European Journal of Preventive Cardiology

Cardiac rehabilitation (CR) improves the symptoms, exercise capacity and quality of life of chronic heart failure (CHF) patients. Its effects on new plasma biomarkers of prognostic importance are unknown. The present study aimed at analysing the effects of a structured CR programme on plasma cardiac biomarkers in a large population of patients with CHF and reduced left ventricular ejection fraction (LVEF).

We enrolled 107 consecutive CHF patients with LVEF ≤ 45% in an ambulatory CR programme. Peak VO₂ and plasma levels of Galectin-3, mid-regional proANP (MR-proADM), soluble suppressor of tumorigenicity 2 (sST2) and mid-regional pro-adrenomedullin (MR-proANP) were assessed at inclusion and at the end of CR. Twenty-four unenrolled patients were managed with standard medical care and evaluated over the same period (no-CR group).

Galectin-3, sST2, MR-proADM and MR-proANP plasma levels decreased after CR, with respective median reductions of 6.3% for Galectin 3 (p < 0.001), 7.4% for sST2 (p = 0.036), 6.4% for MR-proADM (p = 0.001) and 16% for MR-proANP (p < 0.001). MR-proADM was negatively correlated with peak VO₂ (ρ = −0.529, 95% confidence interval [CI] −0.654 to −0.375, p < 0.001), and so were their relative variations along the course of CR (ρ = −0.357, 95% CI –0.518 to −0.172, p < 0.001). No change occurred in terms of biomarkers in the no-CR group.

Plasma cardiac biomarkers such as Galectin-3, MR-proADM, sST2 and MR-proANP all decreased after CR in CHF patients, suggesting an overall improvement in the neuro-hormonal profile.

Extracellular matrix degrading proteases and their regulators play an important role in atherogenesis and subsequent plaque rupture leading to acute cardiovascular manifestations.

In this prospective cohort study, we investigated the prognostic value of circulating matrix metalloproteinase-8, tissue inhibitor of matrix metalloproteinase-1 concentrations, the ratio of matrix metalloproteinase-8/ tissue inhibitor of matrix metalloproteinase-1 and, for comparison, myeloperoxidase and C-reactive protein concentrations for incident cardiovascular disease endpoints. The population-based FINRISK97 cohort comprised 7928 persons without cardiovascular disease at baseline. The baseline survey included a clinical examination and blood sampling. During a 13-year follow-up the endpoints were ascertained through national healthcare registers. The associations of measured biomarkers with the endpoints, including cardiovascular disease event, coronary artery disease, acute myocardial infarction, stroke and all-cause death, were analysed using Cox regression models. Discrimination and reclassification models were used to evaluate the clinical implications of the biomarkers.

Serum tissue inhibitor of matrix metalloproteinase-1 and C-reactive protein concentrations were associated significantly with increased risk for all studied endpoints. Additionally, matrix metalloproteinase-8 concentration was associated with the risk for a coronary artery disease event, myocardial infarction and death, and myeloperoxidase concentration with the risk for cardiovascular disease events, stroke and death. The only significant association for the matrix metalloproteinase-8/ tissue inhibitor of matrix metalloproteinase-1 ratio was observed with the risk for myocardial infarction. Adding tissue inhibitor of matrix metalloproteinase-1 to the established risk profile improved risk discrimination of myocardial infarction (p=0.039) and death (0.001). Both matrix metalloproteinase-8 (5.2%, p < 0.001) and tissue inhibitor of matrix metalloproteinase-1 (12.9%, p < 0.001) provided significant clinical net reclassification improvement for death.

Serum matrix metalloproteinase-8 and tissue inhibitor of matrix metalloproteinase-1 can be considered as biomarkers of incident cardiovascular disease events and death.

Acute coronary syndrome is associated with platelet hyperactivity, which in its persistent form, promotes recurrent thrombotic events. Complex cardiac rehabilitation after acute coronary syndrome improves clinical outcome; however, its effect on platelet hyperactivity is unknown.

We enrolled 84 acute coronary syndrome patients on dual antiplatelet therapy, who underwent a new complex cardiac rehabilitation programme (NovaCord physiotherapy, lifestyle counselling, strict diet, stress management and regular coaching) and 51 control acute coronary syndrome patients with traditional cardiac rehabilitation. Platelet functionality was determined at enrolment and at three months follow-up by aggregometry, serum platelet-derived growth factor levels, total- and platelet-derived microvesicle counts (PMV; CD41a+/CD61+, CD62P+).

