Altitude-Induced Pulmonary Hypertension on One-Day Rapid Ascent of Mount Fuji: Incidence and Therapeutic Effects of Sildenafil.

AIMS: Exposure to high altitudes especially with rapid ascent may induce hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension (PH) possibly leading to life-threatening high-altitude pulmonary edema (HAPE). The aim of the study was to evaluate the incidence of PH on a 1-day rapid ascent up Mount Fuji (3775 m) in recreational climbers and also to determine the effectiveness of sildenafil for this rapid ascent-induced PH as measured by echocardiography. METHODS AND RESULTS: Twenty-five subjects who climbed Mount Fuji showed significantly increased pulmonary artery systolic pressure (PASP) from 22.3 ± 5.3 mmHg at sea level to 29.4 ± 8.7 mmHg at 3775 m. Five subjects showed PASP >35 mmHg (35.6-46.2 mmHg, average 42.0 ± 3.9 mmHg) and took oral sildenafil 50 mg after which PASP decreased significantly to 24.5 ± 4.6 mmHg (18.7-31.0 mmHg) after 30 minutes. CONCLUSIONS: One-day rapid ascent of Mount Fuji may induce mild-to-moderate PH and intervention with sildenafil can reduce this PH, suggesting that the therapeutic use of sildenafil would be more reasonable for the relatively infrequent occurrence of altitude-induced PH than its prophylactic use.

Febuxostat (Feburic tablet) in the management of hyperuricemia in a general practice cohort of Japanese patients with a high prevalence of cardiovascular problems.

Hyperuricemia is increasing in prevalence and this is paralleled by an increased incidence of acute gout. In addition, there is growing evidence of an association between high serum levels of uric acid (sUA) and cardiovascular disease (CVD). In this preliminary report, we present 12-16 week results from a multicenter, general practice study in which we evaluated the usefulness of febuxostat in a cohort of untreated patients with hyperuricemia with a high prevalence of CVD. Febuxostat titrated from 10 mg/day up to 40 mg/day resulted in statistically significant and clinically relevant reductions in sUA after 12-16 weeks. A "responder" level of 6.0 mg/dL or lower was achieved in 95 of 100 (95%) patients. Significant reductions in sUA were achieved regardless of the presence/absence of coexisting diseases (e.g. CVD, renal insufficiency, diabetes and obesity) or the class of antihypertensive agent being used by the patient. No serious adverse reactions were noted with febuxostat. Although allopurinol has been used generally for hyperuricemia/gout, it is excreted fully via the kidneys, restricting its use in patients with reduced renal function, and its three-times-daily administration leads to poor adherence. Based on the results of this study, febuxostat may provide an easier option than allopurinol for clinicians specializing in CVDs.

Serum angiotensin-converting enzyme levels indicating early sarcoidosis diagnosis and immunosuppressive therapy efficacy.

AIMS: This study aimed to determine the new cut-off value of serum angiotensin-converting enzyme (ACE) levels for detecting patients with sarcoidosis and to examine the change in ACE levels after the initiation of immunosuppressive therapy. METHODS AND RESULTS: We retrospectively examined patients in whom serum ACE levels were measured for suspected sarcoidosis between 2009 and 2020 in our institution. For patients diagnosed with sarcoidosis, changes in ACE levels were also observed. Of the 3781 patients (51.1% men, 60.1 ± 17.0 years old), 477 were excluded for taking ACE inhibitors and/or immunosuppression agents or those with any diseases affecting serum ACE levels. In 3304 patients including 215 with sarcoidosis, serum ACE levels were 19.6 IU/L [interquartile range, 15.1-31.5] in patients with sarcoidosis and 10.7 [8.4-16.5] in those without sarcoidosis (P < 0.01), and the best cut-off value was 14.7 IU/L with 0.865 of the area under the curves. Compared with the current ACE cut-off of 21.4, the sensitivity improved from 42.3 to 78.1 at the new cut-off, although specificity slightly decreased from 98.6 to 81.7. The ACE level significantly decreased more in those with immunosuppression therapy than in those without it (P for interaction <0.01), although it decreased in both groups (P < 0.01). CONCLUSIONS: Because the sensitivity for detecting sarcoidosis is comparatively low at the current standard value, further examinations are needed for patients suspected of sarcoidosis with relatively high ACE levels in the normal range. In patients with sarcoidosis, ACE levels decreased after the initiation of immunosuppression therapy.

