Mitsunobu Murata

Morning Surge in Blood Pressure as a Predictor of Silent and Clinical Cerebrovascular Disease in Elderly Hypertensives: A Prospective Study

Background—Cardiovascular events occur most frequently in the morning hours. We prospectively studied the association between the morning blood pressure (BP) surge and stroke in elderly hypertensives. Methods and Results—We studied stroke prognosis in 519 older hypertensives in whom ambulatory BP monitoring was performed and silent cerebral infarct was assessed by brain MRI and who were followed up prospectively. The morning BP surge (MS) was calculated as follows: mean systolic BP during the 2 hours after awakening minus mean systolic BP during the 1 hour that included the lowest sleep BP. During an average duration of 41 months (range 1 to 68 months), 44 stroke events occurred. When the patients were divided into 2 groups according to MS, those in the top decile (MS group; MS ≥55 mm Hg, n=53) had a higher baseline prevalence of multiple infarcts (57% versus 33%, P =0.001) and a higher stroke incidence (19% versus 7.3%, P =0.004) during the follow-up period than the others (non-MS group; MS <55 mm Hg, n=466). After they were matched for age and 24-hour BP, the relative risk of the MS group versus the non-MS group remained significant (relative risk=2.7, P =0.04). The MS was associated with stroke events independently of 24-hour BP, nocturnal BP dipping status, and baseline prevalence of silent infarct (P =0.008). Conclusions—In older hypertensives, a higher morning BP surge is associated with stroke risk independently of ambulatory BP, nocturnal BP falls, and silent infarct. Reduction of the MS could thus be a new therapeutic target for preventing target organ damage and subsequent cardiovascular events in hypertensive patients.

A Calcium-activated Cation Current by an Alternatively Spliced Form of Trp3 in the Heart

To investigate a cDNA encoding cation current, we isolated an alternatively spliced form of a rat Trp3, designated Trp3sv. Trp3sv encodes 736 amino acids with a unique N terminus and six transmembrane segments. Expression of the cRNA inXenopus oocytes was successfully performed. The cation selective current appeared after the addition of ionomycin or induced by prolonged depolarization but not by hyperpolarization. This induction was not observed by a treatment with thapsigargin, phorbol ester, or ATP. Na+, K+, tetraethylammonium, and divalent cations were permeable, while N-methylglucamine and chloride were nominally impermeable ions. The currents were not inhibited by flufenamate ruthenium red but nonspecifically by 2 mm Gd3+. Northern as well as Western blot suggested lower levels of the expression observed in some organs, while reverse transcriptase-polymerase chain reaction suggested that it widely spread among various organs. Therefore, we may conclude that N-terminal spliced valiant of Trp3, Trp3sv, encodes a calcium-activated cation channel in various organs.

Sleep-disordered breathing predicts cardiovascular events and mortality in hemodialysis patients

BACKGROUND Sleep-disordered breathing (SDB), characterized by repetitive apnea and hypopnea during sleep, is a risk factor for cardiovascular disease. However, the links between SDB and cardiovascular events in hemodialysis (HD) patients have not been clearly evaluated. METHODS We followed the clinical outcome of 94 HD patients, who underwent overnight pulse oximetry on dialysis day. The SDB group was defined as 3% oxygen desaturation index (ODI) over five events per hour, and the others were the normal group. The primary outcome was cardiovascular events and death. We used Kaplan-Meier curve and Cox proportional hazard model for survival analyses. RESULTS Forty-four patients (46.8%) were classified into the SDB group. Body mass index, diabetes mellitus, 3% ODI and Epworth sleepiness scale were significantly higher, and duration of dialysis, Kt/V, normalized protein catabolism rate and hemoglobin were lower in the SDB group than in the normal group. During a median 55 months of follow-up, Kaplan-Meier analysis revealed that the SDB group had a significantly higher rate of cardiovascular events and all-cause mortality than the normal group. Age, cardiothoracic ratio, serum albumin and 3% ODI were predictors of cardiovascular events and all-cause mortality at univariate Cox regression analysis. In the adjusted analysis, SDB is an independent predictor of increased cardiovascular events (hazard ratio 3.10; 95% confidence interval (CI), 1.35-7.12; P = 0.008) and all-cause mortality (hazard ratio 2.81; 95% CI, 1.07-7.41; P = 0.037). CONCLUSIONS SDB is an independent risk factor for cardiovascular events and mortality in HD patients. Effective and earlier treatment for these patients is needed to improve clinical outcome.

Irreversible Cardiomyopathy due to Thyrotoxicosis

We report 4 adult patients with thyrotoxicosis accompanied by irreversible low-output heart failure. Each patient showed elevated plasma levels of thyroid hormone and prolonged low-output heart failure even after thyroid function returned to normal. Specimens of the right ventricular myocardium stained with anti-beta myosin heavy-chain MAb showed a normal staining pattern with a predominance of the beta-form. Our observations suggest that thyrotoxicosis may be one possible cause of irreversible cardiomyopathy.

