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 Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes generated during ischemia/reperfusion (I/R) injury in ST-elevation myocardial infarction (STEMI). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. Whether ALDH2*2 exacerbates I/R injury of in patients with STEMI is not known. The study subjects comprised 218 Japanese patients with STEMI (158 men and 60 women, mean age 67.9 ± 11.9) who underwent successful percutaneous coronary intervention. Of these, 120 (55.0%) were the carriers of variant ALDH2*2 and 98 (45.0%) those of wild ALDH2*1/*1 on genotyping. There were no differences in clinical characteristics between the ALDH2*2 and ALDH2*1/*1 group except lower alcohol habit (14.2% vs 46.3%, P < 0.001) in the ALDH2*2 group. The peak plasma levels of creatine phosphokinase myocardial binding (CKMB), a marker of myocardial injury, however, were significantly higher in the patients with ALDH2*2 than in those with ALDH2*1/*1 [a median 275.0 (175.8-407.5) vs 177.5 (126.9-344.3) U/L, P = 0.001] among men but not among women (P = 0.811). There was a significant interaction between men (male sex) and ALDH2*2 for I/R injury (χ2 = 4.425, P = 0.040). The variant ALDH2*2 was associated with more severe I/R injury than the wild ALDH2*1/*1 in STEMI patients in men with possible sex differences.

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.

Association of East Asian Variant Aldehyde Dehydrogenase 2 Genotype (ALDH2*2*) with Coronary Spasm and Acute Myocardial Infarction.

Coronary spasm plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, acute myocardial infarction (AMI), silent myocardial ischemia, and sudden death. The prevalence of coronary spasm is higher among East Asians probably due to genetic as well as environmental factors. ALDH2 eliminates toxic aldehydes including 4-hydroxy-2-nonenal (4-HNE) derived from lipid peroxidation and acrolein in tobacco smoking as well as ethanol-derived acetaldehyde and thereby protects tissues and cells from oxidative damage. Deficient variant ALDH2*2 genotype is prevalent among East Asians and is a significant risk factor for both coronary spasm and AMI through accumulation of toxic aldehydes, thereby contributing to oxidative stress, endothelial damage, vasoconstriction, and thrombosis. Toxic aldehydes are thus identified as risk factors to be targeted for the treatment of coronary spasm and AMI.

Coronary artery spasm - Clinical features, pathogenesis and treatment.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, myocardial infarction, and sudden death, occurring most often from midnight to early morning. CAS is prevalent among East Asians and is associated with an aldehyde dehydrogenase 2 (ALDH2)-deficient genotype (ALDH2*2) and alcohol flushing, which is prevalent among East Asians but is virtually non-existent in other populations. ALDH2 eliminates not only acetaldehyde but also other toxic aldehydes from lipid peroxidation and tobacco smoking, thereby protecting tissues and cells from oxidative damage. Risk factors for CAS include smoking and genetic polymorphisms including those of ALDH2*2, endothelial NO synthase, paraoxonase I, and interleukin-6. Accordingly, oxidative stress, endothelial dysfunction, and low-grade chronic inflammation play an important role in the pathogenesis of CAS, leading to increased coronary smooth muscle Ca2+ sensitivity through RhoA/ROCK activation and resultant hypercontraction. Ca-channel blockers blocking the intracellular entry of Ca2+ are specifically effective for treatment for CAS.

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.

Variant Aldehyde Dehydrogenase 2 (ALDH2*2) in East Asians Interactively Exacerbates Tobacco Smoking Risk for Coronary Spasm　- Possible Role of Reactive Aldehydes.

BACKGROUND: Coronary spastic angina (CSA) is common among East Asians and tobacco smoking (TS) is an established risk factor for CSA. Aldehyde dehydrogenase 2 (ALDH2) plays a key role in removing reactive toxic aldehydes and a deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. We examined the interaction between TS andALDH2*2as a risk factor for CSA to better understand the disease pathogenesis.Methods and Results:The study subjects comprised 410 patients (258 men, 152 women; mean age, 66.3±11.5) in whom intracoronary injection of acetylcholine was performed on suspicion of CSA.ALDH2genotyping was performed by direct application of the Taqman polymerase chain reaction system. Of the study subjects, 244 had CSA proven and 166 were non-CSA. The frequencies of male sex,ALDH2*2, alcohol flushing syndrome, TS, coronary organic stenosis, and plasma levels of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, P<0.001, and P=0.015, respectively) and that of high-density lipoprotein cholesterol lower (P=0.002) in the CSA than non-CSA group. Multivariable logistic regression analysis revealed thatALDH2*2and TS were significant risk factors for CSA (P<0.001 and P=0.002, respectively).ALDH2*2exacerbated TS risk for CSA more than the multiplicative effects of each. CONCLUSIONS: ALDH2*2synergistically exacerbates TS risk for CSA, probably through aldehydes.

