Integrated Predictors by Propensity Scoring With Tumor Markers and Plasma Levels of microRNA-21-5p, IL-17, and IL-10 Complement Early Detection of Hepatocellular Carcinoma in Patients With Liver Cirrhosis.

Objectives: The clinical usefulness of tumor markers alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP) in the early detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC), including those with marker decline after antiviral therapy, is limited. MicroRNAs (miRNAs) are expected to complement detection; however, their details remain unknown. Our prospective pilot study aimed to improve the surveillance of HCC high-risk LC patients by propensity scoring with tumor markers and additional predictors. Methods: Tumor markers and plasma levels of cytokines and miRNAs were observationally measured and statistically evaluated with propensity scoring in 85 eligible patients: 43 with current HCC (cHCC) including 8 with early-HCC, 22 with previous HCC cured (pHCC), and 20 with intact LC (iLC). Results: The analysis of the area under the receiver operating characteristic curve (AUC) showed that the best single predictor was AFP (0.794 for cHCC-discrimination and 0.771 for pHCC-discrimination). AFP-DCP integrated with miR-21-5p for cHCC-discrimination was 0.896; with IL-10 for pHCC-discrimination was 0.872, these were significantly better than those of AFP alone, independently (P < .01). The best single predictor for iLC-discrimination was IL-17 level (0.756). IL-17 integrated with AFP-DCP was 0.882, which was significantly better than that of IL-17 alone (P < .01). The positive likelihood ratio (pLR) for cHCC-discrimination by integration of AFP-DCP and miR-21-5p was 32.2. Preliminary validation analysis of early-HCCs compared to conventional AFP and DCP showed the combinations of AFP-DCP and 3 integrated predictors, miR-21-5p for cHCC-discrimination, IL-10 for pHCC-discrimination, and IL-17 for iLC-discrimination, sensitivity, specificity, and pLR, improved from 37.5% to 62.5%, 55.8% to 83.1%, and 0.85 to 3.70, respectively. Conclusion: The predictors of AFP-DCP combined with iR-21-5p, IL-10, and IL-17 by propensity scoring achieved higher discrimination of cHCCs, pHCCs, and iLCs, may be beneficial for the surveillance of early-HCCs, improving prediction of early-HCCs over conventional methods. However, further validation is required.

A case report involving suppressed nuclear receptor transcription factors 4a1 and Stevens-Johnson syndrome induced by a single dose of pembrolizumab and successfully treated with early steroid administration, resulting in complete remission of stage III lung cancer.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors is associated with immune-related adverse events (irAEs). A positive correlation between treatment efficacy and irAEs has been reported. Clinical indicators are required for appropriate interventions, such as steroid administration, to prevent fatal outcomes. Nuclear receptor transcription factor 4a (Nr4a), which is involved in T-cell anergy, exhaustion, and regulatory T cells, were observed not only in thymocytes but in peripheral blood mononuclear cells. We describe a case of Stevens-Johnson syndrome (SJS) that was induced by a single dose of pembrolizumab and successfully treated with steroids, leading to complete remission of lung cancer during the monitoring of immune response indices, including Nr4a1 mRNA. CASE PRESENTATION: A 68-year-old male with squamous cell lung cancer (cT2aN3M0, stage IIIb) received a single dose of pembrolizumab (200 mg). On Day 21 of treatment, SJS appeared, and the patient was treated with prednisolone 60 mg/day, which was gradually tapered off. After the disappearance of the SJS symptoms, complete remission of cancer was achieved and was maintained for more than 1 year. Acute increases in the plasma IFN-γ and IL-17 concentrations and a decrease in IL-10 concentrations were observed at the onset of SJS. Simple regression analysis showed that these changes in IL-17, IFN-γ and IL-10 were significantly influenced by the decreased expression of Nr4a1 mRNA. The pembrolizumab levels and prednisolone doses significantly influenced the suppression of Nr4a1 mRNA levels. Although Nr4a1 mRNA levels in the current case fluctuated during the observation period, they were significantly lower than those in a nonresponding progressive-disease case, as well as a pembrolizumab-responding case with non-SJS but similar background. The suppression of Nr4a1 in current case, might result in upregulation of cytotoxic T cells and a reduction in functional regulatory T cells, promoting favorable antitumor immunity. CONCLUSION: The immune responses involving Nr4a1 suppression might relate to complete remission of lung cancer in this case, despite causing SJS, which may be attributed to synergistic effects from pembrolizumab treatment and intervention with steroids. The current case indicates the preliminarily clinical benefit of evaluating Nr4a expression-related indices as the possible clinical covariates and may serve as a milestone for appropriate future chemotherapy interventions.