Platelet aggregation parameters and platelet-derived growth factor levels were significantly decreased in the complex cardiac rehabilitation group at three months (1 µg/ml collagen, median (interquartile range): 22 (10–45) vs 14 (7.5–25.5)%, p = 0.0015; 2 µg/ml collagen: 36 (22–60) vs 26.5 (16–37)%, p = 0.0019; 1.25 µM adenosine-diphosphate: 4.5 (1–10) vs 1 (0–3)%, p = 0.0006; 5 µM adenosine-diphosphate: 27 (16–38) vs 22 (12–31)%, p = 0.0078; epinephrine: 33 (15–57) vs 27 (12–43)%, p = 0.01; platelet-derived growth factor: 434.6 (256.0–622.7) vs 224.8 (148.5–374.1) pg/ml, p = 0.0001). In contrast, these changes were absent or did not reach statistical significance in the traditional cardiac rehabilitation group. Platelet–derived microvesicle counts were significantly decreased in both groups, while total microvesicle count was significantly reduced only in the complex cardiac rehabilitation group (median (interquartile range): 3945.5 (2138–5661) vs 1739 (780–2303) count/µl; p = 0.0001).

Platelet hyperactivity three months after acute coronary syndrome significantly decreased in patients undergoing complex cardiac rehabilitation. Besides dual antiplatelet therapy, effective management and comprehensive control of cardiovascular risk factors might represent a new, non-pharmacological approach to influence platelet functionality.

Extracellular matrix remodelling may influence atherosclerotic progression and plaque stability. We hypothesized that evaluation of extracellular matrix markers, with potentially different roles during atherogenesis, could provide information on underlying mechanisms and risk of myocardial infarction (MI) in apparently healthy individuals.

We conducted a case–control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women, free of known cardiovascular disease, were followed for a first MI. During 11.3 years of follow-up, 1587 incident MIs were registered, and these cases were compared with 3959 age- and sex-matched controls. Circulating levels of the ECM proteins CD147 (ECM metalloproteinase inducer; EMMPRIN), cartilage oligomeric matrix protein (COMP: thrombospondin-5) and YKL-40 (chitinase-3-like-1) were measured by enzyme immunoassays.

We found an inverse association between COMP (quartile (Q) 4 vs. Q1: hazard ratio 0.81 (95% confidence interval: 0.67–0.98)) and YKL-40 (Q4 vs. Q1: hazard ratio 0.77 (0.62–0.95)) with incidence of MI after full multivariable adjustment. Serum CD147 was not associated with MI risk in adjusted analysis.

High levels of COMP and YKL-40 were associated with lower risk of incident MI, suggesting a potential beneficial role in promoting plaque stability in individuals without incident cardiovascular disease.

Chronic kidney disease (CKD) is associated with the development and progression of coronary heart disease (CHD), in addition to classic cardiovascular risk factors. We analysed the prevalence of CKD in CHD patients from 24 European countries in the ambulatory setting and in a preceding hospital stay for CHD (index).

A total of 7998 EUROASPIRE IV participants (median 65 years of age, 76% male) attended a study visit 6–36 months after the index hospitalisation. CKD was classified according to stages of estimated glomerular filtration rate (eGFR) and albuminuria (urinary albumin/creatinine ratio). In stable CHD conditions (study visit), 17.3% had CKD (eGFR <60 mL/min/1.73 m²) with variation among participating countries (range 13.1–26.4%). A further 12% presented with preserved eGFR but significant albuminuria. During the hospital stay due to a coronary event, impaired kidney function was observed in 17.6% (range 7.5–38.2%). Risk factors for impaired kidney function included older age, female gender, classic cardiovascular (CV) risk factors, details of CHD history and congestive heart failure (multivariate regression). Of all patients, 38.9% had declined, 31.3% were stable and 29.8% had improved kidney function between hospital discharge and the study visit, dependent on age, gender, CV risk factors, CHD history and cardiac dysfunction (multivariate regression).

Every fifth CHD patient had CKD, while every tenth exhibited albuminuria as the sole indicator of kidney damage. These subjects are at increased risk of progression of CKD and CHD complications. After hospital stays due to CHD, there is potential of recovery of kidney function, but our findings underline the importance of identifying patients who are at high risk of developing CKD in order to counteract disease progression.

To explore the predictive and explanatory factors on the incidence of cardiovascular disease and the impact of visit-to-visit variability (VVV) of risk factors on incident cardiovascular disease in people with type 2 diabetes with no history of prior cardiovascular disease.

We performed a historical cohort study (2008–2011) on 481 people with type 2 diabetes and no history of cardiovascular disease. Cardiovascular risk factors were assessed at baseline and repeatedly during follow-up. The predictive analysis included the variables at enrollment, and explanatory analyses were based on mean of the variables measured repeatedly. VVV of the main variables was measured using the standard deviation and coefficient of variation of the measured variables. Separate multivariate binary logistic models were constructed for each parameter with the incident cardiovascular disease.

