Cardiac Rehabilitation Increases Plasma Klotho Levels.

Background: Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods: We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results: We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions: In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.

Absence of High Lipoprotein(a) Levels Is an Independent Predictor of Acute Myocardial Infarction without Coronary Lesions.

The pathophysiological mechanisms underlying Myocardial Infarction with Non-Obstructive Coronary Artery Disease (MINOCA) are still under debate. Lipoprotein (a) [Lp(a)] has proinflammatory and prothrombotic actions and has been involved in the pathogenesis of atherosclerosis. However, no previous studies have linked Lp(a) levels with the probability of developing MINOCA. Moreover, the relationship between MINOCA and the plasma levels of other proatherogenic and proinflammatory molecules such as Interleukin-18 (IL18) and proprotein convertase subtilisin/kexin type 9 (PCSK9) has not been studied. We conducted a prospective, multicenter study involving 1042 patients with acute myocardial infarction (AMI). Seventy-six patients had no significant coronary lesions. All patients underwent plasma analysis on admission. MINOCA patients were younger (57 (47-68) vs. 61 (52-72) years; p = 0.010), more frequently female (44.7% vs. 21.0%; p < 0.001), and had lower rates of diabetes and of Lp(a) > 60 mg/dL (9.2% vs. 19.8%; p = 0.037) than those with coronary lesions; moreover, High Density Lipoprotein cholesterol (HDL-c) levels were higher in MINOCA patients. The absence of Lp(a) > 60 mg/dL and of diabetes were independent predictors of MINOCA, as well as female sex, high HDL-c levels, and younger age. IL-18 and PCSK9 levels were not predictors of MINOCA. During a follow-up of 5.23 (2.89, 7.37) years, the independent predictors of the primary outcome (acute ischemic events or death) in the whole sample were Lp(a) > 60 mg/dL, older age, low estimated Glomerular Filtration rate (eGFR), hypertension, previous heart failure (HF), coronary artery bypass graft, use of insulin, and no therapy with acetylsalicylic acid. In conclusion, in AMI patients, the absence of high Lp(a) levels, as well high HDL-c levels, were independent predictors of the inexistence of coronary artery disease. High Lp (a) levels were also an independent predictor of ischemic events or death.

Prevalence and prognostic value of monoclonal gammopathy in heart failure patients with preserved ejection fraction: A prospective study.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) and monoclonal gammopathy of uncertain significance (MGUS) are two entities that share pathophysiological mechanisms. The aim herein, was to assess the prevalence of MGUS in patients with HFpEF and no left ventricular (LV) hypertrophy, as well as its association with a pre-specified clinical endpoint at 12 months. METHODS: The present study prospectively enrolled 69 patients admitted with HF, with ejection fraction ≥ 50%, and LV wall thickness < 12 mm. All patients were screened for MGUS. Clinical events were determined over a 12 month follow-up. The pre-specified composite clinical endpoint was readmission for HF or death. RESULTS: The prevalence of MGUS in this population was 13%. There were no differences in the incidence of the composite clinical endpoint between patients with and without MGUS. Multivariate analysis showed that treatment with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was associated with fewer clinical events (HR: 0.153, 95% CI: 0.037-0.622, p = 0.009) and indicated a trend to lower risk of readmission for HF and death. Beta-blockers were associated with lower rates of the composite clinical endpoint (HR: 0.192, 95% CI: 0.05-0.736, p = 0.016), readmission for HF (HR: 0.272, 95% CI: 0.087-0.851, p = 0.025) and indicated a trend to lower mortality. Moreover, potassium serum levels > 5 mEq/L were associated with higher rates of the composite endpoint (HR: 6.074, 95% CI: 1.6-22.65, p = 0.007). CONCLUSIONS: The prevalence of MGUS in patients with HFpEF without hypertrophy was 3-fold that of the general population. There was no significant correlation between clinical outcomes and the presence of MGUS. Beta-blockers and ACEIs/ARBs reduced the composite of mortality and readmissions for HF in HFpEF patients. Hyperpotassemia was related to worse prognosis.