The Concentration of 8-Hydroxy-2'-Deoxyguanosine in Plasma During the Menstrual Cycle in Young Japanese Women.

Background: The exact pathophysiology of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) is still unknown. This study aimed to investigate the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in plasma in relation to the menstrual cycle and the severity of premenstrual symptoms in young Japanese women. Methods: The study included 21 healthy Japanese women 19-24 years of age. Fourteen women had no or mild PMS [PMS (-)], while five women had moderate to severe PMS and two women exhibited PMDD [PMS (+)]. The concentration of 8-OHdG in plasma was measured by means of high-performance liquid chromatography-electrochemical detector. The Center for Epidemiologic Studies Depression (CES-D) scale was used to evaluate the depressive tendency. Results: The concentration of 8-OHdG before menstruation was significantly higher than that after menstruation in total subjects (p = 0.04). In the PMS (+) group, the 8-OHdG concentration before menstruation was higher than that after menstruation (p = 0.02). Moreover, the PMS (+) group showed a higher 8-OHdG concentration compared with the PMS (-) group before menstruation (p < 0.01), as well as higher CES-D scores compared with the PMS (-) group both before and after menstruation (p < 0.01). Conclusions: These results suggested that the oxidation of DNA occurred before menstruation in PMS. The depression was associated with PMS symptoms both before and after menstruation in patients with PMS. Oxidation of DNA due to oxidative stress and depression in PMS patients may be involved in the pathogenesis of PMS. Clinical Trial Registration number 15-02-011.

Methotrexate mediates the integrity of intestinal stem cells partly through nitric oxide-dependent Wnt/ß-catenin signaling in methotrexate-induced rat ileal mucositis.

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/ß-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/ß-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/ß-catenin signaling and may enhance tolerability to methotrexate-induced injury.

Administration of cyclophosphamide to rats induces pica and potentiates 5-hydroxytryptamine synthesis in the intestine without causing severe intestinal injury.

The effects of cyclophosphamide on 5-hydroxytryptamine (5-HT) synthesis in the intestinal tissue of rats were investigated. Rats received 120 mg/kg cyclophosphamide intraperitoneally as a single administration, and kaolin and food intake was measured by an automatic monitoring apparatus. Ileal tissues were collected at either 24 or 72 h after administration. Cyclophosphamide caused a significant increase in kaolin intake at the acute and the delayed phases and was associated with a decrease in food intake, and body weight. Cyclophosphamide had no significant effect on intestinal mucosal morphology, or inducible nitric oxide synthase and cyclooxygenase-2 expression in the intestine. Cyclophosphamide significantly increased tryptophan hydroxylase 1 (TPH1) mRNA expression, number of anti-TPH antibody-positive cells, and 5-HT content in the intestine. Cyclophosphamide also significantly increased the expression of Tac1 mRNA, encoding preprotachykinin-1, which is a preprotein of substance P, and the number of anti-substance P antibody-positive cells in the intestine. Cyclophosphamide significantly increased Lgr5, Bmi1, and Atoh1 mRNA levels, which are markers for the proliferation and differentiation of stem cells. This study demonstrated that cyclophosphamide induced pica in rats, and potentiated 5-HT synthesis associated with hyperplasia of substance P-containing enterochromaffin cells without causing severe intestinal injury.