Thyroid hormone stimulates Na+-Ca2+ exchanger expression in rat cardiac myocytes

We investigated whether thyroid hormone directly affects Na(+)-Ca2+ exchanger expression in cardiac myocytes. Cultured neonatal rat cardiocytes were prepared from 1-day-old Sprague-Dawley rats. Intracellular Na+ concentration ([Na+]i) in cardiocytes was measured by using the Na(+)-sensitive dye sodium-binding benzofran isophthalate (SBFI). Na(+)-Ca2+ exchanger messenger RNA (mRNA) and protein expression were assayed by Northern and Western blotting, respectively. Triiodothyronine (T3; 10(-8) M) showed no effect on [Na+]i in cardiocytes, whereas ouabain (100 microM) caused a significant increase in [Na+]i from 11.3 +/- 5.0 to 21.8 +/- 5.0 mM. Exposure of cardiocytes to ouabain caused a rapid increase in Na(+)-Ca2+ exchanger mRNA accumulation, with a maximal twofold elevation at 12 h. The ouabain-induced Na(+)-Ca2+ exchanger mRNA accumulation was still observed in the Ca(2+)-free culture medium. On the other hand, exposure of cardiocytes to T3 induced a gradual increase in Na+ exchanger mRNA accumulation, with a maximal threefold increase at 24 h. Even in Na(+)-free medium, T3 still induced a twofold increase in Na(+)-Ca2+ exchanger mRNA accumulation in cardiocytes. Exposure of cardiocytes to T3 for 24-48 h also caused a marked increase in Na(+)-Ca2+ exchanger protein accumulation. In conclusion, thyroid hormone directly increases cardiac Na(+)-Ca2+ exchanger expression, independent of alterations in Na+ mobilization. These findings suggest also that thyroid hormone and Na+ regulate Na(+)-Ca2+ exchanger gene expression through distinct molecular regulatory pathways.

Pulse oximetry is useful for screening sleep apnoea syndrome in dialysis patients.

Sir, Sleep apnoea syndrome (SAS) is characterized by repetitive nocturnal hypoxia, while it is also known to be a risk factor for cardiovascular disease [1]. The prevalence of SAS in dialysis patients has been shown to range from 20 to 50% in comparison to a range of 2–4% in the general population [2,3]. Although the main type of SAS in the general population is obstructive type, SAS in dialysis patients includes features of both central and obstructive types [3]. Moreover, uraemia and metabolic acidosis are good predictors of SAS in dialysis patients [3]. The gold standard diagnostic test for SAS is overnight polysomnography (PSG). However, PSG is costly in terms of both time and money. Pulse oximetry and Epworth Sleepiness Scale (ESS), a questionnaire about daytime sleepiness have been widely used to screen for obstructive SAS because these are simple and easy methods to perform [4,5]. However, no screening method for SAS in dialysis patients has yet been clearly evaluated. The purpose of this study is to evaluate the usefulness of pulse oximetry and ESS for screening SAS in dialysis patients. We studied 54 maintenance haemodialysis (HD) patients [male: 50%, age: 66.0 ± 24.2 years, diabetes mellitus: 39.9%, duration of HD: 5.7 ± 5.1 years and BMI: 22.7 ± 9.1] in Koga Red Cross Hospital during the period from April 2004 to March 2005. Patients with active malignancy and pulmonary disease were excluded. The validity of the pulse oximetry was confirmed by the synchronous recording of both PSG (Morpheus, Teijin Pharma Ltd, Japan) and pulse oximetry (PULSOX-Me300, Teijin Pharma Ltd, Japan) on dialysis day. We used the 3% oxygen desaturation index (ODI) and 4% ODI by pulse oximetry as a screening marker. In addition to pulse oximetry, ESS was used to investigate daytime sleepiness. We compared the apnoea–hypopnoea index (AHI) by PSG to 3% ODI, 4% ODI and ESS scores, respectively. Using a cutoff of AHI≥15 and 3% ODI (4% ODI) ≥15, the sensitivity and specificity were 100% (76.0%) and 55.2% (93.1%) respectively (Table ​(Table1).1). On the other hand, the sensitivity and specificity using a cutoff of AHI≥15 and ESS scores≥11 were 20.0% and 82.8% respectively (Table ​(Table11). Table 1 Sensitivity and specificity of pulse oximetry/ESS scores screening for SAS in dialysis patients (n = 54) Both 3% ODI and 4% ODI were significantly correlated with AHI (3% ODI: r = 0.657, P < 0.0001; 4% ODI: r = 0.618, P < 0.0001) (Figure ​(Figure1).1). However, no significant correlation was seen between ESS scores and AHI (r = 0.149, P = 0.283) (Figure ​(Figure11). Fig. 1 Correlation between AHI and 3% ODI (A)/ESS scores (B) in dialysis patients (n = 54). In dialysis patients, pulse oximetry is superior to ESS for detecting SAS. The less efficacy of ESS may be due to the unique characteristics of SAS in dialysis patients [2,3]. We therefore suggest that pulse oximetry is useful for screening SAS in dialysis patients. Conflict of interest statement. None declared.

