CORRIGENDUM: Deterioration of Phosphate Homeostasis Is a Trigger for Cardiac Afterload　- Clinical Importance of Fibroblast Growth Factor 23 for Accelerated Aging.

[This corrects the article DOI: 10.1253/circrep.CR-22-0124.].

Deterioration of Phosphate Homeostasis Is a Trigger for Cardiac Afterload　- Clinical Importance of Fibroblast Growth Factor 23 for Accelerated Aging.

Background: After the discovery of the Klotho gene, phosphate came into focus as a pathogenetic aging agent. Phosphate homeostasis is controlled by phosphate-regulating hormones: fibroblast growth factor 23 (FGF23), vitamin D3, and parathyroid hormone. This study investigated the relationship between the deterioration in phosphate homeostasis and arterial stiffness by measuring serum FGF23 concentrations. Methods and Results: The study subjects comprised 82 hospitalized patients (31 males, 51 females; mean [±SD] age 78.6±10.5 years). All patients underwent chest computed tomography, measurement of central blood pressure (BP), and blood chemistry tests. Arterial calcification and/or stiffness was evaluated using the Agatston calcification score (ACS) and pulse wave velocity (PWV). PWV was significantly correlated with age (t=23.47, P<0.0001), estimated glomerular filtration rate (eGFR; t=-4.40, P<0.0001), and ACS (t=4.36, P<0.0001). Serum FGF23 concentrations were significantly correlated with age (t=2.52, P=0.014), eGFR (t=-3.37, P<0.001), serum inorganic phosphorus concentrations (t=3.49, P<0.001), serum vitamin D3 concentrations (t=-4.57, P<0.001), ACS (t=2.30, P=0.025), augmentation pressure (t=2.48, P=0.015), central systolic BP (t=2.00, P=0.049), plasma B-type natriuretic peptide (BNP) concentrations (t=3.48, P<0.001), and PWV (t=2.99, P=0.004). PWV was positively related to augmentation pressure (t=4.09, P<0.001), central systolic BP (t=3.13, P=0.002), and plasma BNP concentrations (t=3.54, P<0.001). Conclusions: This study shows that the increase in serum FGF23 concentrations reflects deterioration of phosphate homeostasis and is an important predictor for arterial stiffness, which intensifies cardiac afterload.

ß-Blockers are associated with increased B-type natriuretic peptide levels differently in men and women in heart failure with preserved ejection fraction.

ß-Blocker (BB) use is a mainstay for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF), whereas its efficacy for heart failure with preserved ejection fraction (HFpEF) remains controversial. Women outnumber men in HFpEF, whereas men outnumber women in HFrEF. Plasma B-type natriuretic peptide (BNP) is established as a biomarker for HF. We examined whether BB use is associated with plasma BNP levels differently in men and women with HFpEF. The study subjects comprised 721 patients with HFpEF [left ventricular ejection fraction (LVEF) ≥ 50%] (184 men, mean age 78.2 ± 9.2 yr and 537 women, mean age 83.1 ± 8.8 yr), 179 on BB (66 men and 113 women) and 542 no BB (118 men and 424 women), 583 in sinus rhythm (SR) and 138 in atrial fibrillation (AF). A multivariable logistic regression test was used. Plasma BNP levels were higher (P = 0.0005), systolic blood pressure and LVEF lower (P = 0.0003, and P = 0.0059, respectively) on BBs than on no BBs in women, whereas in men, plasma BNP levels, systolic blood pressure, and LVEF were not altered significantly (P = 0.0849, P = 0.9129, and P = 0.4718, respectively) on BBs compared with no BBs in patients with SR. Multivariable logistic regression analysis revealed that BB use and women were a positive and a negative predictor for high BNP levels (P = 0.003 and P = 0.032, respectively) in SR but not in AF. BB use was associated with high-plasma BNP levels and lower LVEF in women but not in men with HFpEF and SR, suggesting that the pathogenesis and treatment of HFpEF may differ in men and women in SR.NEW & NOTEWORTHY Pathogenesis and treatment for heart failure with preserved ejection fraction (HFpEF) may differ in men and women in sinus rhythm (SR).

