Successful ß-blocker introduction under intra-aortic balloon pumping and ivabradine in a patient with new-onset dilated cardiomyopathy and pulsus alternans: a case report.

Background: Pulsus alternans has been considered a sign of poor prognosis in patients undergoing treatments for heart failure. However, it may be overlooked in patients with intra-aortic balloon pumps (IABPs). The use of IABP and ivabradine for a ß-blocker introduction in a patient with dilated cardiomyopathy (DCM) and pulsus alternans and its consequence have never been reported. Case summary: In a 16-year-old high school boy with idiopathic DCM [left ventricular end-diastolic diameter (LVDd), 72 mm; left ventricular ejection fraction (LVEF), 18%], the introduction of carvedilol therapy failed, causing cardiogenic shock under inotropes. Therefore, an IABP support was provided, and he was transferred to our hospital. The arterial pressure waveform under IABP demonstrated pulsus alternans with sinus tachycardia at 135/min. Ivabradine reduced the heart rate to ∼100/min and eliminated the pulsus alternans neither decreasing the cardiac index nor increasing the pulmonary artery wedge pressure. Subsequently, carvedilol was reintroduced, and IABP and inotropes were discontinued. Then, 112 days after his transfer to our hospital, left ventricular reverse remodelling was confirmed (LVDd, 54 mm; LVEF, 44%), and he returned to school. The carvedilol dose reached 20 mg/day in 4 months after discharge, and further improvement was observed a year after discharge (LVDd, 54 mm; LVEF, 52%). Discussion: Pulsus alternans is considered a predictor of poor prognosis. However, IABP and ivabradine may stabilize the haemodynamics in pulsus alternans, leading to a successful ß-blocker introduction.

Acute coronary syndrome with simultaneous two-vessel occlusion De Winter ST-segment depression or reciprocal change?

We discuss a case of acute coronary syndrome (ACS) with simultaneous two-vessel occlusions in a man in his 20s. The serial electrocardiograms (ECG) showed very early dynamic changes of ST-T configuration resulting from ischemic zone depth or area between anterior wall versus inferior wall. The upsloping ST depression along with tall tentorial T waves in the precordial leads, as shown in the index ECG, raises the possibilities of a de Winter pattern. The retrospective assessment of the index ECG identified prominent T waves and a mild degree of ST-segment elevations in the inferior leads, given the electrocardiographic findings previously recorded at his workplace medical examination obtained at a later date. If the subtle ST-segment elevations in leads II, III, and aVF and the tall T waves were not overlooked in the index ECG, the probability of reciprocal ST-segment depressions in the precordial leads should also be taken into account. We recognize our ECG findings as intriguing ST-T deviation patterns that can change depending on the time sequence and anatomical dominancy of two infarct-related arteries. We finally suggest physicians should bear in mind the possibility of simultaneous multiple vessel occlusions when they encounter ACS patients with hemodynamic instability as in this present case.

A Case of Chronic Heart Failure Complicated by Primary Biliary Cholangitis and Skeletal Myopathy.

Several autoantigens related to inflammatory myopathy have been identified. Antimitochondrial antibody M2 (AMA-M2) is known as one of the serologic hallmarks of primary biliary cholangitis (PBC). There have been several reports on the association between AMA-M2 and various types of inflammatory myopathy, including cardiomyopathy. We report a case of a 58-year-old man with decompensated heart failure who also had PBC and skeletal inflammatory myopathy. Endomyocardial biopsy revealed severe fibrotic replacement of the myocardium without massive inflammatory infiltration, which was pathologically similar to what happens in dilated cardiomyopathy (DCM). Although the potential relationship between chronic autoimmune inflammation and DCM has been discussed, the concept of the inflammatory DCM has not yet been established. When we see elevated liver enzymes, and which is not simply due to congestive hepatopathy, we should consider the coexisting disease such as PBC.

Incidence and Risk Factors of Future Need for Long-Term Care Insurance in Japanese Elderly Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

Possible Coronary Sequelae of Kawasaki Disease in an Elderly Man.