Transcriptional activation of RACTK1 K + channel gene by apical alkalization in renal cortical collecting duct cells

We have previously demonstrated that RACTK1 cDNA encodes a pH sensitive K+ channel expressed in the apical side of renal collecting tubule cells. To determine whether extracellular pH induces the RACTK1 gene expression in the renal cortical collecting duct (CCD) cells, we measured mRNA of the RACTK1 using cultured rabbit CCD cells. Alkalization of incubation medium activated the transcription of the RACKTK1 gene in a time- and dose-dependent manner after 1 h, and reached a maximal level after 12 h. To examine whether the stimulation of mRNA by alkalization of body fluid occurs also in vivo, mRNA levels were measured in mice loaded with acid or alkali. The RACTK1 mRNA was increased in association with the rise in urinary pH. To examine side face of the effect of pH on stimulation of mRNA, we observed the effect of pH in the apical or the basolateral side in the preparation where CCD cells were cultured on filter membrane supports. Alkalization of the apical side but not of the basolateral side, was shown to be a determinant in inducting the RACTK1 mRNA. These findings suggest that, in addition to rapid direct regulation of RACTK1 K+ channel conductance by intracellular pH, this channel is also regulated by the changes in luminal pH through synthesis of channel protein by transcriptional activation.

Nocturnal hypoxia is associated with elevated C-reactive protein in dialysis patients

be associated with the severity of nocturnal hypoxia, the direct relationship between CRP and nocturnal hypoxia has not yet been evaluated. Therefore, the relationship between CRP and nocturnal hypoxia diagnosed by average SaO2 using pulse oximetry was investigated. Moreover, pulse oximetry is a simple tool and is used for screening SAS in dialysis patients [6], while PSG is costly in terms of both time and money. In conclusion, this study demonstrated that nocturnal hypoxia is associated with elevated CRP levels in dialysis patients. These findings suggest that nocturnal hypoxia in dialysis patients may be an additional CVD risk and both a careful follow-up and good control of these patients are needed to prevent CVD.

Can Ischemic Stroke Be Caused by Acute Reduction of Blood Pressure in the Acute Phase of Cardiovascular Disease

Acute‐phase cardiovascular disease (CVD) frequently presents with markedly elevated blood pressure (BP) levels and often requires fairly rapid lowering of BP. On the other hand, aggressive lowering of systemic BP to the point that the cerebral BP decreases below a certain threshold may result in ischemic stroke. The authors retrospectively studied 192 consecutive patients with CVD who had markedly elevated BP and end‐organ damage. Ischemic stroke was noted in 12 of these patients during BP‐lowering therapy. The incidence of ischemic stroke did not differ significantly between a standard BP‐lowering group, in which the target BP reduction was within the parameters of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines, and a rapid BP‐lowering group, in which the target BP was below these guidelines (7.1% vs 2.6%, respectively; P=.27, not significant). In stepwise multiple regression analysis, diabetes mellitus (β=0.203, P=.008) and acute pulmonary edema (β=0.228, P=.003) remained significant factors associated with the incidence of stroke. Thus, acute pulmonary edema and diabetes were the most important factors related to ischemic stroke during BP reduction in patients with marked elevations of BP regardless of the rapidity of BP lowering.

Hyponatremic seizure associated with acute respiratory infection

A 66-year-old woman was admitted to our hospital because of vomiting and appetite loss. For the 2 days prior to admission, she had a cold, which had developed into acute viral bronchitis on admission. Because laboratory data on admission showed hyponatremia, intravenous infusion of Ringers lactate solution was started. However, generalized seizures appeared, and she developed a coma on the day of admission. Her plasma antidiuretic hormone (ADH) level was high in the context of a low serum osmolality on the second hospital day. The infusion rate was increased, and the patients consciousness level returned to normal. However, her normalized serum Na level declined again as she drank much water to reduce throat discomfort. As the throat discomfort caused by the throat inflammation improved with azulene gargling, her water intake was reduced, and the serum Na concentration returned to normal. Thus, polydipsia caused by a throat inflammation partially contributed to hyponatremia in this patient. We note that increased ADH secretion has been reported in adults with acute respiratory infection. Therefore, we concluded that polydipsia caused by the throat inflammation, plus increased ADH secretion, resulted in hyponatremia in this patient. We should pay attention to the behavior of drinking extra fluid in patients with acute respiratory infections.