Cardio-renal interaction: impact of renal function and anemia on the outcome of chronic heart failure.

The purpose of this study is to investigate the effects of renal function and anemia on the outcome of chronic heart failure (CHF). We targeted 711 consecutive patients who were hospitalized at the Division of Cardiology of Fujita Health University Hospital during a 5-year period. The subjects were divided into four groups according to their estimated glomerular filtration rate (e-GFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula. Intergroup comparisons were conducted for underlying heart diseases, clinical findings at the time of hospitalization, treatment, and outcome. Moreover, the patients were divided into two groups according to their serum hemoglobin concentration at the time of hospitalization, using 12.0 g/dl as the dividing point, to study the effects of anemia on the outcome. In the group with decreased renal function, the average age was higher, and ischemic heart disease and associated conditions such as hypertension and diabetes mellitus were observed in most of the patients. In addition, the rate of anemia development and the plasma B-type natriuretic peptide concentration were also high. The greater the deterioration in renal function, the poorer the outcome became (P < 0.0001). Chronic heart failure complicated by anemia showed an especially poor outcome (P < 0.0001). As this study showed that renal function and anemia significantly affected the outcome of CHF, it is clear that the preservation of renal function and the management of anemia are important in addition to the conventional treatments for CHF.

Diagnosis of isolated cardiac sarcoidosis based on new guidelines.

AIMS: In the updated guidelines for cardiac sarcoidosis (CS) proposed by the Japanese Circulation Society (JCS), the definition of isolated CS (iCS) was established for the first time. This prompted us to examine the characteristics of patients with CS including iCS according to them by reviewing patients undergoing 18 F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography (FDG-PET/CT), compared with those with CS determined by the conventional international criteria. METHODS AND RESULTS: From 2013 to 2019, 94 patients (61 ± 15 years, 50 female patients) with suspected CS underwent whole-body and cardiac FDG-PET/CT scanning. In contrast to 22 patients with CS based on the international criteria, 34 [27 with systemic sarcoidosis including cardiac involvement (sCS) and 7 with definitive iCS] were diagnosed with CS according to the new JCS guidelines (P = 0.012), and 60 were not (4 suspected iCS, 13 systematic sarcoidosis without cardiac involvement, and 43 no sarcoidosis). In addition to 26 of 34 patients with CS, corticosteroids were also started in 6 of 60 without CS according to clinical need. CONCLUSIONS: Diagnostic yield with the new JCS guidelines was higher, with approximately 1.5-fold of the patients diagnosed with CS compared with the previous international criteria and definitive iCS accounting for approximately 20% of the whole CS cohort. In addition to 75% of the patients with sCS or definitive iCS in the updated guidelines, 10% in whom CS was not documented were also started on corticosteroids for clinical indications such as reduced cardiac function or arrhythmia.

Management of severe heart failure.

Patients admitted to the hospital with heart failure (HF) include those with new-onset of acute HF and those with acute exacerbation of chronic HF (CHF). In therapy for new-onset acute HF associated with acute myocardial infarction, therapy to inhibit left ventricular (LV) remodeling in the convalescent phase is required in addition to that needed to overcome the acute phase. Hitherto, CHF therapy was aimed at improving LV contractability, whereas more recently the aim has shifted to resting the heart. Most patients with HF should be routinely managed with a combination of 3 types of drugs: a diuretic; an angiotensin converting enzyme inhibitor and/or an angiotensin II receptor blocker; and a beta-blocker. The administration of beta-blockers is of particular importance. For HF unresponsive to medical therapy, non-pharmacological therapies are considered. When a HF patient fails to respond to all available therapies, heart transplantation becomes necessary. Of the 1,000 HF patients admitted to our hospital, two cases received heart transplants. 11 cases were indicated for heart transplantation but died before registration. It should be remembered that although in Japan the possibility of receiving a heart transplant is very low, it is by no means entirely impossible.

