Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure.

Ageing is a major risk factor for the development of cardiovascular disease (CVD) and cancer. Whilst the cumulative effect of exposure to conventional cardiovascular risk factors is important, recent evidence highlights clonal haematopoiesis of indeterminant potential (CHIP) as a further key risk factor. CHIP reflects the accumulation of somatic, potentially pro-leukaemic gene mutations within haematopoietic stem cells over time. The most common mutations associated with CHIP and CVD occur in genes that also play central roles in the regulation of inflammation. While CHIP carriers have a low risk of haematological malignant transformation (<1% per year), their relative risk of mortality is increased by 40% and this reflects an excess of cardiovascular events. Evidence linking CHIP, inflammation and atherosclerotic disease has recently become better defined. However, there is a paucity of information about the role of CHIP in the development and progression of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). While systemic inflammation plays a role in the pathophysiology of both heart failure with reduced and preserved ejection fraction (EF), it may be of greater relevance in the pathophysiology of HFpEF, which is also strongly associated with ageing. This review describes CHIP and its pathogenetic links with ageing, inflammation and CVD, while providing insight into its putative role in HFpEF.

Adverse Outcomes Associated With Interleukin-6 in Patients Recently Hospitalized for Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Inflammation may play a role in the pathophysiology of heart failure with preserved ejection fraction. We examined whether circulating levels of interleukin-6 identify patients at greater risk of adverse outcomes following hospitalization with heart failure with preserved ejection fraction. METHODS: We assessed relationships between interleukin-6 (IL-6) tertiles (T1-3) and all-cause death, cardiovascular death, and subsequent heart failure hospitalization (sHFH) in 286 patients recently hospitalized with heart failure with preserved ejection fraction. Associations between IL (interleukin)-6 and outcomes were examined in a Cox-regression model adjusted for risk factors including BNP (B-type natriuretic peptide). Biomarkers including hsCRP (high-sensitivity C-reactive protein) were assessed. RESULTS: The range of IL-6 (pg/mL) in each tertile was T1 (0.71-4.16), T2 (4.20-7.84), and T3 (7.9-236.32). Compared with T1, patients in the highest IL-6 tertile were more commonly male (56% versus 35%) and had higher creatinine (117±45 versus 101±36 µmol/L), hsCRP (11.6 [4.9-26.6]mg/L versus 2.3[1.1-4.2] mg/L). In univariable analysis, rates of all-cause death, cardiovascular death, and sHFH were higher in T3 versus T1. All-cause and cardiovascular death rates remained higher in T3 versus T1 after adjustment (P<0.001). One log unit increase in IL-6 was associated with higher risk of all-cause death (hazard ratio, 1.46 [1.17-1.81]), cardiovascular death (hazard ratio, 1.40 [1.10-1.77]), and sHFH (hazard ratio, 1.24 [1.01-1.51]) after adjustment. One log unit increase in hsCRP was associated with a higher risk of cardiovascular death and all-cause death before and after adjustment for other factors but was not associated with risk of sHFH before or after adjustment. CONCLUSIONS: In patients recently hospitalized with heart failure with preserved ejection fraction, IL-6 is an independent predictor of all-cause mortality, cardiovascular death, and sHFH after adjustment for risk factors including BNP. These findings are of particular relevance in the context of current anti-IL-6 drug development.

Reference Ranges for NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) and Risk Factors for Higher NT-proBNP Concentrations in a Large General Population Cohort.

BACKGROUND: Demographic differences in expected NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration are not well established. We aimed to establish reference ranges for NT-proBNP and explore the determinants of moderately elevated NT-proBNP under the universal definition of heart failure criteria. METHODS: This is a cross-sectional study. NT-proBNP was measured in serum from 18 356 individuals without previous cardiovascular disease in the Generation Scotland Scottish Family Health Study. Age- and sex-stratified medians and 97.5th centiles were generated. Sex stratified risk factors for moderately elevated NT-proBNP (≥125 pg/mL) were investigated. RESULTS: In males, median (97.5th centile) NT-proBNP concentration at age <30 years was 21 (104) pg/mL, rising to 38 (195) pg/ml at 50 to 59 years, and 281 (6792) pg/mL at ≥80 years. In females, median NT-proBNP at age <30 years was 51 (196) pg/mL, 66 (299) pg/mL at 50 to 59 years, and 240 (2704) pg/mL at ≥80 years. At age <30 years, 9.8% of females and 1.4% of males had elevated NT-proBNP, rising to 76.5% and 81.0%, respectively, at age ≥80 years. After adjusting for risk factors, an NT-proBNP ≥125 pg/mL was more common in females than males (OR, 9.48 [95% CI, 5.60-16.1]). Older age and smoking were more strongly associated with elevated NT-proBNP in males than in females (Psex interaction <0.001, 0.07, respectively). Diabetes was inversely associated with odds of elevated NT-proBNP in females only (Psex interaction=0.007). CONCLUSIONS: An NT-proBNP ≥125 pg/mL is common in females without classical cardiovascular risk factors as well as older people. If NT-proBNP becomes widely used for screening in the general population, interpretation of NT-proBNP levels will require that age and sex-specific thresholds are used to identify patients with potential pathophysiology.

Impact of Chronic Obstructive Pulmonary Disease in Patients With Heart Failure With Preserved Ejection Fraction: Insights From PARAGON-HF.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P<0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P<0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P<0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 µmol/L versus 96 µmol/L) and neutrophil-to-lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25-1.83), total heart failure hospitalization 1.54 (95% CI, 1.24-1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10-1.82), and all-cause death (adjusted HR, 1.52; 95% CI, 1.25-1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex-Specific Criteria.

Background Sex-specific criteria are recommended for the diagnosis of myocardial infarction, but the impact of these on presenting characteristics is unknown. Methods and Results We evaluated patient-reported symptoms in 1941 patients (39% women) with suspected acute coronary syndrome attending the emergency department in a substudy of a prospective trial. Standardized criteria defined typical and atypical presentations based on pain nature, location, radiation, and additional symptoms. Diagnosis of myocardial infarction was adjudicated using a high-sensitivity cardiac troponin I assay with sex-specific thresholds (>16 ng/L women, >34 ng/L men). Patients identified who were missed by the contemporary assay with a uniform threshold (≥50 ng/L) were reclassified by this approach. Type 1 myocardial infarction was diagnosed in 16% (184/1185) of men and 12% (90/756) of women, with 9 (5%) men and 27 (30%) women reclassified using high-sensitivity cardiac troponin I and sex-specific thresholds. Chest pain was the presenting symptom in 91% (1081/1185) of men and 92% (698/756) of women. Typical symptoms were more common in women than in men with myocardial infarction (77% [69/90] versus 59% [109/184]; P=0.007), and differences were similar in those reclassified (74% [20/27] versus 44% [4/9]; P=0.22). The presence of ≥3 typical features was associated with a positive likelihood ratio for the diagnosis of myocardial infarction in women (positive likelihood ratio, 1.18; 95% CI, 1.03-1.31) but not in men (positive likelihood ratio 1.09; 95% CI, 0.96-1.24). Conclusions Typical symptoms are more common and have greater predictive value in women than in men with myocardial infarction whether or not they are diagnosed using sex-specific criteria. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier NCT01852123.