Impact of renal function on the prognostic value of mineral metabolism in patients with chronic ischaemic heart disease patients with chronic ischaemic heart disease. / Impacto de la función renal en el valor pronóstico del metabolismo mineral en pacientes con cardiopatía isquémica crónica.

BACKGROUND: Parathormone (PTH) is a component of the Mineral Metabolism (MM) system that has been shown recently to add prognostic value in pts. with stable coronary artery disease (SCAD) and average renal function. However, the influence of renal function on the prognostic role of PTH in pts. with SCAD has not been shown yet. PURPOSE: To assess the influence of estimated glomerular filtration rate (eGFR) on the prognostic role of PTH and other MM markers in pts. with SCAD. METHODS: We analyzed the prognostic value of MM markers (PTH, klotho, phosphate, calcidiol [25-hydroxyvitamin D], and fibroblast growth factor-23 [FGF23]) in 964 pts. with SCAD and eGFR<60ml/min/1.73 m2 (LGFR) vs pts. with eGFR≥60ml/min/1.73 m2 (HGFR) included in five hospitals of Madrid. The main outcome was the combination of death with ischemic events (any acute coronary syndrome, ischemic stroke or transient ischemic attack). eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). RESULTS: Age was 60.0 (52.0-72.0) years, 76.2% of patients were men, and eGFR was 80.4 (65.3-93.1) ml/min/1,73 m2. Median follow-up was 5.39 (2.81-6.92) years. There were 790 pts. with HGFR and 174 with LGFR. In HGFR pts., predictors of ischemic events or death were plasma levels of calcidiol [HR=0.023 (0.94-0.99) p=0.023], FGF23 [HR=1.00 (1.00-1.003) p=0.036], non-HDL cholesterol [HR=1.01 (1.00-1.01) p=0.026] and high sensitivity troponin I [HR=5.12 (1.67-15.59) p=0.004], along with age [HR=1.03 (1.01-1.05) p=0.01], treatment with statins [HR=0.36 (0.19-0.68) p=0.002], nitrates [HR=1.13 (1.07-2.79) p=0.027], dihydropyridines [HR=1.71 (1.05-2.77) p=0.032], verapamil [HR=5.71 (1.35-24.1) p=0.018], and proton-pump inhibitors [HR=2.23 (1.36-3.68) p= 0.002]. In the LGFR subgroup, predictors of death or ischemic events were PTH plasma levels, [HR=1.01 (1.00-1.01) p=0.005], eGFR [HR=0.96 (0.94-0.99) p=0.004], age [HR=1.06 (1.02-1.10) p=0.003], caucasian race [HR=0.04 (0.004-0.380) p=0.005], and treatment with insulin [HR=2.6 (1.20-5.63) p=0.015]. CONCLUSIONS: In pts. with SCAD, PTH is an independent predictor of poor outcomes only in those with eGFR<60ml/min/1.73 m2, while in pts. with eGFR≥60ml/min/1.73 m2 calcidiol and FGF23 become the only components of MM that may predict prognosis. Then, renal function influences the predictive power of MM markers in pts. with SCAD.

Anti-Inflammatory Drugs in Patients with Ischemic Heart Disease.

Inflammation has long been known to play a role in atherogenesis and plaque complication, as well as in some drugs used in therapy for atherosclerotic disease, such as statins, acetylsalicylic acid, and modulators of the renin-angiotensin system, which also have anti-inflammatory effects. Furthermore, inflammatory biomarkers have been demonstrated to predict the incidence of cardiovascular events. In spite of this, and with the exception of acetylsalicylic acid, non-steroidal anti-inflammatory drugs are unable to decrease the incidence of cardiovascular events and may even be harmful to the cardiovascular system. In recent years, other anti-inflammatory drugs, such as canakinumab and colchicine, have shown an ability to reduce the incidence of cardiovascular events in secondary prevention. Colchicine could be a potential candidate for use in clinical practice given its safety and low price, although the results of temporary studies require confirmation in large randomized clinical trials. In this paper, we discuss the evidence linking inflammation with atherosclerosis and review the results from various clinical trials performed with anti-inflammatory drugs. We also discuss the potential use of these drugs in routine clinical settings.

Prevalence of transthyretin amyloidosis in patients with heart failure and no left ventricular hypertrophy.