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

BACKGROUND: Although 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: Our 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.

Recovery from anthracycline-induced cardiomyopathy with biventricular assist and valve repairs: A case report and literature review.

INTRODUCTION: Ventricular assist device is used in the patients with severe heart failure due to cardiotoxicity of anthracyclines, which are widely used chemotherapeutic agents for a wide range of malignant tumors. However, recovery of cardiac function is rare. METHODS: We present the clinical course of a 43-year-old woman in remission from diffuse large B-cell lymphoma after the chemotherapy including anthracyclines, who presented in cardiogenic shock 8 months after the end of chemotherapy. RESULTS: The patient was initially treated with intra-aortic balloon pumping, followed by conversion to left ventricular assist device with an Abiomed AB5000 (Abiomed, Inc, Danvers, MA) and right ventricular assist device with a centrifugal pump and a membrane oxygenator, in addition to tricuspid annuloplasty, due to rapid deterioration to cardiogenic shock. With intensive medical treatments during biventricular support, her cardiac and respiratory functions gradually improved, although moderate mitral regurgitation persisted despite of left ventricular unloading. At 64 days of biventricular support, she underwent mitral valve annuloplasty to correct regurgitation under cardiopulmonary bypass. She was consequently weaned from biventricular assist successfully 8 days after mitral surgery (72 days of biventricular support). The patient discharged uneventfully from our hospital and survives at home 12 months after weaning from the ventricular assist devices. CONCLUSION: Our case and the literature review highlight potential usefulness of aggressive mechanical biventricular support for cardiac recovery in patients with anthracycline-induced cardiomyopathy. Additional valve surgery and neurohormonal medications may be also promising in such patients with cancer, who are contraindicated for heart transplantation.

Relief of left ventricular outflow obstruction by cibenzoline in a patient with Fabry's disease--a case report.

A 46-year-old man was admitted for further evaluation of exertional chest discomfort. One family member had experienced sudden death, and 2 others had died of heart failure, including 1 known to have had Fabry's disease. The patient was also diagnosed with Fabry's disease, based on reduced leukocyte alpha-galactosidase A activity, 2.0 nmol/mg protein/hour, as well as endomyocardial biopsy findings of marked sarcoplasmic vacuolization of cardiac muscle cells by light microscopy and lamellated "zebra bodies'' in the cytoplasm shown by electron microscopy. Echocardiography disclosed marked left ventricular hypertrophy and systolic anterior motion of the mitral leaflets. On cardiac catheterization, a left ventricular peak systolic outflow gradient of 50 mm Hg was noted; this decreased to 10 mm Hg following intravenous administration of 100 mg of cibenzoline. It is imperative to recognize the existence of cases with Fabry's disease associated with left ventricular outflow obstruction.

Suppressed expression of GTP cyclohydrolase I mRNA and accelerated expression of inducible nitric oxide synthase mRNA in endomyocardial biopsy specimens from patients with dilated cardiomyopathy.

BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase, and GTP cyclohydrolase I (GCHI) is a rate-limiting enzyme in the biosynthesis of BH4. The expression of inducible nitric oxide synthase (iNOS) was earlier demonstrated in the ventricles of patients with dilated cardiomyopathy (DCM) although that of GCHI was not clarified. The present study was designed to determine the GCHI mRNA expression as well as to confirm iNOS mRNA expression in endomyocardial biopsy specimens from patients with DCM. METHODS: Clinical details were assessed in 19 patients with DCM and in 9 control subjects. The real-time reverse transcription polymerase chain reaction (PCR) was performed on total RNA extracted from endomyocardial biopsy specimens. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was quantified for use as an internal control. RESULTS: iNOS/GAPDH for the DCM samples was 4.8-fold greater than that for the control ones (P<0.01), whereas the GCHI/GAPDH for the DCM samples was reduced to 31.1% of the control (P<0.05). CONCLUSIONS: The increased expression of iNOS mRNA was confirmed in endomyocardial biopsy specimens from patients with DCM. The GCHI mRNA level was suppressed in these specimens.

National survey on status of steroid therapy for cardiac sarcoidosis in Japan.

