Chronobioethics: Symphony of biological clocks observed by 7-day/24-hour ambulatory blood pressure monitoring and cardiovascular health.

BACKGROUND: The high prevalence of desynchronized biological rhythms is becoming a primary public health concern. We assess complex and diverse inter-modulations among multi-frequency rhythms present in blood pressure (BP) and heart rate (HR). SUBJECTS: and Methods: We performed 7-day/24-hour Ambulatory BP Monitoring in 220 (133 women) residents (23 to 74 years) of a rural Japanese town in Kochi Prefecture under everyday life conditions. RESULTS: A symphony of biological clocks contributes to the preservation of a synchronized circadian system. (1) Citizens with an average 12.02-h period had fewer vascular variability disorders than those with shorter (11.37-h) or longer (12.88-h) periods (P<0.05), suggesting that the circasemidian rhythm is potentially important for human health. (2) An appropriate BP-HR coupling promoted healthier circadian profiles than a phase-advanced BP: lower 7-day nighttime SBP (106.8 vs. 112.9 mmHg, P=0.0469), deeper nocturnal SBP dip (20.5% vs. 16.8%, P=0.0101), and less frequent incidence of masked non-dipping (0.53 vs. 0.86, P=0.0378), identifying the night as an important time window. CONCLUSION: Adaptation to irregular schedules in everyday life occurs unconsciously at night, probably initiated from the brain default mode network, in coordination with the biological clock system, including a reinforced about 12-hour clock, as "a biological clock-guided core integration system".

Appropriate Circadian-Circasemidian Coupling Protects Blood Pressure from Morning Surge and Promotes Human Resilience and Wellbeing.

Background: Blood pressure (BP) variability is involved in the appraisal of threat and safety, and can serve as a potential marker of psychological resilience against stress. The relationship between biological rhythms of BP and resilience was cross-sectionally assessed by 7-day/24-hour chronobiologic screening in a rural Japanese community (Tosa), with focus on the 12-hour component and the "circadian-circasemidian coupling" of systolic (S) BP. Subjects and Methods: Tosa residents (N = 239, 147 women, 23-74 years), free of anti-hypertensive medication, completed 7-day/24-hour ambulatory BP monitoring. The circadian-circasemidian coupling was determined individually by computing the difference between the circadian phase and the circasemidian morning-phase of SBP. Participants were classified into three groups: those with a short coupling interval of about 4.5 hours (Group A), those with an intermediate coupling interval of about 6.0 hours (Group B), and those with a long coupling interval of about 8.0 hours (Group C). Results: Residents of Group B who showed optimal circadian-circasemidian coordination had less pronounced morning and evening SBP surges, as compared to residents of Group A (10.82 vs 14.29 mmHg, P < 0.0001) and Group C (11.86 vs 15.21 mmHg, P < 0.0001), respectively. The incidence of morning or evening SBP surge was less in Group B than in Group A (P < 0.0001) or Group C (P < 0.0001). Group B residents showed highest measures of wellbeing and psychological resilience, assessed by good relation with friends (P < 0.05), life satisfaction (P < 0.05), and subjective happiness (P < 0.05). A disturbed circadian-circasemidian coupling was associated with elevated BP, dyslipidemia, arteriosclerosis and a depressive mood. Conclusion: The circadian-circasemidian coupling of SBP could serve as a new biomarker in clinical practice to guide precision medicine interventions aimed at achieving properly timed rhythms, and thereby resilience and wellbeing.

The effect of night shift work on the expression of clock genes in beard hair follicle cells.

OBJECTIVE: Shift work encompasses a broad range of work time arrangements. However, how shift work affects the circadian expression of clock genes remains to be explored. The objective of this study was to evaluate the pattern of clock gene expression in shift workers in the field. METHODS: We examined clock gene expression in Japanese men who work: (1) one night shift followed by a day off (caregivers: nurses and doctors; the one-night group); (2) three or more consecutive night shifts (factory workers; the consecutive-night group); or (3) daytime only (the daytime group), using beard follicle samples. The expression of Period3, Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1), and Nuclear Receptor Subfamily 1 Group D Member 2 (Nr1d2) was examined by real-time polymerase chain reaction. RESULTS: Period3 expression in the daytime and one-night groups together with Nr1d2 expression in the one-night group fitted a 24-h-period cosine curve better than in the consecutive-night group (p = 0.004, 0.012, and 0.001, respectively). The level of overall Period3 gene expression, calibrated with that of 18S-rRNA, was decreased in the consecutive-night group compared with that in the daytime group (p = 0.006). The patterns of Period3 and Nr1d2 expression in the daytime and one-night groups were more coherent than those in the consecutive-night group. CONCLUSIONS: These results suggest that night shift work affects the rhythms and levels of circadian Period3 and Nr1d2 expression dependent on the shift schedule or type of the shift; however, there is substantial variation between individuals.