Abnormal Pressure Stress Reduces Interleukin-1ß-Induced Cyclooxygenase-2 Expression in Cultured Rat Vascular Smooth Muscle Cells.

Elevated mechanical stress on blood vessels associated with hypertension has a direct effect on the function of vascular endothelial cells and vascular smooth muscle cells (VSMCs). In the present study, we have identified the effect of pulsatile pressure stress on cyclooxygenase-2 (COX-2) expression induced by interleukin (IL)-1ß in cultured rat VSMCs. VSMCs were isolated from aortic media of Wistar rats and cultured. Pulsatile pressure applied to VSMCs was repeatedly given between either 80 and 160 mmHg, which simulates systolic hypertension, or 80 and 120 mmHg, which simulates normal blood pressure, at a frequency of 4 cycles per min using our original apparatus. Pressure loading that simulates systolic hypertension reduced IL-1ß-induced COX-2 expression. The pressure also inhibited the rapid and transient phosphorylation of extracellular signal-regulated kinase (ERK) induced by IL-1ß. IL-1ß-induced COX-2 expression was significantly inhibited by a specific conventional protein kinase C (PKC) inhibitor. Pressure loading that simulates systolic hypertension also reduced phorbol myristate 13-acetate (PMA) (a PKC activator)-induced COX-2 expression and the rapid and transient phosphorylation of ERK. Pressure loading that simulates normal blood pressure had no effect on IL-1ß- and PMA-induced COX-2 expression. The present study shows that pressure stress between 80 and 160 mmHg, which simulates systolic hypertension reduces IL-1ß-induced COX-2 expression by affecting a mechanism involving PKC and ERK signaling pathways. Downregulation of COX-2 expression in VSMCs by abnormal pressure stress may further worsen local vascular injury associated with hypertension.

The role of nitric oxide in small intestine differs between a single and a consecutive administration of methotrexate to rats.

The role of nitric oxide (NO) on intestinal mucosal injury induced by single or consecutive administration of methotrexate was investigated in a rodent model. Rats received methotrexate intraperitoneally either as a single administration (50 mg/kg) or as a consecutive administration (12.5 mg/kg/day) for 4 days. NG-nitro-l-arginine methyl ester (L-NAME) was given subcutaneously to inhibit NO synthase (NOS). Ninety-six hours after the first administration of methotrexate, ileal tissues were collected for analysis. Consecutive administration of methotrexate led to decreased body weight and reduced intake of food and water, which were further worsened by L-NAME. Although a slight mucosal injury resulted from single administration of methotrexate, L-NAME had almost no effect. Consecutive administration of methotrexate caused a significant mucosal injury, which was further worsened by L-NAME. Consecutive, but not single, administration of methotrexate induced mRNA expression of inflammatory cytokines in ileal tissue. Consecutive administration of methotrexate significantly induced constitutive NOS expression in ileal tissue. These results suggest that consecutive administration, rather than single administration, of methotrexate aggravates mucosal injury. Potentiation of constitutive NOS expression by consecutive administration might be one of the main reason to antagonize the intestinal mucosal injury as well as lead to a reduction in rat quality of life.

Plasma Interleukin-10 Levels Are Altered in Women with Severe Premenstrual Syndrome: A Preliminary Study.

Background: The precise pathophysiology of premenstrual syndrome (PMS) is unknown, and chronic inflammation has been implicated in PMS. However, inflammatory markers, including cytokines and C-reactive protein (CRP), have not been investigated before and after menstruation in relation to PMS among the same participants. This study investigated whether the plasma levels of tumor necrosis factor-α, interleukin (IL)-6, IL-10, and CRP are related to PMS. Methods: The study included 21 healthy Japanese women (aged 19-24 years) with a regular menstrual cycle. Inflammatory marker levels in plasma were determined using enzyme-linked immunosorbent assay. In addition, the level of depressiveness was assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Results: Of the 21 women, 7 were considered to have moderate-to-severe PMS (PMS [+] group) and 14 were considered to have no or mild PMS (PMS [-]), and none of the participants had premenstrual dysphoric disorder. The IL-10 levels were significantly lower before than after menstruation in the PMS (-) group. The IL-10 levels before menstruation were significantly higher in the PMS (+) group than in the PMS (-) group. Other markers did not show relevant differences between the groups. The CES-D scores were higher in the PMS (+) group than in the PMS (-) group both before and after menstruation. There were positive correlations between the CES-D scores and IL-6 levels before menstruation and the CES-D scores and IL-10 levels after menstruation. Conclusions: The IL-10 levels before menstruation were higher in women with PMS than in those without PMS, and these levels might be related to PMS.