AIM: This investigation was undertaken to clarify the current status of steroid therapy for cardiac sarcoidosis in Japan. METHODS: A questionnaire survey was conducted throughout Japan concerning cases in which steroid therapy had been administered. Replies describing 52 cases (15 men, 37 women; mean age +/- SD, 59.8 +/- 14.5 years) were analyzed. RESULTS: Of the 49 patients whose New York Heart Association (NYHA) functional classification was reported, 29 (55.8%) were in class I; 13 (25.0%) class II; 4 (7.7%) class III and 3 (5.8%) class IV. The most common initial steroid dose (used in 35 cases, or 67.3%) was 30 mg/day or 60 mg on alternate days. In most cases (85.4%), this dose was continued for 1 month followed by tapering by 5 mg every 2 to 4 weeks until reaching the maintenance dose of 5 to 10 mg/day. Steroid therapy was reported to result in improvement in 54%, no change in 40%, and deterioration in 6%. CONCLUSION: This nationwide questionnaire survey indicated fairly uniform patterns of steroid therapy for cardiac sarcoidosis in Japan, with clinical improvement in over one-half of cases and possible stabilization in most others.

Relationship between basal thinning of the interventricular septum and atrioventricular block in patients with cardiac sarcoidosis.

BACKGROUND: Basal thinning of the interventricular septum (IVS) and atrioventricular block (AVB) are characteristic features of cardiac sarcoidosis. Since the conduction system passes along IVS, it has been considered that a close connection exists between basal thinning of IVS and AVB. However, neither the incidence of cases showing basal thinning of IVS nor the relation between it and AVB has been clarified. We thus investigated to elucidate these two issues. METHODS: Thirty-five patients with cardiac sarcoidosis were selected for this study and underwent echocardiographic examination. The wall thickness of IVS was measured at a site 1 cm below the aortic valve inserted point of IVS. Thickness of this site < or = 5 mm was defined as thinning. Twelve-lead and Holter electrocardiograms were obtained to determine the presence/absence and degree of AVB. RESULTS: Basal thinning of IVS was noted in 7 of the 35 patients (20%). AVB was present in 4 of these 7 (57%), and was first degree in 3 (43%) and third degree in one (14%). AVB was not present in 3 patients. Basal thinning of IVS was not apparent in 28 of the 35 patients (80%). AVB was observed in 14 of the 28 patients, 3 had first degree block, 2 had second degree block, and 9 had third degree block. AVB was not observed in 14 of the 28 patients. CONCLUSIONS: These results clarified that basal thinning of IVS is not as common as previously thought in cardiac sarcoidosis, basal thinning of IVS and the presence/absence and degree of AVB are not necessarily correlated.

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

BACKGROUND: Cardiac 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. OBJECTIVE: The purpose of this study was to examine whether the QRS score can be applied to CS. METHODS: CS-associated myocardial scar was assessed by both CMR-LGE and QRS scoring in patients with extra-CS (n = 59). RESULTS: Of 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). CONCLUSION: The 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.

Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.

BACKGROUND: The usefulness of corticosteroid therapy for cardiac sarcoidosis has not yet been fully clarified. METHODS: Of 40 patients diagnosed with cardiac sarcoidosis, twenty patients complicated by atrioventricular block but normal cardiac function (left ventricular ejection fraction > or = 50%) were divided retrospectively into one group (n = 7) receiving corticosteroids and another (n = 13) not receiving these agents. Over a mean observation period of 79.4 +/- 39.9 months, long-term outcome and laboratory findings were compared between the two groups and side effects also were noted. RESULTS: There were no deaths in the corticosteroid-treated group. In the untreated group, 2 patients died (15.4%). Atrioventricular block resolved in 4 of the 7 patients in the treated group (57.1%), but did not resolve or improve in any of the untreated patients (p < 0.05). Left ventricular ejection fraction did not differ significantly between the treated and untreated groups at the time of initial evaluation (66.7 +/- 6.5% vs. 60.5 +/- 6.4%). In the follow-up period, a marked decline in the ejection fraction had occurred in the untreated group (37.6 +/- 17.3%), but not in the treated group (62.1 +/- 4.4%; p < 0.005). Ventricular tachycardia was not present at the initial assessment in any patient in either group. In the follow-up period, ventricular tachycardia occurred in only 1 of 7 treated patients (14.3%), but was present in 8 of 13 untreated patients (61.5%; p < 0.05). However, side effects of corticosteroid therapy were noted in 6 of the 7 treated patients (85.7%). CONCLUSION: Our findings suggest that corticosteroids are useful in the treatment of cardiac sarcoidosis complicated by atrioventricular block but with normal cardiac function. However, these agents must be used with caution, with the maintenance dose kept as low as possible.