Kawasaki disease (KD) is an acute self-limited syndrome that predominantly affects children. Coronary sequelae have been identified to be responsible for a small, but significant percentage of young adults who present with myocardial ischemia. In this study, we present a case of an elderly patient with possible coronary sequelae of KD. A 76-year-old man was referred to our outpatient department for silent myocardial ischemia. Axial images of coronary computed tomography showed multiple lumens in the proximal left anterior descending (LAD) artery. Coronary angiography demonstrated braid-like appearance in the proximal and distal segment of the LAD. Coronary intervention was successfully performed for the proximal LAD lesion using directional atherectomy (DCA) catheter. Microscopic examination of the DCA specimens showed the following histological features: tissues in densely hyalinized fibrosis with occasional microcalcification, or those containing a number of smooth muscle cells (SMCs) with myxoid extracellular matrix. There was paucity of cholesterin crystals and aggregation of foamy cells. In addition, scarcely any inflammatory cell filtration was identified. In the section of SMC-containing samples, formation of multiple re-canalized vessels embracing endothelial cells was confirmed. These histopathologic findings indicated that the present coronary artery lesion has a high possibility of very late cardiovascular sequelae caused by arteritis due to KD, rather than arteriosclerosis. This is the oldest adult case with coronary artery disease possibly resulting from KD sequelae. This case highlights that KD sequelae must be considered as a cause of coronary artery lesion even in older patients.

A rare case of nivolumab-related myasthenia gravis and myocarditis in a patient with metastatic gastric cancer.

BACKGROUND: Although rare, several immune-related adverse effects can be life-threatening. Here, we describe a metastatic gastric cancer patient presenting with nivolumab-related myasthenia gravis and myocarditis, a previously unreported adverse effect of gastric cancer treatment. CASE PRESENTATION: A 66-year-old man with metastatic gastric cancer visited the emergency department because of dizziness after the first dose of nivolumab. Diagnoses of nivolumab-related myasthenia gravis and myocarditis were established. Myocardial biopsy results and anti-acetylcholine receptor antibody positivity confirmed the diagnoses. Despite plasma exchange and intravenous methylprednisolone and immunoglobulin administration, the patient's general condition gradually worsened, and he died. CONCLUSIONS: Strict monitoring for cardiac and neuromuscular symptoms after nivolumab administration is necessary to rapidly treat these adverse effects.

The effect of the debulking by excimer laser coronary angioplasty on long-term outcome compared with drug-coating balloon: insights from optical frequency domain imaging analysis.

This study evaluated the 1-year efficacy of excimer laser coronary angioplasty (ELCA) before drug-coated balloon (DCB) dilatation for the treatment of in-stent restenosis (ISR). Forty consecutive patients with ISR were treated by DCB with or without the use of ELCA (ELCA plus DCB, N = 20; DCB alone, N = 20). Debulking efficiency (DE) value was defined as the neointima area on optical frequency domain imaging (OFDI) debulked by ELCA. The patients in the ELCA plus DCB group were divided into two groups (greater DE (GDE), N = 10; smaller DE (SDE), N = 10) based on the median value of DE. Thereafter, the ISR segment was prepared with a scoring balloon, followed by DCB. At follow-up, binary restenosis and target lesion revascularization (TLR) were evaluated. There were no significant differences in baseline characteristics such as age, comorbidity, and ISR type. Overall, the incidence of neoatherosclerosis in the ISR segment was 17.5%. Post-PCI, acute gain of minimum lumen diameter on quantitative coronary angiography and of minimum lumen area on OFDI was numerically higher in the GDE than in the SDE and the DCB alone group. At follow-up, the occurrences of binary restenosis and TLR in the ELCA plus DCB group were 20.0% and 10.0%; these values in the DCB alone group were 20.0% and 20.0%, respectively. Two patients from the SDE and none from the GDE developed TLR. DCB alone treatment was inferior to ELCA plus DCB treatment. However, greater ELCA debulking might be required to obtain optimal outcomes.

Impaired glucose tolerance and future cardiovascular risk after coronary revascularization: a 10-year follow-up report.

AIMS: Practical management guidelines for impaired glucose tolerance (IGT) have not been established. Although IGT is a potent marker of cardiovascular disease (CVD), it is still controversial whether its magnitude of CVD risk is comparable to that of frank diabetes. Moreover, information on long-term clinical outcomes of IGT patients undergoing coronary revascularization is limited. The aim of the present work was to investigate the 10-year prognostic impact of IGT in comparison with diabetes in patients with CAD undergoing coronary revascularization. METHODS: This cohort recruited from two Japanese clinical sites included patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) between 2004 and 2008. Patients were categorized into previously known diabetes (PKD, n = 197), newly diagnosed diabetes (NDD, n = 51), and IGT (n = 50) groups according to oral glucose tolerance test results except for PKD. The primary end point was defined as a composite of cardiovascular death, myocardial infarction, stroke, repeat revascularization, and heart failure hospitalization. RESULTS: The cumulative risk of the primary outcome was significantly higher in the PKD and IGT than in the NDD (log-rank test p = 0.017). A Cox proportional hazards model demonstrated that IGT (hazard ratio [HR], 7.91; 95% confidence interval [CI], 1.84-27.58) and creatinine clearance (HR, 7.89, 95% CI, 2.73-19.10) were predictors of long-term CVD risk, while NDD and PKD were not. CONCLUSIONS: IGT significantly increased the long-term risk of developing CVD in patients with CAD after PCI compared with diabetes.