East Asians Variant Mitochondrial Aldehyde Dehydrogenase 2 Genotype Exacerbates Nitrate Tolerance in Patients With Coronary Spastic Angina.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) plays a central role in the biotransformation of glyceryl trinitrate (GTN) or nitroglycerin, which is widely used for the treatment of coronary artery disease (CAD). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. This study examined whether there are differences in nitroglycerine-mediated dilation (NMD) and flow-mediated dilation (FMD) response between wildALDH2*1/*1and variantALDH2*2patients with CAD.Methods and Results:The study subjects comprised 55 coronary spastic angina (CSA) patients, confirmed by coronary angiography and intracoronary injection of acetylcholine (42 men and 13 women, mean age 68.0±9.0 years). They underwent NMD and FMD tests in the morning before and after continuous transdermal GTN administration for 48 h. NMD was lower at baseline inALDH2*2than in theALDH2*1/*1group (P=0.0499) and decreased significantly in both groups (P<0.0001 and P<0.0001, respectively) after GTN, with significantly lower levels in theALDH2*2group (P=0.0002). FMD decreased significantly in bothALDH2*1/*1andALDH2*2groups (P<0.0001and P=0.0002, respectively) after continuous GTN administration, with no significant differences between the 2 groups both before and after GTN. CONCLUSIONS: Continuous administration of GTN produced endothelial dysfunction as well as nitrate tolerance in bothALDH2*1/1andALDH2*2patients with CSA.ALDH2*2attenuated GTN response and exacerbated GTN tolerance, but not endothelial dysfunction, as compared toALDH2*1/*1in patients with CSA.

Sex Differences in Heart Failure With Preserved Ejection Fraction Reflected by B-type Natriuretic Peptide Level.

BACKGROUND: Prevalence of heart failure with preserved ejection fraction (HFpEF) increases with advancing age, particularly among women. Plasma levels of B-type natriuretic peptide (BNP), a surrogate marker of heart failure, have consistently been shown to be higher in women in the general populations. Whether BNP levels differ as per the sex of HFpEF patients remains largely unknown. MATERIALS AND METHODS: The study subjects were 733 HFpEF patients (204 men and 529 women, aged 80.9 ± 9.6 years) who underwent echocardiography and routine clinical examination, including plasma BNP level evaluation. These parameters were compared between women and men. RESULTS: Plasma levels of BNP were significantly lower in women than in men (104 [61, 192] versus 133 [78, 255] pg/mL, P < 0.001), just as hemoglobin, atrial fibrillation, diabetes mellitus, beta-blockers, left ventricular diastolic dimension, left ventricular mass index, left ventricular eccentric hypertrophy and left atrial dimension were. Age, systolic blood pressure, pulse pressure, heart rate, left ventricular relative wall thickness, left ventricular ejection fraction and left ventricular concentric hypertrophy were higher in women than in men. Multiple regression analyses revealed that left ventricular mass index, body mass index, the ratio of early diastolic mitral flow velocity to tissue annular motion velocity divided by left ventricular diastolic dimension, estimated glomerular filtration rate, beta-blockers, left atrial dimensions, female sex and atrial fibrillation were significant predictors for BNP levels (t = 5.41, P < 0.001; t = -4.06, P < 0.001; t = 3.76, P < 0.001; t = -3.68, P < 0.001; t = 3.32, P = 0.001; t = 3.11, P = 0.002; t = -3.07, P = 0.002; and t = 2.65, P = 0.008, respectively). CONCLUSIONS: Plasma BNP levels were lower in women and were related to left ventricular concentric remodeling and hypertrophy among HFpEF patients, contrary to those in the general population.

The diabetic heart utilizes ketone bodies as an energy source.

BACKGROUND: Diabetic heart is characterized by failure of insulin to increase glucose uptake and increasingly relies on free fatty acids (FFAs) as a source of fuel in animal models. However, it is not well known how cardiac energy metabolism is altered in diabetic hearts in humans. We examined cardiac fuel metabolism in the diabetics as compared to non-diabetics who underwent cardiac catheterization for heart diseases. MATERIAL AND METHODS: The study subjects comprised 81 patients (male 55, female 26, average age 63.0±10.0years) who underwent the cardiac catheterization for heart diseases. Thirty-six patients were diagnosed as diabetics (diabetic group) and 45 as non-diabetics (non-diabetic group). Blood samplings were done in both the aortic root (Ao) and coronary sinus (CS) simultaneously and the plasma levels of FFAs, glucose, lactate, pyruvate, total ketone bodies and ß-hydroxybutyrate were measured and compared between the two groups. RESULTS: The myocardial uptake of glucose, lactate and pyruvate were decreased, whereas those of total ketone bodies, ß-hydroxybutyrate and acetoacetate were increased in the diabetics as compared to the non-diabetics. However, the myocardial uptakes of FFAs were not significantly increased in the diabetics as compared to the non-diabetics. CONCLUSIONS: Cardiac uptakes of carbohydrate (glucose, lactate and pyruvate) were decreased, whereas those of total ketone bodies and ß-hydroxybutyrate were increased in the diabetics as compared to the non-diabetics in humans. Ketone bodies therefore are utilized as an energy source partially replacing glucose in the human diabetic heart.

