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Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome.
Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.
Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).
Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.
Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.
Background: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined.
Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Results: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1% to 1.0%), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).
Conclusions: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)
Mutations in blood stem cells do not necessarily have to result in leukaemia. It was only recently discovered that clones of mutated blood cells can be identified in many healthy people in old age. Nonetheless, clonal haematopoiesis, as scientists baptised this finding, is far from innocent. It is a formidable risk factor for cardiovascular diseases – on par with smoking, excess weight or high blood pressure. Why this is, is still a riddle to be solved.
Background: Patients with chronic kidney disease (CKD) have considerable cardiovascular morbidity and mortality. Aortic stiffness is an independent predictor of cardiovascular risk and related to left ventricular remodeling and heart failure. Myocardial fibrosis is the pathophysiological hallmark of the failing heart.
Methods and results: An observational study of consecutive CKD patients (n = 276) undergoing comprehensive clinical cardiovascular magnetic resonance imaging. The relationship between aortic stiffness, myocardial fibrosis, left ventricular remodeling and the severity of chronic kidney disease was examined. Compared to age-gender matched controls with no known kidney disease (n = 242), CKD patients had considerably higher myocardial native T1 and central aortic PWV (p ≪ 0.001), as well as abnormal diastolic relaxation by E/e′ (mean) by echocardiography (p ≪ 0.01). A third of all patients had LGE, with similar proportions for the presence and the (ischaemic and non-ischaemic) pattern between the groups. PWV was strongly associated with and age, NT-proBNP and native T1 in both groups, but not with LGE presence or type; the associations were amplified in severe CKD stages. In multivariate analyses, PWV was independently associated with native T1 in both groups (p ≪ 0.01) with near two-fold increase in adjusted R2 in the presence of CKD (native T1 (10 ms) R2, B(95%CI) CKD vs. non-CKD 0.28, 0.2(0.15–0.25) vs. 0.18, 0.1(0.06–0.15), p ≪ 0.01).
Conclusions: Aortic stiffness and interstitial myocardial fibrosis are interrelated; this association is accelerated in the presence of CKD, but independent of LGE. Our findings reiterate the significant contribution of CKD-related factors to the pathophysiology of cardiovascular remodeling.
Mutationen in Blutstammzellen müssen nicht unbedingt zu Blutkrebs führen. Erst vor Kurzem hat man entdeckt, dass Klone mutierter Blutzellen bei vielen gesunden Menschen im Alter nachweisbar sind. Dennoch stufen Forscher die klonale Hämatopoese inzwischen als Risikofaktor für Herz-Kreislauf-Erkrankungen ein – mit einer ähnlichen Bedeutung wie Rauchen, Übergewicht oder Bluthochdruck.
Bone marrow and plasma FGF‐23 in heart failure patients : novel insights into the heart–bone axis
(2019)
Aims: Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients.
Methods and results: We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF‐23‐BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF‐23‐BM levels were significantly higher than FGF‐23‐P levels in both CHF patients and in healthy controls (P < 0.001). FGF‐23‐P and FGF‐23‐BM correlated significantly with LVEF (r = −0.37 and r = −0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = −0.43 and r = −0.41, respectively) (P for all <0.001) and were independently associated with all‐cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18–6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19–6.57], P = 0.018, respectively.
Conclusions: In CHF patients, FGF‐23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all‐cause mortality. The failing heart seems to interact via FGF‐23 within a heart–bone axis.
Background. Transcatheter aortic valve implantation (TAVI) is currently recommended for patients with severe aortic stenosis at intermediate or high surgical risk. The decision process during TAVI evaluation includes a thorough benefit-risk assessment, and knowledge about long-term benefits and outcomes may improve patients’ expectation management. Objective. To evaluate patients’ perceived health status and self-reported long-term outcome more than 5 years after TAVI. Methods and Results. Demographic and procedure data were obtained from all patients treated with TAVI at our institution from 2006 to 2012. A cross-sectional survey was conducted on the patients alive, measuring health status, including the EQ-5D-5L questionnaire, and clinical outcomes. 103 patients (22.8%) were alive at a median follow-up period of 7 years (5.4–9.8). 99 (96%) of the 103 patients were included in the final analysis. The mean age at follow-up was 86.5 years ± 8.0 years, and 56.6% were female. Almost all patients (93.9%) described an improvement of their quality of life after receiving TAVI. At late follow-up, the mean utility index and EQ-VAS score were 0.80 ± 0.20 and 58.49 ± 11.49, respectively. Mobility was found to be the most frequently reported limitation (85.4%), while anxiety/depression was the least frequently reported limitation (19.8%). With respect to functional class, 64.7% were in New York Heart Association (NYHA) class III or IV, compared to 67.0% prior to TAVI (p = 0.51). Self-reported long-term outcomes revealed mainly low long-term complication rates. 74 total hospitalizations were reported after TAVI, and among those 43% for cardiovascular reasons. Within cardiovascular rehospitalizations, new pacemaker implantations were the most frequently reported (18.9%), followed by cardiac decompensation and coronary heart disease (15.6%). Conclusion. The majority of the patients described an improvement of health status after TAVI. More than five years after TAVI, the patients’ perceived health status was satisfactory, and the incidence of clinical events and hospitalizations was very low.
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies.
Despite advances in the medical and interventional clinical management of patients, cardiovascular diseases (CVDs) remain the leading cause of death worldwide. It is well appreciated that atherosclerosis represents the underlying cause of most CVDs [1]. Atherosclerosis is a chronic inflammatory disease that leads to the formation of atheromatous lesions in the vessel associated with increased recruitment, adhesion, and proliferation of different leukocyte subsets to the endothelium [1]. Several cardiovascular risk factors (CRFs) have been found to enhance the risk of CVD (Figure 1), including hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking [2]. Inflammation plays a crucial role in the development of CVDs and several studies have reported that CRFs enhance production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow and in this way may promote atherosclerosis and disease development [3].