Mean age of the participants was 54.9 years, mean glycated hemoglobin was 56 mmol/mol, and mean blood pressure was 125/78 mmHg. Incident cardiovascular disease developed in 14.3% of the participants. The 2-h post breakfast blood glucose was associated with incident cardiovascular disease (odds ratio 1.44; confidence interval = 1.08–1.90; p = 0.01). For each 1 mmol/l increase in postprandial glucose there was a 44% increase in risk of incident cardiovascular disease. VVV of glycemic indices, blood pressure, lipids, body mass index and creatinine were not associated with occurrence of cardiovascular events.

In this population of patients with type 2 diabetes and no history of cardiovascular disease in whom other cardiovascular risk factors are within or near to the recommended targets, 2-h post breakfast blood glucose level is associated with incident cardiovascular disease.

Unexplained dyspnea is a common diagnosis that often results in repeated diagnostic testing and even delayed treatments while a determination of the cause is being investigated. Through a retrospective study, we evaluated the diagnostic efficacy of a multidisciplinary dyspnea evaluation center (MDEC) using invasive cardiopulmonary exercise test to diagnose potential causes of unexplained dyspnea.

We reviewed the medical records of all patients referred with unexplained dyspnea to the MDEC between March 2011 and October 2014. We assessed the diagnostic efficacy before and after presentation to the MDEC.

During the study period a total of 864 patients were referred to the MDEC and, of those, 530 patients underwent further investigation with invasive cardiopulmonary exercise test and constituted the study sample. The median age was 57 (44–68) years, 67.2% were women, and median body mass index was 26.22 (22.78–31.01). A diagnosis was made in 530 patients including: exercise pulmonary arterial hypertension of 88 (16.6%), heart failure with preserved ejection fraction of 94 (17.7%), dysautonomia 112 (21.1%), oxidative myopathy of 130 (24.5%), primary hyperventilation of 43 (8.1%), and other 58 (10.9%). The time from initial presentation to referral was significantly longer than time to diagnosis after referral for non-standardized conventional methods versus diagnosis through MDEC using invasive cardiopulmonary exercise test (511 days (292–1095 days) vs. 27 days (13–53 days), p < 0.0001). In a subgroup analysis, we reviewed that patients referred from cardiovascular clinics were more likely to have a greater number of diagnostic tests performed and, conversely, patients referred from pulmonary clinics were more likely to have a greater number of treatments prescribed before referral to MDEC.

As a result of this retrospective study, we have evaluated that a multidisciplinary approach that includes invasive cardiopulmonary exercise test dramatically reduces the time to diagnosis compared with traditional treatment and testing methods.

Familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by substantially elevated low-density lipoprotein (LDL) cholesterol. Although affecting approximately one in 250 individuals worldwide, FH is currently underreported and a greater awareness of this condition is required. Opportunistic screening for FH in acute coronary syndrome patients offers utility for identifying previously undiagnosed individuals and for initiating treatment.

The purpose of this commentary is to provide a brief update on recent data investigating several key aspects of FH in patients with acute coronary syndromes, including prevalence, risk of coronary artery disease, molecular diagnosis, cardiac imaging, as well as the efficacy of PCSK9 inhibition.

FH is relatively common among patients with coronary artery disease and is associated with a considerably increased risk of premature and recurrent cardiovascular events. Computed tomographic coronary angiography may be useful for identifying high-risk FH individuals. FH patients with a pathogenic mutation have a greater risk of the same LDL cholesterol than individuals without a mutation. PCSK9 monoclonal antibodies significantly lower LDL cholesterol in heterozygous and homozygous FH patients, with a greater attainment of LDL cholesterol targets, and can reduce the need for lipoprotein apheresis.

These data support the opportunistic screening for FH at the time of angiography or an acute coronary syndrome, followed by cascade testing of relatives of index cases. PCSK9 monoclonal antibodies are an important therapeutic advance for safely inhibiting the progression of atherosclerotic burden in FH, as supported by the most recent clinical endpoint trials.

Atrial fibrillation is associated with increased cardiovascular morbidity and mortality. Hypertension is an important risk factor for the development of atrial fibrillation.

This study assessed the relationship between blood pressure control and new-onset atrial fibrillation in hypertensive patients.