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　- Relevance to Age-Related Left Ventricular Modeling in Japanese.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is increasing with aging of the population. Plasma levels of B-type natriuretic peptide (BNP) increase in proportion to the severity of left ventricular (LV) dysfunction. The object of this study was to examine the plasma levels of BNP in HFpEF to better understand the pathogenesis of HFpEF as compared with HF with reduced EF (HFrEF).Methods and Results:The study subjects comprised 468 HFpEF patients (158 men, 310 women, mean age 81.3±9.6 years) and 126 HFrEF patients (77 men, 49 women, mean age 75.4±12.0 years) who underwent echocardiography and routine clinical examinations including plasma BNP. Age, female prevalence, systolic blood pressure and pulse pressure were higher in the HFpEF patients than in the HFrEF patients (P<0.0001, P<0.001, P<0.0001, and P<0.0001, respectively). Plasma BNP levels, LV diastolic dimensions, and LV mass index (LVMI) were lower (P<0.0001, P<0.0001, and P<0.0001, respectively), while relative wall thickness was higher (P<0.0001) in the HFpEF patients than in the HFrEF patients. Multiple regression analysis revealed that LVMI, EF, plasma levels of albumin, C-reactive protein, and uric acid were the predictors of BNP levels (P<0.001, P<0.001, P=0.009, P=0.012, and P=0.018, respectively). CONCLUSIONS: Plasma BNP levels were lower and related to aging-related LV concentric remodeling/hypertrophy in HFpEF patients as compared with HFrEF patients, who were associated predominantly with eccentric LV hypertrophy.

Low responsiveness to thienopyridine in hemodialysis patients.

We sought to evaluate whether thienopyridine low responsiveness, a predictor of stent thrombosis, is found in hemodialysis patients. We measured platelet aggregation at the site of implantation of drug-eluting stents in 333 patients with angina pectoris undergoing dual anti-platelet therapy. Thirty-one patients were on hemodialysis (HD group), and 302 were not (N-HD group). We used a novel whole-blood aggregometer. The aggregometer used the screen filtration method, with adenosine diphosphate as an agonist. The concentration of agonist required to induce 50% of the maximum pressure rate was calculated and indicated as the platelet aggregatory threshold index (PATI). Low responsiveness for thienopyridine was defined if the PATI levels were <4 µmol/l. PATI levels (µmol/l) were significantly lower in the HD group than in the N-HD group (6.8 ± 4.8 vs. 9.1 ± 5.4, P = 0.023), and the rate of low responsiveness for thienopyridine was significantly higher in the HD group than in the N-HD group (45.7 vs. 26.8%, P = 0.019). Non-fatal myocardial infarction and stent thrombosis occurred in three of the HD group and in nine of the N-HD group (P = 0.122). Late stent thrombosis occurred at a significantly higher rate in the HD group than in the N-HD group (P = 0.002). The rate of target lesion revascularization was significantly higher in the HD group than in the N-HD group (38 vs. 11.8%, P = 0.0001). In conclusion, low responsiveness to thienopyridine, as an indicator of platelet reactivity, is found more frequently in hemodialysis patients.

[Bilateral multiple border zone infarctions after massive bleeding: report of two cases].

We present two patients who developed bilateral border zone brain infarctions after massive bleeding. Patient 1 was a 46-year old woman who developed bilateral visual disturbance and left hand monoparesis after excessive menstruation with severe anemia. Diffusion-weighted MRI of brain showed multiple border zone infarcts bilaterally in cerebral and cerebellar hemispheres while brain MRA was normal. Patient 2 was a 67-year old man who developed disturbance of consciousness and right hemiplegia after upper gastrointestinal tract bleeding. Diffusion-weighted MRI of brain showed bilateral multiple border zone infarcts in cerebral hemispheres, although he had asymptomatic occlusion of the left internal carotid artery. The bilateral multiple border zone infarcts are one of the key findings suggesting the presence of anemic hypoxia as a result of global brain hypoperfusion caused by massive blood loss.