Potentiation of Glucagon-Like Peptide-2 Dynamics by Methotrexate Administration in Rat Small Intestine.

The aim of this study was to clarify the relationship between chemotherapy-induced mucositis and endogenous glucagon-like peptide-2 (GLP-2) dynamics in the small intestine following treatment with either methotrexate or 5-fluorouracil. Rats were injected intraperitoneally with a single dose of either 50 mg/kg methotrexate or 100 mg/kg 5-fluorouracil. At 24 and 72 h after drug administration, ileal tissues and plasma were used to investigate GLP-2 dynamics. Administration of methotrexate caused moderate but not significant intestinal injury within 72 h, while administration of 5-fluorouracil caused severe injury in a time-dependent manner. Methotrexate significantly increased proglucagon mRNA expression and the number of anti-GLP-2 antibody-positive cells in the ileal tissue at 24 h after administration. Methotrexate also significantly induced GLP-2 receptor, insulin-like growth factor-1 (IGF-1), and transforming growth factor-ß2 (TGF-ß2) mRNA expression in ileal tissue. In contrast, 5-fluorouracil significantly inhibited proglucagon, GLP-2 receptor, IGF-1, and TGF-ß2 mRNA expression as well as the number of anti-GLP-2 antibody-positive cells. Methotrexate slightly increased dipeptidyl peptidase IV (DPP-4) mRNA expression, whereas 5-fluorouracil significantly increased DPP-4 mRNA expression. These results suggest that potentiation of endogenous GLP-2 dynamics by methotrexate is associated with a mechanism that preserves gastrointestinal mucosal integrity at a moderate level.

Nitric oxide plays a critical role in methotrexate-induced hyperplasia of enterochromaffin cells containing 5-hydroxytryptamine in rat small intestine.

The role of nitric oxide (NO) in the changes in enterochromaffin cells and ileal 5-hydroxytryptamine (5-HT) content induced by a single i.p. administration of methotrexate was investigated in rats. Methotrexate significantly increased inducible NO synthase (iNOS) mRNA and protein expressions in the intestinal tissue at 96 h. Methotrexate also significantly caused hyperplasia of the enterochromaffin cells at 96 h; this was associated with a significant increase in 5-HT content. The methotrexate-induced hyperplasia of enterochromaffin cells and increase in 5-HT content were, however, completely suppressed by daily treatment with dexamethasone, and with NG-nitro-l-arginine methyl ester (l-NAME); this was not observed when meloxicam was administered. Histological examination showed slight but not pronounced mucosal injury, at 96 h after methotrexate administration. The methotrexate-induced decrease in body weight did not fully recover to the control level up to 96 h; however, the methotrexate-induced decrease in food/water intake slightly returned to the control level up to 96 h. l-NAME had no significant effect on methotrexate-induced body weight loss and anorexia. To conclude, the present study suggests that NO derived from methotrexate-induced iNOS plays a critical role in the mechanism of hyperplasia of enterochromaffin cells containing 5-HT in the intestinal tissue of rats.

Methotrexate causes acute hyperplasia of enterochromaffin cells containing substance P in the intestinal mucosa of rats.