Even mild depression is associated with among-day blood pressure variability, including masked non-dipping assessed by 7-d/24-h ambulatory blood pressure monitoring.

The effect of mild depression on blood pressure (BP) was assessed in 116 Japanese (32-79 years). As compared to non-depressive (Geriatric Depression Scale, GDS-15 score <5) subjects, mild depressives (GDS-15 score: 1-15) had shorter sleep duration (p = 0.021), lower subjective quality of life (health: p = 0.016; life satisfaction: p < 0.001; and happiness: p < 0.001), and higher 7-d systolic BP (p < 0.05). "Masked non-dipping" (dipping on day 1, but non-dipping on at least 1 of the following 6 d) was more frequent among depressive than non-depressive normotensives (p = 0.008). Among-day BP variability may underlie cardiovascular disease accompanying a key component of psychological depression.

[Vascular variability syndromes].

Analytical global and local methods applied to human blood pressure (BP) records of around-the-clock measurements. The chronobiological interpretation of ambulatory BP monitoring records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability disorders (VVDs) for an assessment of cardio-, cerebro-, and renovascular disease risk. VVD includes circadian BP over-swinging (CHAT, short for circadian hyper-amplitude tension), deficient heart rate variability, MESOR (midline-estimating statistic of rhythm) hypertension, excessively elevated pulse pressure over 60 mmHg, BP ecphasia (an odd timing of the circadian rhythms in BP but not in that of heart rate) and frequency alteration. The term MESOR-hypertension indicates only one of several VVDs that can combine to for sets of 2, 3 and n-component vascular variability syndromes.

Usefulness of left ventricular diastolic function assessed by magnetic resonance imaging over invasive coronary flow reserve measurement for detecting cardiac allograft vasculopathy in heart transplant recipients.

Heart transplant recipients undergo annual screening of early-stage cardiac allograft vasculopathy (CAV) by invasive coronary flow reserve (CFR) measurement. We compared the sensitivity for CAV detection between the CFR measurement and noninvasive magnetic resonance (MR) assessment of left ventricular (LV) diastolic function. In 46 asymptomatic recipients (29 men, aged 35.2 ± 16.1 years) 7.9 ± 4.3 years after transplantation, we measured LV peak filling rate (PFR) using cine MR and CFR in the left anterior descending artery by Doppler guidewire; classified recipients of class 0-2 as negative for CAV and class 3-4, positive, according to Stanford classification assessed by IVUS; compared those values between the 2 groups; and calculated receiver operating characteristic curve in the relationship between PFR value and CAV. We classified 20 recipients (43%) positive and 26 (57%) negative for CAV. Although there was no significant difference in CFR value, the PFR value was significantly lower in the positive (3.54 ± 0.84 EDV/s) than in negative group (4.39 ± 0.85 EDV/s, P = 0.002). Area under the curve was 0.78, and the sensitivity was 78% and specificity, 61%, when PFR cut-off value was 4.20. MR PFR measurement provides noninvasive prediction of CAV, preceding impaired CFR in asymptomatic recipients.

Switching to tacrolimus extended-release improved the effectiveness of immunosuppressive therapy in a heart transplant patient: A case report.

