Masahide Harada

Role of Inflammation in Atrial Fibrillation Pathophysiology and Management

Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets.

Physically triggered Takotsubo cardiomyopathy has a higher in-hospital mortality rate

BACKGROUNDnTakotsubo cardiomyopathy (TC) is a myopathy triggered by severe stressful events. However, little is known about the determinants of in-hospital outcomes. We prospectively determined the effect of different triggers on the prognosis of TC.nnnMETHODS AND RESULTSnWe enrolled patients who were admitted for suspected acute coronary syndrome (ACS) from January 2008 to December 2015. TC was diagnosed according to the Mayo Clinic diagnosis criteria. The outcome was in-hospital death. Among 1861 consecutive patients with suspected ACS, 82 (4.4%) patients were diagnosed with TC. There were 43 patients (52%) with physical triggers (Physical), 26 (31%) with emotional triggers, and 13 (17%) with no identifiable triggers. The latter two groups were combined and categorized as the Non-physical trigger group. Compared with non-physical triggered TC, patients with physical triggered TC were more likely to have a malignancy (p=0.008), lower blood pressure (p=0.001), lower hemoglobin (p<0.001), higher serum creatinine (p<0.001) and higher norepinephrine levels (p=0.007). During a mean hospital stay of 16±12days, 9 (20.9%) of the Physical and 1 (2.6%) of the Non-physical patients died in-hospital (log-rank p=0.007). After adjusting for the age, gender, trigger, malignancy, and hemoglobin level, being male (hazard ratio 11.9, 95% confidence interval, 2.43-58.5, p=0.002) and having a physical trigger (14.7, 1.19-166, p=0.03) were associated with in-hospital mortality.nnnCONCLUSIONnThere was a significant difference in in-hospital mortality depending on the trigger type in TC. Being male and having a physical trigger were independent risk factors of in-hospital mortality from TC.

QRS-based assessment of myocardial damage and adverse events associated with cardiac sarcoidosis

BACKGROUNDnCardiac sarcoidosis (CS) generates myocardial scar and arrhythmogenic substrate. CS diagnosis according to the Japanese Ministry of Health and Welfare guidelines relies, among others, on cardiac magnetic resonance imaging with late gadolinium enhancement (CMR-LGE). However, access to CMR-LGE is limited. The electrocardiography-based Selvester QRS score has been validated for identifying myocardial scar in ischemic/nonischemic cardiomyopathy, but its efficacy has not been tested to evaluate CS.nnnOBJECTIVEnThe purpose of this study was to examine whether the QRS score can be applied to CS.nnnMETHODSnCS-associated myocardial scar was assessed by both CMR-LGE and QRS scoring in patients with extra-CS (n = 59).nnnRESULTSnOf 59 patients, 35 (59%) were diagnosed with CS according to the Japanese Ministry of Health and Welfare guidelines. QRS-estimated scar mass positively correlated with that quantified by CMR-LGE (signal intensity ≥2SD above the reference; r = 0.68; P < .001). Receiver operating characteristic curves demonstrated optimal cutoffs of 9% CMR-LGE scar and 3-point QRS score to identify patients with CS. The areas under the curves of CMR-LGE and the QRS score were not significantly different (0.83 and 0.78, respectively; P = .27); both methods demonstrated similar diagnostic performance. A QRS score of ≥3 led to a higher incidence of CS-associated adverse events (death/fatal arrhythmia/heart failure hospitalization) than did a QRS score of <3 (35 ± 21 months of follow-up; P = .01). QRS score was an independent predictor of risk in multivariate analysis (P = .03).nnnCONCLUSIONnThe Selvester QRS scoring estimates CS-associated myocardial damage and identifies patients with CS equally well as CMR-LGE. A higher QRS score is also associated with an increased risk of life-threatening events in CS, indicating its potential use as a risk predictor.

Combination of high-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide predicts future hospital admission for heart failure in high-risk hypertensive patients with preserved left ventricular ejection fraction

Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to the Japanese hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident heart failure (HF) in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF). Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 Japanese hypertensive outpatients (mean age, 68.5 years) with LVEFu2009≥u200950%, no symptomatic HF, and at least one of the following comorbidities: stage 3–4 chronic kidney disease, diabetes mellitus, and stable coronary artery disease. During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved ejection fraction (HFpEF) and 13 for HF with reduced ejection fraction (HFrEF; LVEF <50%). Both hsTnI (pu2009<u20090.01) and NT-proBNP (pu2009<u20090.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (≥highest tertile value of 10.6xa0pg/ml) and/or increased NT-proBNP (≥highest tertile value of 239.7xa0pg/ml), the adjusted relative risks for patients with increased levels of both biomarkers versus neither biomarker were 13.5 for HF admission (pu2009<u20090.0001), 9.45 for HFpEF (pu2009=u20090.0009), and 23.2 for HFrEF (pu2009=u20090.003). Finally, the combined use of hsTnI and NT-proBNP enhanced the C-index (pu2009<u20090.05), net reclassification improvement (pu2009=u20090.0001), and integrated discrimination improvement (pu2009<u20090.05) to a greater extent than that of any single biomarker. The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.