This study aimed to investigate the acute and chronic effect of methotrexate on the intestinal substance P metabolism after a single administration to rats. Methotrexate caused a significant increase in the number of substance P-containing cells in the ileal mucosa both at 24 and 96 h. Most of enterochromaffin cells expressing l-tryptophan hydroxylase contained substance P. The expression of Tac1 mRNA was increased by methotrexate at 24 h, but not at 96 h. Thus, methotrexate causes acute hyperplasia of enterochromaffin cells in the intestinal mucosa of rats with a transient increase in the production of substance P.

Administration of olanzapine as an antiemetic agent changes glucose homeostasis in cisplatin-treated rats.

We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulin-secreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting.

Carvedilol improves uptake-1 in patients with systolic congestive heart failure.

BACKGROUND: The sympathetic nervous system (SNS) of the whole body, including cardiac sympathetic nerves, is activated in patients with severe congestive systolic heart failure (CHF). Carvedilol can improve clinical status in such patients. This study aimed to determine how carvedilol acts on the SNS to improve CHF. METHODS AND RESULTS: Ten subjects (New York Heart Association criteria III) were treated using carvedilol at 2.5 mg/d for 1 week. Before and after treatment, subjects walked on a treadmill for 6 minutes, and plasma concentrations of carvedilol, norepinephrine, and 3,4-dihydroxyphenyl glycol were measured. After treatment, norepinephrine was decreased at rest (3.2 ± 0.3 pmole/mL to 2.1 ± 0.4 pmole/mL, P < 0.05), while standing (5.4 ± 1.2 to 3.3 ± 0.7 pmole/mL, P < 0.01) and during exercise (6.5 ± 1.3 pmole/mL to 5.1 ± 1.1 pmole/mL, P < 0.05). Regression lines for percentage changes in norepinephrine and 3,4-dihydroxyphenyl glycol were compared before and after treatment, showing steeper slopes after treatment (P < 0.05). Plasma carvedilol concentrations (1.8 ± 0.3 ng/mL) did not reach ß-adrenoceptor-blocking levels of effect. CONCLUSIONS: Carvedilol is considered to improve function of uptake-1 for the whole-body SNS, including the cardiac SNS, and does not seem to block adrenoceptors at such low doses in CHF patients. However, both effects seem to work at high doses in clinical settings.

Excretions of urinary albumin and various proteins increase in hypertension.

AIMS: Hypertension causes proteinuria and is an important factor in the progress of renal dysfunction. Increases in various proteins in urine are caused by malfunction of the glomerulus and the renal tubules. In the present study, the effects of hypertension on urinary excretion levels of various proteins were investigated to show the tubular cell malfunction in hypertensive patients. METHODS AND SUBJECTS: The subjects included 55 non-diabetic hypertensive patients without previous treatment and 42 normotensive individuals without microalbuminuria. Total urinary protein/creatinine ratio was measured, and urinary proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). FINDINGS: Total urinary protein/creatinine ratio was higher in hypertensive patients than in normotensive individuals (122.0+/-11.0 vs. 60.6+/-3.1 mg/gCr; p<0.001). SDS-PAGE resolved 15 protein fractions from the urine of both groups. Thirteen fractions were more intensely stained in samples from the hypertensive than from the normotensive. Two fractions did not differ between the groups. Hypertension increased the urinary excretion of various proteins including proteins of less than 40 kDa, called tubular proteins, in addition to albumin. CONCLUSIONS: Hypertension differently influenced the excretion of each urinary protein fraction. Tubular malfunction should be considered in hypertensive patients in addition to glomerular malfunction.

Simultaneous analysis of human plasma catecholamines by high-performance liquid chromatography with a reversed-phase triacontylsilyl silica column.