We followed 45,530 hypertensive patients with no previously documented atrial fibrillation, attending primary healthcare in Sweden during 2001–2008. After a mean follow-up of 3.5 years 2057 patients (4.5%) developed atrial fibrillation. Compared to patients with no atrial fibrillation, the new-onset atrial fibrillation group (after adjustment for age, sex, diabetes mellitus, heart failure, ischaemic heart disease, cerebrovascular disease and number of visits) had higher mean in-treatment systolic blood pressure (SBP) and diastolic blood pressure of 3.8 mmHg (95% confidence interval (CI) 3.0–4.6; P < 0.0001) and 1.6 mmHg (95% CI 1.2–2.0; P < 0.0001), respectively. Similarly, mean in-treatment pulse pressure in the new-onset atrial fibrillation group was 2.2 mmHg (95% CI 1.6–2.9; P < 0.001) higher. In a logistic regression analysis, achieved SBP ≥ 140 mmHg was associated with a higher risk of new-onset atrial fibrillation, compared to SBP 130–139 mmHg (odds ratio (OR) 1.5; 95% CI 1.3–1.7) and to SBP < 130 mmHg (OR 1.3; 95% CI 1.1–1.5). There was no difference in risk for new-onset AF between SBP 130–139 and <130 mmHg (OR 0.9; 95% CI 0.7–1.1).

The present findings indicate that blood pressure control in hypertension is associated with a lower risk of new-onset atrial fibrillation.

Although high resting heart rates are associated with adverse outcomes in heart failure with reduced ejection, the reports for heart failure with preserved ejection fraction (HFpEF) are conflicting.

A secondary analysis was conducted in order to examine the relationship between resting heart rate and adverse outcomes in 2705 patients (mean age = 68 ± 10 years; 47% men; 88% white) with HFpEF who were in sinus rhythm from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT).

Baseline heart rate was obtained from baseline electrocardiogram data. Outcomes were adjudicated by a clinical end-point committee and included the following factors: hospitalisation, hospitalisation for heart failure, death and cardiovascular death.

Over a median follow-up of 3.4 years (25th–75th percentiles = 2.0–4.9 years), a total of 1157 hospitalisations, 311 hospitalizations for heart failure, 369 deaths and 233 cardiovascular deaths occurred. An increased risk (per 5-beats per minute [bpm] increase) for hospitalisation (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1.004–1.060), hospitalisation for heart failure (HR = 1.10, 95% CI = 1.05–1.15), death (HR = 1.10, 95% CI = 1.06–1.16) and cardiovascular death (HR = 1.13, 95% CI = 1.07–1.19) was observed. When the analysis was limited to those who did not report the use of β-blockers, the magnitude of the association for each outcome (per 5-bpm increase) was not materially altered (hospitalisation: HR = 1.03, 95% CI = 0.97–1.09; hospitalisation for heart failure: HR = 1.12, 95% CI = 0.98–1.27; death: HR = 1.16, 95% CI = 1.05–1.28; cardiovascular death: HR = 1.12, 95% CI = 0.99–1.27).

High resting heart rate is a risk factor for adverse outcomes in patients with HFpEF, and future studies are needed in order to determine whether reducing heart rate improves outcomes in HFpEF.

To perform a systematic literature review and meta-analysis of clinical risk factors for sudden cardiac death (SCD) in childhood hypertrophic cardiomyopathy.

Medline and PubMed databases were searched for original articles published in English from 1963 through to December 2015 that included patients under 18 years of age with a primary or secondary end-point of either SCD or SCD-equivalent events (aborted cardiac arrest or appropriate implantable cardioverter–defibrillator discharge) or cardiovascular death (CVD).

Twenty-five studies (3394 patients) met the inclusion criteria. We identified four conventional major risk factors that were evaluated in at least four studies and that we found to be statistically associated with an increased risk of death in at least two studies: previous adverse cardiac event (pooled hazard ratio [HR] 5.4, 95% confidence interval [CI] 3.67–7.95, p < 0.001); non-sustained ventricular tachycardia (pooled HR 2.13, 95% CI 1.21–3.74, p = 0.009); unexplained syncope (pooled HR 1.89, 95% CI 0.69–5.16, p = 0.22); and extreme left ventricular hypertrophy (pooled HR 1.80, 95% CI 0.75–4.32, p = 0.19). Left atrial diameter did not meet the major risk factor criteria; however, this is likely to be an additional significant risk factor. ‘Minor’ risk factors included a family history of SCD, gender, age, symptoms, electrocardiogram changes, abnormal blood pressure response to exercise and left ventricular outflow tract obstruction.

A lack of well-designed, large, population-based studies in childhood hypertrophic cardiomyopathy means that the evidence base for individual risk factors is not robust. We have identified four clinical parameters that are likely to be associated with increased risk of SCD, SCD-equivalent events or CVD. Multi-centre prospective studies are needed in order to further determine the relevance of these factors in predicting SCD in childhood hypertrophic cardiomyopathy and to identify novel risk markers.

A systematic review and meta-analysis of clinical risk factors predicting sudden cardiac death in childhood hypertrophic cardiomyopathy was performed, identifying four ‘major’ factors: previous adverse cardiac event; non-sustained ventricular tachycardia; syncope; and extreme left ventricular hypertrophy. Well-designed multi-centre studies are required in the future in order to confirm these findings.