Impact of glycemic variability on myocardial infarct size in patients with ST-segment elevation myocardial infarction: quantitative assessment of left ventricular wall motion severity.

Glycemic variability (GV) is relevant to impaired myocardial salvage in acute ST-elevation myocardial infarction (STEMI). Severity of hypokinesis at the infarct site as assessed from contrast left ventriculography can reportedly predict infarct size in STEMI. We prospectively studied 58 consecutive patients (mean age, 63 ± 11 years) with anterior or inferior STEMI who underwent successful reperfusion therapy. Mean amplitude of glucose excursion (MAGE) was obtained from continuous glucose monitoring system. Patients were divided into the upper tertile of MAGE as Group H, and the other two-thirds as Group L. Serial regional wall motion severity at the infarct site was computed postprocedure and at follow-up using a quantitative left ventricular analysis system. Impaired myocardial salvage was defined as severity recovery ratio < 20%. Significantly shorter onset-to-balloon time (196.9 vs. 279.0 min, p = 0.033) and relatively lower postprocedural wall motion severity (2.4 vs. 2.9, p = 0.096) were observed in Group H, but absolute severity recovery was significantly smaller in Group H (0.5 vs. 1.3, p = 0.017). Multivariate analysis showed higher MAGE as predictive of impaired myocardial salvage (OR, 406.10; 95% CI, 4.41-37,366.60; p = 0.009). Recovery of reginal wall motion severity at the infarct site was compromised in STEMI patients with higher MAGE. Our results suggest that final infarct size is potentially larger than expected in STEMI patients with higher GV.

Clinical Predictors of Recurrent Ventricular Arrhythmias in Secondary Prevention Implantable Cardioverter Defibrillator Recipients With Coronary Artery Disease　- Lower Left Ventricular Ejection Fraction and Incomplete Revascularization.

BACKGROUND: The implantable cardioverter defibrillator (ICD) is a standard prevention therapy for patients at high risk for sudden cardiac death (SCD) due to life-threatening ventricular arrhythmia (VA), that is, ventricular fibrillation and ventricular tachycardia. However, clinical predictors of recurrent VA in secondary prevention ICD recipients with coronary artery disease (CAD) remain unknown. Methods and Results: We followed up 96 consecutive patients with CAD undergoing ICD implantation for secondary prevention of SCD. Long-term rates and clinical predictors of appropriate ICD therapy (ICD-Tx) for VA were analyzed. Appropriate ICD-Tx occurred in 41 (42.7%) patients during a median follow-up of 2.4 years (interquartile range, 0.9-6.1). These patients had significantly greater left ventricular end-diastolic diameter (62.3±1.3 vs. 54.6±1.1 mm, P<0.001), lower left ventricular ejection fraction (LVEF; 36.3±2.0% vs. 45.7±1.8%, P<0.001), and more incomplete revascularization (ICR; 70.7% vs. 45.5%, P=0.014) than those without appropriate ICD-Tx. Multivariable analysis showed that LVEF (hazards ratio [HR], 0.950; 95% CI: 0.925-0.975; P<0.001) and ICR (HR, 2.293; 95% CI: 1.133-4.637; P=0.021) were significant predictors of appropriate ICD-Tx for VA. CONCLUSIONS: Lower LVEF and ICR were independent predictors of recurrent VA in secondary prevention ICD recipients with CAD.

Dynamic left ventricular outflow tract obstruction complicated with takotsubo cardiomyopathy: The acute phase of takotsubo cardiomyopathy manifests latent left ventricular outflow tract obstruction.