We report on a 25-year-old female heart transplant patient who presented with recurrent episodes of cellular rejection due to decreased adherence to immunosuppressive therapy. She received a heart transplantation in 1994 when she was 10 years old. In order to improve her adherence to immunosuppressive therapy, switching to the once-daily extended-release formulation of tacrolimus was performed in a step-wise fashion. First, the twice-daily formulation of cyclosporin A was replaced with the twice-daily preparation of tacrolimus. When the trough blood levels of tacrolimus reached a plateau in the range of 5.0 ng/mL, it was changed to the once-daily extended-release formulation of tacrolimus after confirming the absence of new rejection episodes. There were no significant changes in renal function before and after the switch. After being discharged from the hospital, the patient made significant advancements in adherence to immunosuppressive therapy. Her subsequent clinical course was uneventful, with no adverse events observed. Most patients who undergo solid organ transplantation must receive lifelong immunosuppressive therapy. This case demonstrates that conversion to the extended-release formulation of tacrolimus from other calcineurin inhibitor preparations is a reasonable choice to consider in the management of compromised immunosuppressive therapy adherence in heart transplant patients during the late posttransplant period.

Magnetic resonance assessment of left ventricular diastolic dysfunction for detecting cardiac allograft vasculopathy in recipients of heart transplants.

Cardiac allograft vasculopathy (CAV) is a major late complication in heart transplant recipients, graded based on intravascular ultrasound (IVUS), and accelerates left ventricular (LV) diastolic dysfunction. We investigated the clinical feasibility of using magnetic resonance (MR) to assess LV diastolic dysfunction noninvasively in transplant recipients. Thirty-eight asymptomatic recipients (25 men, 37.2 ± 14.9 years) underwent both IVUS and cardiac MR. Based on IVUS, we divided the individuals into 2 groups using Stanford classification to categorize CAV development as either nonsignificant or advanced. We measured LV peak filling rate (PFR) and systolic function parameters, including LV ejection fraction (EF), stroke volume (SV), and cardiac output (CO) using cine MR; compared those values between groups; calculated receiver operating characteristic curve in the relationship between PFR value and CAV; and assessed myocardial late gadolinium enhancement (LGE) on contrast-enhanced MR. We classified CAV as advanced in 20 patients (53%) and nonsignificant in 18 (47%). LV EF, SV, and CO values were not significantly different. PFR was significantly lower in the advanced (3.63 ± 0.90 EDV/s) than nonsignificant group (4.43 ± 0.84 EDV/s, P = 0.01). The area under the curve was 0.76. We observed no myocardial LGE. MR measurement of PFR may permit noninvasive assessment of diastolic dysfunction associated with CAV before LV systolic dysfunction and myocardial infarction or scar formation develop.

Evaluation of cardiac allograft vasculopathy by multidetector computed tomography and whole-heart magnetic resonance coronary angiography.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major complication that limits the long-term survival of recipients of heart transplants. In the present study the feasibility of 2 noninvasive approaches for detecting CAV (multidetector computed tomography (MDCT) and whole-heart magnetic resonance coronary angiography (MRCA)) was compared with conventional coronary angiography (CCAG). METHODS AND RESULTS: Of 22 heart transplant recipients who underwent CCAG screening, 13 had only MDCT, 16 had only MRCA, and 7 had both noninvasive modalities. The coronary arterial tree was divided into 9 segments. Detection of vasculopathy by coronary segments was compared between 16-/64-detector computed tomography (CT) or MRCA and CCAG. The sensitivity of both 16- and 64-detector CT for diagnosing CAV was 69.6%, and specificity was 96.8%. The sensitivity and specificity by 64-detector CT alone were 90.0% and 97.5%, respectively; its positive and negative predictive values were 81.8% and 98.7% respectively. For MRCA, sensitivity was 60%, specificity, 100%, positive predictive value, 100% and negative predictive value, 92.2%. MRCA showed no false positives. CONCLUSIONS: MDCT, especially 64-detector CT, is feasible for detecting CAV, whereas MRCA currently shows limited sensitivity.

Tuberculous liver abscess not associated with lung involvement.

Hepatic tuberculosis is one of the uncommon forms of extrapulmonary tuberculosis. We report a 78-year-old woman who developed tuberculous liver abscesses with splenic abscess not associated with pulmonary foci. Ultrasonography and computed tomography of the abdomen showed the low-density lesions in the liver and spleen. Histopathology of specimens obtained by percutaneous needle biopsy revealed coagulation necrosis and epithelioid cells but not tumor cells, suggesting tuberculosis infection in the liver and spleen. Systemic chemotherapy with anti-tuberculous agents led to the improvement of the lesions in the liver as well as spleen. Although tuberculous liver abscess is a very rare case, it should be included in the differential diagnosis of unknown hepatic mass lesions.