Brain Natriuretic Peptide Counteracting the Renin-angiotensin-aldosterone System in Accelerated Malignant Hypertension.

We describe 2 patients, a 52-year-old woman and a 57-year-old man, with rapidly progressive hypertension and marked elevation of brain natriuretic peptide who exhibited polyuria, natriuresis, hypokalemia, posterior reversible encephalopathy syndrome and left ventricular dysfunction together with retinopathy and nephropathy, which were attenuated in a short time span of 1-2 months with normalization of blood pressure after the antihypertensive treatment. The possible role of brain natriuretic peptide in the pathophysiology of accelerated malignant hypertension was discussed and a review of the literature was completed.

Variant Aldehyde Dehydrogenase 2 (ALDH2*2) Is a Risk Factor for Coronary Spasm and ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a key role in removing toxic aldehydes. Deficient variant ALDH2*2 genotype is prevalent in up to 40% of the East Asians and reported to be associated with acute myocardial infarction (AMI). To elucidate the mechanisms underlying the association of ALDH2*2 with AMI, we compared the clinical features of AMI patients with ALDH2*2 to those with wild-type ALDH2*1/*1. METHODS AND RESULTS: The study subjects consisted of 202 Japanese patients with acute ST-segment elevation myocardial infarction (STEMI) (156 men and 46 women; mean age, 67.3±12.0) who underwent primary percutaneous coronary intervention (PCI). In 85 patients, provocation test for coronary spasm was also done 6 month post-PCI. ALDH2 genotyping was performed by direct application of the TaqMan polymerase chain system. Of the 202 patients, 103 (51.0%) were carriers of ALDH2*2 and 99 (49.0%) those of ALDH2*1/*1. There were no differences in clinical features between ALDH2*2 and ALDH2*1/*1 carrier groups except higher frequencies of coronary spasm and alcohol flush syndrome (AFS) (88.6% vs 56.1%; P=0.001 and 94.3% vs 17.6%; P<0.001), less-frequent alcohol habit (14.6% vs 51.5%; P<0.001), and higher peak plasma creatine phophokinase levels (2224 vs 1617 mg/dL; P=0.002) in the ALDH2*2 than the ALDH2*1/*1 carrier group. CONCLUSIONS: ALDH2*2 is prevalent (51.0%) among Japanese STEMI patients, and those with ALDH2*2 had higher frequencies of coronary spasm and AFS and more-severe myocardial injury compared to those with ALDH2*1/*1.

East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.

BACKGROUND: Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. METHODS AND RESULTS: The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). CONCLUSIONS: East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

Differences and interactions between risk factors for coronary spasm and atherosclerosis--smoking, aging, inflammation, and blood pressure.

Objective Coronary spasm as well as atherosclerosis plays an important role in the pathogenesis of coronary heart disease. However, the relationship between coronary spasm and atherosclerosis is not well known. The purpose of the present study was to examine the differences and interactions between risk factors for coronary spasm and atherosclerosis and thereby explore the pathogenesis of coronary spasm. Methods The study subjects consisted of 938 patients with chest discomfort (522 men and 416 women, mean age 65.2±11.0) who underwent intracoronary-acetylcholine provocation tests for coronary spasm. Coronary risk factors, including age, gender, body mass index, blood pressure, high-sensitivity C-reactive protein (hsCRP), white blood cells, glucose, lipid profiles, and other laboratory chemistries were examined. Results Four hundred and ninety-six patients (315 men and 181 women, mean age: 65.1±11.4) were diagnosed with coronary spastic angina (CSA), while the remaining 442 patients (207 men and 235 women, mean age: 65.3±10.7) were diagnosed with non-CSA. A multiple logistic regression analysis revealed men, smoking, hsCRP, and low diastolic blood pressure (DBP) to be predictors (p=0.001, p=0.009, p=0.034, and p=0.041, respectively) for CSA, while age, diabetes mellitus, low high-density lipoprotein-cholesterol, systolic blood pressure (SBP), uric acid and male gender were found to be predictors (p<0.001, p<0.001, p<0.001, p=0.002, p=0.006 and p=0.029, respectively) for atherosclerosis. Conclusion Predictors for coronary spasm were smoking, hsCRP and low DBP, whereas those for atherosclerosis were age, diabetes mellitus, high SBP, and uric acid in that order. These findings suggest that the pathogenesis of coronary spasm differs from that of atherosclerosis.