Thromboembolisms in atrial fibrillation and heart failure patients with a preserved ejection fraction (HFpEF) compared to those with a reduced ejection fraction (HFrEF)

Heart failure (HF) is classified into three clinical subtypes: HF with a preserved ejection fraction (HFpEF: EFxa0≥xa050%), HF with a mid-range ejection fraction (HFmrEF: 40xa0≤xa0EFxa0<xa049%), and HF with a reduced ejection fraction (HFrEF: EFxa0<xa040%). These types often coexist with atrial fibrillation (AF). We investigated the rate of strokes/systemic embolisms (SSEs) in AF patients with HFpEF (AF-HFpEF) compared to that in those with HFrEF (AF-HFrEF: HFmrEF and HFrEF), and examined the independent predictors. We prospectively enrolled 1350 patients admitted to our hospital for worsening HF. We identified 301 patients with either AF-HFpEF (nxa0=xa0129, 43%) or AF-HFrEF (nxa0=xa0172, 57%). Compared to the patients with AF-HFrEF, those with AF-HFpEF were older and more likely to be female. Oral anticoagulant use was 63 vs. 66%, respectively. During a mean follow-up period of 26xa0months, 21 (7%) and 66 (22%) patients had SSEs and all-cause death, respectively. The crude annual rates of SSEs (3.9 vs. 2.7%, Pxa0=xa00.47) were similar between the groups. In a multivariate Cox regression analysis, an agexa0≥xa075xa0years (hazard ratio 2.14, 95% confidence interval 1.32–3.58, Pxa0<xa00.01) and the plasma B-type natriuretic peptide (BNP) levelxa0≥xa0341xa0pg/ml (hazard ratio 1.60, 95% confidence interval 1.07–2.39, Pxa0<xa00.05) were associated with SSEs. The EF was not an independent predictor of SSEs (hazard ratio 1.01, 95% confidence interval 0.98–1.04, Pxa0=xa00.51). There were no significant differences in the rates of SSEs between AF-HFpEF and AF-HFrEF. Patients with HF and concomitant AF should be treated with anticoagulants irrespective of EF.

Prognostic Importance of Novel Oxygen Desaturation Metrics in Patients With Heart Failure and Central Sleep Apnea.

BACKGROUNDnSleep-disordered breathing, particularly central sleep apnea (CSA), is highly prevalent in heart failure (HF) and an independent prognostic marker. We assessed the hypothesis that an increased hypoxemic burden during sleep may have greater prognostic value than the frequency of apneic and hypopneic episodes.nnnMETHODS AND RESULTSnWe prospectively conducted overnight cardiorespiratory polygraphy on consecutive HF patients referred to our hospital from 2008 to 2011. We studied CSA defined by an apnea-hypopnea index (AHI) of ≥5 events/h with >75% of all events being central in origin. We determined the AHI, proportion of the sleep time with SpO2 <90% (T90%), and proportion of the recording time that 4% desaturation events occurred (4%POD). We studied 112 HF patients with either systolic or diastolic dysfunction. During a follow-up period of 37u2009±u200925 months, 32 patients (29%) died. Nonsurvivors had a higher 4%POD compared with survivors (11u2009±u20096.4% vs 19u2009±u200913%; Pu2009=u2009.001), but did not differ significantly from survivors regarding AHI and T90%. An adjusted logistic regression analysis revealed that the 4%POD was the best independent predictor of mortality.nnnCONCLUSIONSnThe 4%POD, a novel metric for the nocturnal hypoxemic burden, is an independent prognostic marker in HF patients affected by CSA.