The clinical importance of simultaneous analysis of 3,4-dihydroxyphenylglycol with other human plasma catecholamines has been investigated to better understand the sympathetic nervous system. However, previous reports have had analytical difficulties with both resolution and extraction. The current study uses a reversed-phase triacontylsilyl silica (C30) column under the mobile phase condition without ion-pair reagents to separate catecholamines and their metabolites, with above 91% recoveries for intra-assay, above 85% for inter-assay, and less than 10% (n=5) coefficient of variation. Lower detection limits (S/N=4) and quantification limits (S/N=6) were 40 and 100 pg/mL for norepinephrine, 3,4-dihydroxyphenylglycol, and 3,4-dihydroxyphenylalanine, 10 and 20 pg/mL for epinephrine, 10 and 40 pg/mL for dopamine. Linear ranges were from 40 to 5000 pg/mL for norepinephrine and 3,4-dihydroxyphenylalanine, from 100 to 5000 pg/mL for 3,4-dihydroxyphenylglycol, and from 10 to 2000 pg/mL for epinephrine and dopamine. The C30 column may prove clinically useful, as it provides a convenient and simultaneous method of evaluation of human plasma catecholamines.

High-sodium diets in Japanese evacuation centers increase blood pressures of evacuees.

AIMS: High blood pressure after a natural disaster is tentatively considered to be due to elevation of sympathetic nerve activity. A volcano in Japan erupted on March 31, 2000, and people living in the vicinity of the volcano were evacuated to safe shelters. We found that many evacuees developed high blood pressure while staying at evacuation centers. The aim of this study was to investigate why their blood pressures stayed elevated. METHODS AND SUBJECTS: Sixty-five evacuees, who were staying evacuation centers for 4 months, were examined for blood pressure, urinary sodium excretion, urinary potassium excretion, and plasma and urinary catecholamines. RESULTS: Associations were found between systolic blood pressure and sodium excretion (r = 0.311, p < 0.05) and between systolic blood pressure and the ratio of urinary sodium to urinary potassium (r = 0.320, p < 0.05). However, no association was found between blood pressure and plasma and urinary catecholamines (NE, DHPG and MHPG). CONCLUSION: High sodium consumption was thought to be an important factor in the elevation of blood pressure of the evacuees after acute phase reactions.

Measurement of carvedilol in plasma by high-performance liquid chromatography with electrochemical detection.

Carvedilol is a beta/alpha1-adrenoceptor blocker. A sensitive method for measuring plasma levels of carvedilol in human administrated low doses is needed since its plasma concentration is low. We measured carvedilol and carvedilol M21-aglycon using high-performance liquid chromatography (HPLC) with electrochemical detection. The amperometric detector was operated at 930 mV versus Ag/AgCl. Mean coefficients of variation (n = 5) for carvedilol and M21-aglycon were 4.0 and 7.7% (intra) and 6.1 and 6.7% (inter), respectively. The lower limit of quantification for each analyte was 0.10 ng/ml (signal-to-noise ratio = 3). This lower limit of quantification for carvedilol was sufficient for clinical use.

Different coronary blood flow increase in left ventricular hypertrophy due to hypertension compared to hypertrophic cardiomyopathy at elevated heart rate.

Coronary vasodilator reserve (CVR) is reduced in patients with left ventricular hypertrophy (LVH). However, it is not clear whether there is any difference between the coronary blood flow increase in LVH caused by hypertension (HTH) and that caused by hypertrophic cardiomyopathy (HCM) when the heart rate increases. In this study, 16 subjects with HTH, 10 subjects with HCM, and 10 subjects with normotension (NT) were investigated. Average peak velocities at rest, at pacing, and at dilatation were measured using a Doppler catheter placed at the left descending coronary artery to calculate coronary blood flow (CBF) and CVR. CVR at rest was identical in the HTH and HCM groups, and in both cases was lower than the resting CVR in NT subjects. There were significant differences in the CVR values at a pacing rate of 120 beats/min among the groups. These values were lowest in HCM, highest in NT, and intermediary in HTH subjects. And the percent increase in CBF in HCM at that pacing rate was higher than that in HTH (p < 0.05) or NT (p < 0.05). There was no difference in the percent increase in CBF at this pacing rate between the HTH and NT groups. The effects of elevated heart rate on the percent increase in CBF were different between the HTH and HCM groups. We conclude that cardiac hypertrophy has qualitatively different effects on coronary circulation depending on whether patients have HTH or HCM.