Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation.

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Relationship of Circulating Vegetable Omega-3 to Prognosis in Patients With Heart Failure.

BACKGROUND: There is an urgent need for cost-effective strategies to promote quality of life in patients with heart failure (HF). Several studies reported benefits in HF prognosis for marine omega-3 fatty acids and plant-based dietary patterns. OBJECTIVES: The aim of this study was to explore whether dietary alpha-linolenic acid (ALA), the main plant omega-3, relates to a better HF prognosis. METHODS: ALA was determined in serum phospholipids (which reflect long-term dietary ALA intake and metabolism) by gas chromatography in 905 ambulatory patients with HF caused by different etiologies. RESULTS: After a median follow-up of 2.4 years (range: 0.02-3 years), 140 all-cause deaths, 85 cardiovascular (CV) deaths, and 141 first HF hospitalizations (composite of all-cause death and first HF hospitalization, n = 238) were documented. Using Cox regression analyses, we observed that, compared with patients at the lowest quartile of ALA in serum phospholipids (Q1), those at the 3 upper quartiles (Q2-Q4) exhibited a reduction in the risk of composite of all-cause death and first HF hospitalization (HR: 0.61; 95% CI: 0.46-0.81). Statistically significant reductions were observed for all-cause death (HR: 0.58; 95% CI: 0.41-0.82), CV death (HR: 0.51; 95% CI: 0.32-0.80), first HF hospitalization (HR: 0.58; 95% CI: 0.40-0.84), and the composite of CV death and HF hospitalization (HR: 0.58; 95% CI: 0.42-0.79). CONCLUSIONS: HF patients with bottom 25% ALA levels in serum phospholipids had a worse prognosis during a mid-term follow-up compared with those with the highest levels. This might be a target population in whom to test dietary ALA-rich interventions to promote quality of life.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

The "FIFTY SHADOWS" of the RALES Trial: Lessons about the Potential Risk of Dietary Potassium Supplementation in Patients with Chronic Kidney Disease.

Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin-angiotensin-aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of "occult" CKD, HF, and in patients taking RAASis and/or MRAs.

Mechanisms governing the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles: A scoping review of preclinical evidence.

Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs.

Circulating Omega-3 Fatty Acids and Incident Adverse Events in Patients With Acute Myocardial Infarction.

BACKGROUND: Dietary omega-3 eicosapentaenoic acid (EPA) has multiple cardioprotective properties. The proportion of EPA in serum phosphatidylcholine (PC) mirrors dietary EPA intake during previous weeks. Circulating EPA in ST-segment elevation myocardial infarction (STEMI) relates to smaller infarct size and preserved long-term ventricular function. OBJECTIVES: The authors investigated whether serum-PC EPA (proxy for marine omega-3 consumption) levels at the time of STEMI were associated with a lower incidence of major adverse cardiovascular events (MACE), all-cause mortality, and readmission for cardiovascular (CV) causes at 3 years' follow-up. We also explored the association of alpha-linolenic acid (ALA, proxy for vegetable omega-3 intake) with all-cause mortality and MACE. METHODS: The authors prospectively included 944 consecutive patients with STEMI (mean age 61 years, 209 women) undergoing primary percutaneous coronary intervention. We determined serum-PC fatty acids with gas chromatography. RESULTS: During follow-up, 211 patients had MACE, 108 died, and 130 were readmitted for CV causes. A Cox proportional hazards model adjusted for known clinical predictors showed that serum-PC EPA at the time of STEMI was inversely associated with both incident MACE and CV readmission (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.62 to 0.94, and HR: 0.74; 95% CI: 0.58 to 0.95, respectively, for a 1-standard deviation [SD] increase). Serum-PC ALA was inversely related to all-cause mortality (HR: 0.65; 95% CI: 0.44 to 0.96, for a 1-SD increase). CONCLUSIONS: Elevated serum-PC EPA and ALA levels at the time of STEMI were associated with a lower risk of clinical adverse events. Consumption of foods rich in these fatty acids might improve the prognosis of STEMI.

Effects of a polysaccharide-based multi-ingredient supplement on salivary immunity in non-elite marathon runners.

BACKGROUND: Extreme exercise may alter the innate immune system. Glycans are involved in several biological processes including immune system regulation. However, limited data regarding the impact of glycan supplementation on immunological parameters after strenuous exercise are available. We aimed to determine the impact of a standardized polysaccharide-based multi-ingredient supplement, Advanced Ambrotose© complex powder (AA) on salivary secretory Immunoglobulin A (sIgA) and pro- and anti-inflammatory protein levels before and after a marathon in non-elite runners. METHODS: Forty-one male marathon runners who completed the 42.195 km of the 2016 Barcelona marathon were randomly assigned to two study groups. Of them, n = 20 (48%) received the AA supplement for 15 days prior the race (AA group) and n = 21 (52%) did not receive any AA supplement (non-AA group). Saliva and blood samples were collected the day before the marathon and two days after the end of the race. Salivary IgA, pro-inflammatory chemokines (Gro-alpha, Gro-beta, MCP-1) and anti-inflammatory proteins (Angiogenin, ACRP, Siglec 5) were determined using commercially ELISA kits in saliva supernatant. Biochemical parameters, including C-reactive protein, cardiac biomarkers, and blood hemogram were also evaluated. RESULTS: Marathon runners who did not receive the AA supplement experienced a decrease of salivary sIgA and pro-inflammatory chemokines (Gro-alpha and Gro-beta) after the race, while runners with AA supplementation showed lower levels of anti-inflammatory chemokines (Angiogenin). Gro-alpha and Gro-beta salivary levels were lower before the race in the AA group and correlated with blood leukocytes and platelets. CONCLUSIONS: Changes in salivary sIgA and inflammatory chemokines, especially Gro-alfa and Gro-beta, were observed in marathon runners supplemented with AA prior to the race. These findings suggested that AA may have a positive effect on immune response after a strenuous exercise.