Prognostic Value of Combination of Plasma D-Dimer Concentration and Estimated Glomerular Filtration Rate in Predicting Long-Term Mortality of Patients With Stable Coronary Artery Disease

BACKGROUNDnA modestly elevated circulating D-dimer level may be relevant to coronary artery disease (CAD), but its prognostic value, both independently and in combination with estimated glomerular filtration rate (eGFR), for long-term death has not been fully evaluated in stable CAD patients.Methodsu2004andu2004Results:Baseline plasma D-dimer levels and eGFR were measured in 1,341 outpatients (mean age: 65 years) with prior myocardial infarction (MI), coronary revascularization, and/or angiographic evidence of a significant stenosis (>50%) for at least one of the major coronary arteries. Among these patients, 43% had prior MI, 47% had prior coronary revascularization, 41% had multivessel CAD, 14% had paroxysmal or persistent atrial fibrillation, 32% had diabetes, and 32% had chronic kidney disease (eGFR <60 mL/min/1.73 m2). D-dimer levels weakly correlated with eGFR (r=-0.25; P<0.0001). During a mean follow-up period of 73 months, there were 124 deaths, including 61 cardiovascular deaths. Multivariate Cox regression analysis identified D-dimer levels (P=0.001) and eGFR (P=0.006) as independent predictors of all-cause death. Adding both D-dimer and eGFR to a baseline model with established risk factors improved the net reclassification (P<0.005) and integrated discrimination improvement (P<0.05) greater than that of any single biomarker or baseline model alone.nnnCONCLUSIONSnThe combinatorial value of assessing D-dimer levels and eGFR may provide useful insight regarding stable CAD patients long-term risk stratification.

Metabolic Considerations in Atrial Fibrillation ― Mechanistic Insights and Therapeutic Opportunities ―

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with morbidity and mortality. Over the past 2 decades, there have been major advances in understanding AF pathophysiology, but important knowledge gaps, particularly about targetable basic mechanisms, remain. Recent metabolomic and proteomic studies have shown changes in the expression of molecules involved in metabolic pathways in human and experimental AF, indicating a role for metabolic alterations in AF pathophysiology. AF is characterized by irregular high-frequency excitation and contraction that affect atrial energy demands, circulation and oxygen supply, and change the balance between metabolic demand and supply, causing metabolic stress. Here, we review the information available about AF-induced metabolic changes and their pathophysiological contribution. We also discuss the possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF.

Serum microRNA-126 and -223 as new-generation biomarkers for sarcoidosis in patients with heart failure

BACKGROUNDnAlthough cardiac sarcoidosis is associated with poor prognosis, diagnosis of the disease is challenging and the sensitivity and specificity of diagnostic modalities are limited. This study was performed to evaluate the potential of serum microRNAs (miRNAs) as diagnostic biomarkers for cardiac sarcoidosis.nnnMETHODSnWe performed genome-wide expression profiling for 2565 miRNAs (Human-miRNA ver.21) using peripheral blood samples from 5 patients with cardiac sarcoidosis (61±9 years) and 3 healthy controls (54±7 years). From this screening study, we selected 12 miRNAs that were significantly related to cardiac sarcoidosis. Next, we performed real-time polymerase chain reaction (PCR) on blood samples from 15 new patients with cardiac sarcoidosis and 4 healthy controls to quantify the expression of these 12 miRNAs.nnnRESULTSnIn the screening study, 12 miRNAs were differentially expressed (p<0.01) in all 5 patients with cardiac sarcoidosis, showing greater fold-change values (>4 or <0.25) compared with the expression in the 3 healthy controls. Analysis of the real-time PCR for blood samples from the other 15 patients and 4 controls using Mann-Whitney U tests revealed that the expression of miR-126 and miR-223 was significantly higher in the patients than in the healthy individuals. However, there were no differences in the expressions of miRNA-126 and miR-223 between patients with only cardiac lesions and those with extra-cardiac lesions.nnnCONCLUSIONSnOur results demonstrate the potential of serum miR-126 and miR-223 as new-generation biomarkers for the differential diagnosis of cardiac sarcoidosis in patients with heart failure.

Assessment of trough rivaroxaban concentrations on markers of coagulation activation in nonvalvular atrial fibrillation population

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10xa0mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1xa0+xa02 (F1xa0+xa02) levels, and protein C activities were measured at 0 (baseline), 12 and 24xa0weeks of rivaroxaban treatment just before the patient’s regular dosing time (trough phase). For 49 patients, D-dimer, F1xa0+xa02, and rivaroxaban concentrations were also measured twice between 28 and 32xa0weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1xa0+xa02 levels were significantly reduced (pxa0<xa00.01) from baseline at 12 and 24xa0weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (pxa0<xa00.01) for F1xa0+xa02. Protein C activity was unchanged in the naive group and was increased (pxa0<xa00.01) in the warfarin group. Prothrombin time (rxa0=xa00.92, pxa0<xa00.0001) and activated partial thromboplastin time (rxa0=xa00.54, pxa0<xa00.0001) correlated with rivaroxaban concentration, but not D-dimer and F1xa0+xa02 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1xa0+xa02 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1xa0+xa02 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.