Dynamic left ventricular (LV) outflow tract (LVOT) obstruction is sometimes complicated with takotsubo cardiomyopathy (TC). The present case involves a 70-year-old woman with chest discomfort. Seven years earlier, transthoracic echocardiography revealed LVOT obstruction due to a sigmoid-shaped septum. She underwent urgent cardiac catheterization for suspected acute coronary syndrome. She was diagnosed as having TC with LVOT obstruction. After undergoing conservative treatment, her LV function normalized and the LVOT obstruction resolved. After the LV wall motion normalized, administering an intravenous infusion of dobutamine again provoked LVOT obstruction. In this situation, the presence of TC manifested latent LVOT obstruction. .

Efficacy of Corticosteroid Treatment for Refractory Multivessel Vasospastic Coronary Angina with Hypereosinophilia.

A 43-year-old man was diagnosed with acute myocardial infarction (AMI) due to multivessel coronary vasospasm. Accordingly, two coronary vasodilators were administered, and he was discharged without an angina attack. However, from the following day, he reported frequent chest pain and was re-hospitalized. Despite adding multiple coronary vasodilators, it was difficult to completely suppress the angina attack. He also demonstrated hypereosinophilia from the onset of AMI, and his eosinophil count gradually increased up to 6,238/µL. After corticosteroid administration was started, the vasospasm was completely controlled, and his eosinophil count normalized. He remained free from angina attacks for two years with corticosteroid therapy.

Significance of Sarcopenia Evaluation in Acute Decompensated Heart Failure.

In patients with chronic heart failure (HF), the clinical importance of sarcopenia has been recognized in relation to disease severity, reduced exercise capacity, and adverse clinical outcome. Nevertheless, its impact on acute decompensated heart failure (ADHF) is still poorly understood. Dual-energy X-ray absorptiometry (DXA) is a technique for quantitatively analyzing muscle mass and the degree of sarcopenia. Fat-free mass index (FFMI) is a noninvasive and easily applicable marker of muscle mass.This was a prospective observational cohort study comprising 38 consecutive patients hospitalized for ADHF. Sarcopenia, derived from DXA, was defined as a skeletal muscle mass index (SMI) two standard deviations below the mean for healthy young subjects. FFMI (kg/m2) was calculated as 7.38 + 0.02908 × urinary creatinine (mg/day) divided by the square of height (m2).Sarcopenia was present in 52.6% of study patients. B-type natriuretic peptide (BNP) levels were significantly higher in ADHF patients with sarcopenia than in those without sarcopenia (1666 versus 429 pg/mL, P < 0.0001). Receiver operator curves were used to compare the predictive accuracy of SMI and FFMI for higher BNP levels. Areas under the curve for SMI and FFMI were 0.743 and 0.717, respectively. Multiple logistic regression analysis showed sarcopenia as a predictor of higher BNP level (OR = 18.4; 95% CI, 1.86-181.27; P = 0.013).Sarcopenia is associated with increased disease severity in ADHF. SMI based on DXA is potentially superior to FFMI in terms of predicting the degree of severity, but FFMI is also associated with ADHF severity.

Dual Antiplatelet Therapy Guided by CYP2C19 Polymorphisms after Implantation of Second-Generation Drug-Eluting Stents for Management of Acute Coronary Syndrome.

Prasugrel, a novel P2Y12 receptor inhibitor, is administered to patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI), but it can increase the risk of bleeding. The Japanese exhibit weaker responses to clopidogrel than other races because of CYP2C19 polymorphisms; thus, it is unclear whether these patients should continue dual antiplatelet therapy (DAPT) using prasugrel or switch to clopidogrel in the chronic phase. Here we evaluated the clinical outcomes of DAPT guided by CYP2C19 polymorphisms after implantation of second-generation drug-eluting stents (DESs) for ACS management. Patients with ACS receiving PCI via DES from November 2011 to March 2015 were divided into two groups: conventional DAPT with clopidogrel (n = 41) and gene-guided DAPT (n = 24). In the gene-guided DAPT group, all patients with ACS were given DAPT using prasugrel as soon as possible; extensive and intermediate metabolizers receiving PCI for the first time were switched to clopidogrel at least 2 weeks after discharge, and intermediate metabolizers with repeated ACS and poor metabolizers continued on DAPT using prasugrel. Notably, gene-guided DAPT significantly reduced major adverse cardiovascular/cerebrovascular events (MACCEs; 22.0% versus 4.2%, hazard ratio [HR]: 0.15, 95% confidence interval [CI]: 0.01-0.81; P = 0.0247). Hemorrhagic complications were observed in 3.1% of patients receiving conventional DAPT and absent in the gene-guided group. Moreover, multivariate analysis showed that gene-guided DAPT significantly decreased MACCE incidence (HR: 0.15, 95% CI: 0.01-0.81; P = 0.033). Collectively, these data suggest that CYP2C19 polymorphism analysis may improve treatment decisions in patients with ACS receiving DES-PCI.