AIMS: As evidenced by scintigraphy imaging, the prevalence of transthyretin (TTR) cardiac amyloidosis in heart failure patients with preserved ejection fraction (HFpEF) and left ventricular hypertrophy (LVH) ranges between 13% and 19%. The natural evolution of cardiac amyloidosis begins with the deposition of amyloid material in the myocardium, with LVH ensuing at later stages. With current imaging modalities, it is possible to detect TTR cardiac amyloidosis before the hypertrophic stage. The aim of this study was to determine the prevalence of TTR cardiac amyloidosis in HFpEF patients without LVH. METHODS AND RESULTS: The study prospectively enrolled patients admitted for HF with LV ejection fraction (LVEF) ≥ 50% and LV wall thickness <12 mm. TTR cardiac amyloidosis was diagnosed according to accepted criteria, which include positive cardiac 99-Tc-DPD scintigraphy in the absence of monoclonal protein expansion in blood. Transthyretin gene sequencing was performed in positive patients. From July 2017 to January 2020, 329 patients with HFpEF and LV thickness <12 mm were identified. After exclusions, 58 patients completed the study with cardiac scintigraphy (79 years, 54% men; median LVEF 60% and LV wall thickness 10.5 mm). Three patients (5.2%) were positive for TTR cardiac amyloidosis; genetic analysis excluded the presence of hereditary TTR amyloidosis. Positive patients baseline characteristics (84 years, 67% men, LVEF 60%, and LV wall thickness 11 mm) were similar to patients without TTR, except for troponin levels (0.05 vs. 0.02 ng/mL, P = 0.03) and glomerular filtration rate (82 vs. 60 mL/min, P = 0.032), which were higher in TTR patients. CONCLUSIONS: In a cohort of patients with HFpEF without LVH, the prevalence of TTR cardiac amyloidosis was 5%. Early diagnosis of cardiac involvement in TTR amyloidosis (before manifest LVH) would seem recommendable because newly approved specific treatments can prevent additional deposition of amyloid material.

MCP-1 Predicts Recurrent Cardiovascular Events in Patients with Persistent Inflammation.

Clinical data indicate that patients with C-reactive protein (CRP) levels higher than 2 mg per liter suffer from persistent inflammation, which is associated with high risk of cardiovascular disease (CVD). We determined whether a panel of biomarkers associated with CVD could predict recurrent events in patients with low or persistent inflammation and coronary artery disease (CAD). We followed 917 patients with CAD (median 4.59 ± 2.39 years), assessing CRP, galectin-3, monocyte chemoattractant protein-1 (MCP-1), N-terminal fragment of brain natriuretic peptide (NT-proBNP) and troponin-I plasma levels. The primary outcome was the combination of cardiovascular events (acute coronary syndrome, stroke or transient ischemic event, heart failure or death). Patients with persistent inflammation (n = 343) showed higher NT-proBNP and MCP-1 plasma levels compared to patients with CRP < 2 mg/L. Neither MCP-1 nor NT-proBNP was associated with primary outcome in patients with CRP < 2 mg/L. However, NT-proBNP and MCP-1 plasma levels were associated with increased risk of the primary outcome in patients with persistent inflammation. When patients were divided by type of event, MCP-1 was associated with an increased risk of acute ischemic events. A significant interaction between MCP-1 and persistent inflammation was found (synergy index: 6.17 (4.39-7.95)). In conclusion, MCP-1 plasma concentration is associated with recurrent cardiovascular events in patients with persistent inflammation.

Statin use is associated with reduced mortality after respiratory viral infection.