Coil migration into coronary sinus: a rare complication of percutaneous transhepatic obliteration of portal systemic collaterals.

A 62-year-old woman underwent percutaneous transhepatic obliteration of a giant portal-systemic shunt. Just after inserting a coil into the shunt, it slipped through the giant shunt and migrated to the right atrium. CT showed coil migration into the coronary sinus.

(99m)Tc-MIBI Washout Rate to Evaluate the Effects of Steroid Therapy in Cardiac Sarcoidosis.

OBJECTIVE: We sought to determine the usefulness of the (99m)Tc-MIBI (MIBI) washout rate for the evaluation of steroid therapy in cardiac sarcoidosis (CS). METHODS: Eleven CS patients underwent MIBI myocardial SPECT both before and 6 months after initiating steroid therapy. The washout rate (WOR) of MIBI was calculated using early and delayed polar map images. The washout score (WOS) of MIBI was derived from the difference between the early and delayed total defect scores (TDS). RESULTS: Serum ACE and BNP exhibited significant improvement after the therapy (p = 0.004, p = 0.045). In the LV function, EDV and E/A ratio exhibited significant improvement after the therapy (p = 0.041, p = 0.007), while there were no significant differences between before and after therapy in EF or ESV. Early and delayed TDS showed no significant differences between before and after the therapy. In contrast, WOR differed significantly (p <. 0001), while WOS did not differ significantly between before and after the therapy. CONCLUSION: The washout rate of MIBI is suitable for assessment of cardiac function in CS with steroid therapy, being especially better than the washout score of MIBI for assessment of disease activity of mild myocardial damage in CS with steroid therapy.

Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure.

It has been reported that angiotensin converting enzyme (ACE) 2, a homologue of ACE, has direct effects on cardiac function. However, the role of ACE2 in the development of human heart failure is not fully understood. We evaluated the expression of the ACE2 gene by means of real-time RT-PCR in myocardium from 14 patients with end-stage heart failure. The amount of ACE2 mRNA positively correlated with left ventricular (LV) end-diastolic diameter (r(2)=0.56, p<0.01) but did not significantly correlate with LV ejection fraction or plasma brain natriuretic peptide levels. In conclusion, our data show that the up-regulation of the ACE2 gene in the LV myocardium of patients with severe heart failure was associated with the degree of LV dilatation and may thereby constitute an important adaptive mechanism to retard the progression of adverse LV remodeling.

Long term prognosis of chronic heart failure: reduced vs preserved left ventricular ejection fraction.

BACKGROUND: Left ventricle diastolic dysfunction is attracting increasing attention of one of the etiologies of chronic heart failure (CHF). METHODS AND RESULTS: The study sample included 560 patients with CHF who were hospitalized during the 5-year period. They were classified into 2 groups according to the left ventricular ejection fraction (LVEF): reduced group (LVEF <50%, n=431); or preserved group (LVEF >or=50%, n=129). The degree of cardiac symptoms did not differ between the 2 groups; however, no difference was found between the 2 groups in the mortality rate (P=0.898), and readmission rates (P=0.674). The results of a multivariate analysis using a Cox proportional hazards model to identify predictors of the prognosis of heart failure revealed no difference in prognosis according to the presence/absence of decreased LVEF, whereas renal dysfunction and anemia were identified as significant prognostic determinants. Also, in the reduced group, the administration of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARB), beta-blockers reduced mortality. In the preserved group, ACE-I and/or ARB administration reduced mortality, whereas beta-blockers did not. CONCLUSION: In the present study, the likelihood of LVEF influencing prognosis was considered to be low, with the contribution of non-cardiac factors such as renal function and anemia concluded to be greater.