Pioglitazone, a peroxisome proliferator-activated receptor γ activator, suppresses coronary spasm.

OBJECTIVE: We examined whether a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, suppresses coronary spasm. BACKGROUND: Patients with coronary spastic angina (CSA) also have endothelial dysfunction and inflammation. Activation of PPAR-γ improves endothelial dysfunction and inflammation. PARTICIPANTS AND METHODS: The study participants included 73 consecutive CSA patients (47 men and 26 women, mean age 63.6±10.4 years) who were admitted to our institution with a suspicion of CSA because of episodes of chest discomfort occurring mostly at rest in whom coronary spasm was induced by an intracoronary acetylcholine injection and a repeat acetylcholine provocation injection was administered after 6 months of follow-up. Thirty-six of the patients were administered pioglitazone15-30 mg/day added on calcium channel blockers (CCBs) (pioglitazone group) and 37 were administered CCBs alone (control group). Clinical and laboratory data were also examined before and after 6 months of follow-up and the results between the two groups were compared. RESULTS: Coronary spasm was suppressed in 18/36 patients (50.0%) in the pioglitazone group (P<0.001) and 8/37 patients (21.6%) in the control group (P=0.008) after 6 months of treatment. Coronary spasm was thus significantly reduced in the pioglitazone group compared with the control group (P=0.011). The levels of total white blood cell count and high-sensitivity C-reactive protein decreased significantly (P<0.001 and P<0.001, respectively) in the pioglitazone group, whereas these levels did not differ in the control group (P=0.15 and 0.39, respectively) after the treatment. CONCLUSION: Pioglitazone added on CCBs significantly reduced coronary spasm compared with CCBs alone after 6 months of treatment. Pioglitazone may thus prove to be a novel therapy for coronary spasm.

Alcohol flushing and positive ethanol patch test in patients with coronary spastic angina: possible role of aldehyde dehydrogenase 2 polymorphisms.

OBJECTIVE: Coronary spasm plays an important role in the pathogenesis of coronary heart disease (CHD) and angina pectoris caused by coronary spasm or coronary spastic angina (CSA) is prevalent in Japan. However, the precise mechanisms underlying coronary spasm are unclear. Alcohol intolerance is prevalent among East Asians, and we previously reported that coronary spasm could be induced by alcohol intake in CSA patients. We herein examined whether CSA is associated with alcohol intolerance in Japanese subjects. METHODS: The study subjects consisted of 80 CSA patients (57 men/ 23 women, mean age 62 ± 12) and 52 non-CSA patients (25 men/27 women, mean age 63 ± 10). The ethanol patch test (EPT) and questionnaire which evaluates flushing after ethanol intake, along with an examination of clinical features and laboratory chemistry data for CHD risk factors were done. Gender (male) and smoking were higher (p=0.007, and p=0.019, respectively) and plasma HDL cholesterol level was lower (p=0.035) in the CSA patients than in the non-CSA patients. Multivariable logistic regression analysis including age, EPT, smoking, and plasma HDL cholesterol level as independent variables revealed that positive EPT and smoking were significant predictors of CSA (p=0.011 and p=0.016, respectively). CONCLUSION: Positive EPT and alcohol flushing following alcohol intake, as well as smoking and plasma levels of HDL cholesterol, were significantly associated with CSA in Japanese patients. Therefore, alcohol ingestion as well as smoking is a significant risk factor for CSA in Japanese.