BACKGROUND: Several studies suggest that statins, besides reducing cardiovascular disease, have anti-inflammatory properties which might provide a benefit in downregulating the immune response after a respiratory viral infection (RVI) and, hence, decreasing subsequent complications. We aim to analyse the effect of statins on mortality after RVI. METHODS: A single-centre, observational and retrospective study was carried out including all adult patients with a RVI confirmed by PCR tests from October 2, 2017 to May 20, 2018. Patients were divided between statin users and non-statin users and followed-up for 1 year, and all causes of death were recorded. In order to analyse the effect of statin treatment on mortality after RVI we planned two different approaches, a multivariate Cox regression model with the overall population and a univariate Cox model with a propensity-score matched population. RESULTS: We included 448 patients, 154 (34.4%) of whom were under statin treatment. Statin users had a worse clinical profile (older population with more comorbidities). During the 1-year follow-up, 67 patients died, 17 (11.0%) in the statin group and 50 (17.1%) in the non-statin group. Multivariate Cox analysis showed that statins were associated with mortality benefit (HR 0.47, 95% CI 0.26-0.83; p=0.01). In a matched population (101 statins users and 101 non-statins users) statins also remained associated with mortality benefit (HR 0.32, 95% CI 0.14-0.72; p=0.006). Differences were mainly driven by non-cardiovascular mortality (HR 0.31, 95% CI 0.13-0.73; p=0.004). CONCLUSIONS: Chronic statin treatment was associated with reduced 1-year mortality in patients with laboratory-confirmed RVI. Further studies are needed to determine the exact role of statin therapy after RVI.

PCSK9 and HS-CRP Predict Progression of Aortic Stenosis in Patients with Stable Coronary Artery Disease.

It is essential to study the factors associated with the evolution of aortic stenosis progression (ASP) to develop therapies that could reduce it. We studied 283 patients 6 months after acute coronary syndrome (ACS). ASP was defined as an increase in the maximum aortic velocity of at least 0.5 m/s between the echocardiogram performed during ACS hospitalization and the last one recorded in the electronic medical registry. The median follow-up was 72.4 months. Twenty patients (7%) had ASP. A multivariate binary logistic regression analysis was performed showing that PCSK9 plasma levels (OR, 0.668 CI (0.457-0.977); p = 0.038), HS-CRP (OR, 1.034 CI (1.005-1.063); p = 0.022), the presence of dyslipidemia (OR, 4.622 CI (1.285-16.618); p = 0.019), the history of PAD (OR, 9.453 CI (1.703-52.452); p = 0.010), and GFR (OR, 0.962 CI (0.939-0.986); p = 0.002) were independent predicting factors of ASP. In patients with ischemic heart disease, low plasma levels of PCSK9 and elevated levels of HS-CRP are independent predictors of ASP.

Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System.

Coronavirus disease 2019 (COVID-19) is usually more severe and associated with worst outcomes in individuals with pre-existing cardiovascular pathologies, including hypertension or atherothrombosis. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an age- and sex-dependent manner. In particular, cardiovascular (CV) cells (e.g., endothelial cells, cardiomyocytes) could be directly infected and indirectly disturbed by systemic alterations, leading to hyperinflammatory, apoptotic, thrombotic, and vasoconstrictive responses. Until now, hundreds of clinical trials are testing antivirals and immunomodulators to decrease SARS-CoV-2 infection or related systemic anomalies. However, new therapies targeting the CV system might reduce the severity and lethality of disease. In this line, activation of the non-canonical pathway of the renin-angiotensin-aldosterone system (RAAS) could improve CV homeostasis under COVID-19. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1-9) and Ang-(1-7) peptides. The association of specific ACE2 polymorphisms with increased susceptibility of infection and related CV pathologies suggests potential genetic therapies. Moreover, specific agonists of Ang-(1-7) receptor could counter-regulate the hypertensive, hyperinflammatory, and hypercoagulable responses. Interestingly, sex hormones could also regulate all these RAAS components. Therefore, while waiting for an efficient vaccine, we suggest further investigations on the non-canonical RAAS pathway to reduce cardiovascular damage and mortality in COVID-19 patients.

Monocyte Chemoattractant Protein-1 Is an Independent Predictor of Coronary Artery Ectasia in Patients with Acute Coronary Syndrome.

Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT). We studied 270 patients who underwent coronary angiography during an acute coronary syndrome 6 months before. Plasma levels of several biomarkers were assessed, and patients were followed during a median of 5.35 (3.88-6.65) years. Two interventional cardiologists reviewed the coronary angiograms, diagnosing CAE according to previously published criteria in 23 patients (8.5%). Multivariate binary logistic regression analysis was used to search for independent predictors of CAE. Multivariate analysis revealed that, aside from gender and a diagnosis of dyslipidemia, only monocyte chemoattractant protein-1 (MCP-1) (OR = 2.25, 95%CI = (1.35-3.76) for each increase of 100 pg/mL, p = 0.001) was independent predictor of CAE, whereas mineral metabolism markers or proprotein convertase subtilisin/kexin type 9 were not. Moreover, CAE was a strong predictor of AAT during follow-up after adjustment for other clinically relevant variables (HR = 2.67, 95%CI = (1.22-5.82), p = 0.013). This is the first report showing that MCP-1 is an independent predictor of CAE, suggesting that CAE and coronary artery disease may share pathogenic mechanisms. Furthermore, CAE was associated with an increased incidence of AAT.

Use of Proton-Pump Inhibitors Predicts Heart Failure and Death in Patients with Coronary Artery Disease.

OBJECTIVES: Proton-pump inhibitors (PPIs) seem to increase the incidence of cardiovascular events in patients with coronary artery disease (CAD), mainly in those using clopidogrel. We analysed the impact of PPIs on the prognosis of patients with stable CAD. METHODS: We followed 706 patients with CAD. Primary outcome was the combination of secondary outcomes. Secondary outcomes were 1) acute ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and 2) heart failure (HF) or death. RESULTS: Patients on PPIs were older [62.0 (53.0-73.0) vs. 58.0 (50.0-70.0) years; p = 0.003] and had a more frequent history of stroke (4.9% vs. 1.1%; p = 0.004) than those from the non-PPI group, and presented no differences in any other clinical variable, including cardiovascular risk factors, ejection fraction, and therapy with aspirin and clopidogrel. Follow-up was 2.2±0.99 years. Seventy-eight patients met the primary outcome, 53 developed acute ischaemic events, and 33 HF or death. PPI use was an independent predictor of the primary outcome [hazard ratio (HR) = 2.281 (1.244-4.183); p = 0.008], along with hypertension, body-mass index, glomerular filtration rate, atrial fibrillation, and nitrate use. PPI use was also an independent predictor of HF/death [HR = 5.713 (1.628-20.043); p = 0.007], but not of acute ischaemic events. A propensity score showed similar results. CONCLUSIONS: In patients with CAD, PPI use is independently associated with an increased incidence of HF and death but not with a high rate of acute ischaemic events. Further studies are needed to confirm these findings.

Relationship between different doses of beta-blockers and prognosis in elderly patients with reduced ejection fraction.

BACKGROUND: Beta-blockers (BBs) remain underused in elderly patients with reduced ejection fraction (REF). Our aim was to determine the prognostic impact of different doses of BB in this setting. METHODS AND RESULTS: A single-center observational study was conducted. Inclusion criteria were age≥75 and EF≤0.35. Six months after diagnosis, patients were divided into 3 groups depending on BB dose: no BB (NBB), low dose (<50% of the target dose) (LD), and high dose (≥50%) (HD). Two different analytical approaches were employed: multivariate Cox model and propensity-score (PS) matching. Outcomes were all-cause death and heart failure (HF) admission. We included 559 patients (134 NBB, 259 LD, and 166 HD) with median follow-up of 29.9months. There were 212 deaths (NBB: 70 (52.2%); LD: 94 (36.3%); and HD: 48 (28.9%)) and 171 HF admissions (NBB: 42 (31.3%); LD: 85 (32.8%); and HD: 44 (26.5%)). On multivariate analysis, both LD and HD were associated with improved survival, with no differences between them (HD vs. NBB=0.67, 95% CI=[0.46-0.98], p=0.037; HD vs. LD=1.03, 95% CI=[0.72-1.46], p=0.894; and LD vs. NBB=0.65, 95% CI=[0.48-0.90], p=0.009). However, BB therapy failed to show benefits in HF admissions (p=NS, for each comparison). PS-matched analysis included 198 patients, with similar results to those mentioned above. CONCLUSIONS: BB therapy was associated with a significant reduction in mortality among elderly patients with REF, regardless of dose. Nevertheless, it was not associated with a decrease in HF admissions. Further studies are needed to determine the optimal BB dose in these patients.