Manifestation of Latent Left Ventricular Outflow Tract Obstruction in the Acute Phase of Takotsubo Cardiomyopathy.

Objective Left ventricular outflow tract (LVOT) obstruction is a complication in 15-25% of patients with Takotsubo cardiomyopathy and sometimes leads to catastrophic outcomes, such as cardiogenic shock or cardiac rupture. However, the underlying mechanisms have not been clarified. Methods and Results We experienced 22 cases of Takotsubo cardiomyopathy during 3 years, and 4 of these 22 cases were complicated with LVOT obstruction in the acute phase (mean age 79±5 years, 1 man, 21 women). The LVOT pressure gradient in the acute phase was 100±17 mmHg. Transthoracic echocardiogram (TTE) revealed left ventricular hypertrophy (LVH) in one case and sigmoid-shaped septum without LVH in three cases. The complete resolution of the LVOT obstruction was achieved in a few days with normalization of the left ventricular wall motion following administration of beta-blockers. A dobutamine provocation test after normalization of the left ventricular wall motion reproduced the LVOT obstruction in all cases and revealed the presence of latent LVOT obstruction. Conclusion The manifestation of latent LVOT obstruction in the acute phase of Takotsubo cardiomyopathy is one potential reason for the complication of LVOT obstruction with Takotsubo cardiomyopathy.

Follistatin like 1 Regulates Hypertrophy in Heart Failure with Preserved Ejection Fraction.

OBJECTIVE: We sought to determine whether Fstl1 plays a role in the regulation of cardiac hypertrophy in HFpEF. BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF), accounts for ~50% of all clinical presentations of HF and its prevalence is expected to increase. However, there are no evidence-based therapies for HFpEF; thus, HFpEF represents a major unmet need. Although hypertension is the single most important risk factor for HFpEF, with a prevalence of 60-89% from clinical trials and human HF registries, blood pressure therapy alone is insufficient to prevent and treat HFpEF. Follistatin like 1 (Fstl1), a divergent member of the follistatin family of extracellular glycoproteins, has previously been shown to be elevated in HF with reduced ejection fraction (HFrEF) and associated with increased left ventricular mass. METHODS AND RESULTS: In this study, blood levels of Fstl1 were increased in humans with HFpEF. This increase was also evident in mice with hypertension-induced HFpEF and adult rat ventricular myocytes stimulated with aldosterone. Treatment with recombinant Fstl1 abrogated aldosterone-induced cardiac myocyte hypertrophy, suggesting a role for Fstl1 in the regulation of hypertrophy in HFpEF. There was also a reduction in the E/A ratio, a measure of diastolic dysfunction. Furthermore, HFpEF induced in a mouse model that specifically ablates Fstl1 in cardiac myocytes (cFstl1-KO), showed exacerbation of HFpEF with worsened diastolic dysfunction. In addition, cFstl1-KO-HFpEF mice demonstrated more marked cardiac myocyte hypertrophy with increased molecular markers of anp and bnp expression. CONCLUSIONS: These findings indicate that Fstl1exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF.

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.

[Anti-hypertensive therapies in patients with heart disease].

Abstract Hypertension is the major cause of cardiovascular disease. Persistent hypertension leads to cardiovascular remodeling and resulted in heart diseases such as coronary artery disease, heart failure, and arrhythmia. The presence of hypertension could also be a precipitating factor of heart diseases and form vicious cycle. Therefore, perfect blood pressure control is essential for the prevention of cardiovascular events. Additionally, it is ideal to choose anti-hypertensive agents, which have cardiovascular-protective effects as well as strong blood pressure-lowering effects. We herein describe anti-hypertensive therapies in patients with heart disease in accordance with JSH2014 and JCS guidelines.

Elevated Endomyocardial Biopsy Macrophage-Related Markers in Intractable Myocardial Diseases.

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients (n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction (n = 78) and immunohistochemistry (n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as "improved" or "non-improved" defined as a 10% increase in left ventricular ejection fraction by echocardiograph and a value greater than 30% at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as "non-improvement diseases," had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC.

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.