Contemporary Yield of 24-hour Holter Monitoring: Role of Inter-Atrial Block Recognition.

BACKGROUND: The diagnostic yield of 24-hour ECG Holter monitoring (24H) is currently overcome by alternative ECG monitoring techniquesand it needs to be optimized. The recognition of inter-atrial block (IAB) has emerged as a reliable indicator of patients at risk of atrial fibrillation relapses, and its role enhancing the yield of 24H is yet to be determined. We hypothesized that a presumably low yield of 24H may be ameliorated by means of incorporating the assessment for IAB. METHODS: We retrospectively analyzed 1017 consecutive 24H registers performed in a Multidisciplinary Integrated Health Care Institution, in which a restrictive definition of diagnostic 24H findings was used. A univariate and multivariate regression analysis served to determine the variables associated with a higher 24H's yield, including the requesting medical specialty, type of indication and a number of clinical, echocardiographic and ECG variables, including IAB. RESULTS: The mean age of our population was 62 ± 17 years (55% males). The majority of 24H were indicated from the Cardiology department (48%). The overall yield was 12.8%, higher for the assessment of the integrity of the electrical conduction system (26.1%) and poorer for the assessment of syncope (3.2%) and cryptogenic stroke (4.6%). The variables associated with higher diagnostic performance were indication from Cardiology (p < 0.001), IAB (p = 0.004), structural heart disease (p = 0.008) and chronic renal failure (p = 0.009). Patients ≤ 50 years old only retrieved a 7% yield. In the multivariate analysis, indication from Cardiology and IAB remained significant predictors of higher 24H's yield. In a secondary analysis including echocardiographic data, only identification of IAB remained statistically significant. CONCLUSIONS: The recognition of IAB and the type of indication are major determinants of a higher 24H's diagnostic yield and may help to optimize the selection of candidates.

Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: The TRAINING-HF Trial.

INTRODUCTION AND OBJECTIVES: Despite the prevalence of heart failure with preserved ejection fraction (HFpEF), there is currently no evidence-based effective therapy for this disease. This study sought to evaluate whether inspiratory muscle training (IMT), functional electrical stimulation (FES), or a combination of both (IMT + FES) improves 12- and 24-week exercise capacity as well as left ventricular diastolic function, biomarker profile, and quality of life in HFpEF. METHODS: A total of 61 stable symptomatic patients (New York Heart Association II-III) with HFpEF were randomized (1:1:1:1) to receive a 12-week program of IMT, FES, or IMT + FES vs usual care. The primary endpoint of the study was to evaluate change in peak exercise oxygen uptake at 12 and 24 weeks. Secondary endpoints were changes in quality of life, echocardiogram parameters, and prognostic biomarkers. We used a mixed-effects model for repeated-measures to compare endpoints changes. RESULTS: Mean age and peak exercise oxygen uptake were 74 ± 9 years and 9.9 ± 2.5mL/min/kg, respectively. The proportion of women was 58%. At 12 weeks, the mean increase in peak exercise oxygen uptake (mL/kg/min) compared with usual care was 2.98, 2.93, and 2.47 for IMT, FES, and IMT + FES, respectively (P < .001) and this beneficial effect persisted after 6 months (1.95, 2.08, and 1.56; P < .001). Significant increases in quality of life scores were found at 12 weeks (P < .001). No other changes were found. CONCLUSIONS: In HFpEF patients with low aerobic capacity, IMT and FES were associated with a significant improvement in exercise capacity and quality of life. This trial was registered at ClinicalTrials.gov (Identifier: NCT02638961)..

Changes in myocardial electrical impedance in human heart graft rejection.

BACKGROUND: Monitoring of post-transplant heart rejection is currently based on endomyocardial biopsy analysis. This study aimed to assess the effects of heart graft rejection on myocardial electrical impedance. METHODS AND RESULTS: Twenty-nine cardiac transplant patients and 9 controls underwent measurement of myocardial electrical impedance using a specifically designed amplifying system. The module and phase angle of myocardial impedance were measured. Histopathological rejection grading was performed according to ISHLT classification. Fifty impedance tests were performed in transplanted patients. Myocardial impedance (Z) was higher in controls than in transplanted patients (p<0.001) and followed a progressive decline at increasing current frequencies (p<0.001). Likewise, the phase angle of impedance in controls ranged from positive values at low frequencies to negative values at higher frequencies (from 2.5+/-0.9 degrees at 10 kHz to -3.8+/-2.1 degrees at 300 kHz, p<0.001). Rejection was associated with a significant decrease in myocardial impedance (Z) (15+/-6.6 Omega in grade 0, 13+/-6.0 Omega in grade 1A, and 3.3+/-0.9 Omega in grade 3A at 10 kHz, p<0.003). CONCLUSIONS: Mild degrees of cardiac graft rejection are associated with significant changes in myocardial electrical impedance in transplant patients. Further clinical investigation is warranted to assess the potential of cardiac impedance to detect heart graft rejection.