypertension (TRH) was defined as systolic blood pressure above these thresholds but not on the 3-drug combination; and normal blood pressure was defined as under these thresholds. In each left ventricular ejection fraction (LVEF) category, patient factors associated with aTRH and non-TRH and outcomes (HF hospitalization and cardiovascular death composite, its components, and all-cause death) according to hypertension category were examined. RESULTS: Among 46,597 patients, aTRH was present in 2,693 (10%), 1,514 (14%), and 1,450 (17%) patients with HFrEF, HFmrEF, and HFpEF, respectively. Older age, obesity, diabetes, and kidney disease were associated with a greater likelihood of aTRH and non-TRH (vs normal blood pressure). Associations were generally similar irrespective of LVEF category. Compared with normal blood pressure, aTRH was associated with a lower adjusted risk of the composite outcome in HFrEF and HFmrEF (HR: 0.79 [95% CI: 0.74-0.85] and HR: 0.86 [95% CI: 0.77-0.96]) but not in HFpEF (HR: 0.93 [95% CI: 0.84-1.04]). CONCLUSIONS: aTRH was most common in HFpEF and least common in HFrEF. Associated patient characteristics were similar irrespective of LVEF category. aTRH (vs normal blood pressure) was associated with a lower risk of first HF hospitalization or cardiovascular death in HFrEF and HFmrEF but not in HFpEF.

Clinical Outcomes Related to Background Diuretic Use and New Diuretic Initiation in Patients With HFrEF.

BACKGROUND: Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them. OBJECTIVES: The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started. METHODS: Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined. RESULTS: At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P < 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P < 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002). CONCLUSIONS: Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials.

BACKGROUND: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. METHODS: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. RESULTS: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. CONCLUSIONS: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

CX3CL1 Action on Microglia Protects from Diet-Induced Obesity by Restoring POMC Neuronal Excitability and Melanocortin System Activity Impaired by High-Fat Diet Feeding.

Both hypothalamic microglial inflammation and melanocortin pathway dysfunction contribute to diet-induced obesity (DIO) pathogenesis. Previous studies involving models of altered microglial signaling demonstrate altered DIO susceptibility with corresponding POMC neuron cytological changes, suggesting a link between microglia and the melanocortin system. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling to protect against DIO. We performed metabolic analyses in high fat diet (HFD)-fed mice with targeted viral overexpression of CX3CL1 in the hypothalamus. Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. Hypothalamic overexpression of CX3CL1 increased leptin sensitivity and POMC gene expression, while reducing weight gain in animals fed an HFD. In electrophysiological recordings from hypothalamic slice preparations, HFD feeding was associated with reduced POMC neuron excitability and increased amplitude of inhibitory postsynaptic currents. Microglial silencing using minocycline or CX3CL1 treatment reversed these HFD-induced changes in POMC neuron electrophysiologic properties. Correspondingly, blockade of melanocortin receptor signaling in vivo prevented both the acute and chronic reduction in food intake and body weight mediated by CX3CL1. Our results show that suppressing microglial activation during HFD feeding reduces DIO susceptibility via a mechanism involving increased POMC neuron excitability and melanocortin signaling.

COVID-19 Vaccine Provider Access and Vaccination Coverage Among Children Aged 5-11 Years - United States, November 2021-January 2022.

On October 29, 2021, the Pfizer-BioNTech pediatric COVID-19 vaccine received Emergency Use Authorization for children aged 5-11 years in the United States.† For a successful immunization program, both access to and uptake of the vaccine are needed. Fifteen million doses were initially made available to pediatric providers to ensure the broadest possible access for the estimated 28 million eligible children aged 5-11 years, especially those in high social vulnerability index (SVI)§ communities. Initial supply was strategically distributed to maximize vaccination opportunities for U.S. children aged 5-11 years. COVID-19 vaccination coverage among persons aged 12-17 years has lagged (1), and vaccine confidence has been identified as a concern among parents and caregivers (2). Therefore, COVID-19 provider access and early vaccination coverage among children aged 5-11 years in high and low SVI communities were examined during November 1, 2021-January 18, 2022. As of November 29, 2021 (4 weeks after program launch), 38,732 providers were enrolled, and 92% of U.S. children aged 5-11 years lived within 5 miles of an active provider. As of January 18, 2022 (11 weeks after program launch), 39,786 providers had administered 13.3 million doses. First dose coverage at 4 weeks after launch was 15.0% (10.5% and 17.5% in high and low SVI areas, respectively; rate ratio [RR] = 0.68; 95% CI = 0.60-0.78), and at 11 weeks was 27.7% (21.2% and 29.0% in high and low SVI areas, respectively; RR = 0.76; 95% CI = 0.68-0.84). Overall series completion at 11 weeks after launch was 19.1% (13.7% and 21.7% in high and low SVI areas, respectively; RR = 0.67; 95% CI = 0.58-0.77). Pharmacies administered 46.4% of doses to this age group, including 48.7% of doses in high SVI areas and 44.4% in low SVI areas. Although COVID-19 vaccination coverage rates were low, particularly in high SVI areas, first dose coverage improved over time. Additional outreach is critical, especially in high SVI areas, to improve vaccine confidence and increase coverage rates among children aged 5-11 years.

Diabetes and pre-diabetes in patients with heart failure and preserved ejection fraction.

AIM: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF. METHODS AND RESULTS: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre-diabetes, 6.0%-6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre-diabetes. Compared to patients with normal HbA1c, patients with pre-diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT-proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35-1.88), total HFH (RR 1.67, 95% CI 1.39-2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07-1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre-diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00-1.60) and HFH (HR 1.35, 95% CI 1.03-1.77), but not of CV death (HR 1.02, 95% CI 0.75-1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with 'lean diabetes' had similar mortality rates to those with a higher body mass index, but lower rates of HFH. CONCLUSION: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920711.

Effect of sacubitril/valsartan on investigator-reported ventricular arrhythmias in PARADIGM-HF.

AIMS: Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias. METHODS AND RESULTS: Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65-0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020). CONCLUSIONS: Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology.

Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction.

AIMS: Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan. METHODS AND RESULTS: In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89). CONCLUSION: Sacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA. CLINICAL TRIAL REGISTRATION: PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.