PPARγ Agonist Rosiglitazone and Antagonist GW9662: Antihypertensive Effects on Chronic Intermittent Hypoxia-Induced Hypertension in Rats.

The increased incidence of hypertension associated with obstructive sleep apnea (OSA) presents significant physical, psychological, and economic challenges. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a role in both OSA and hypertension, yet the therapeutic potential of PPARγ agonists and antagonists for OSA-related hypertension remains unexplored. Therefore, we constructed a chronic intermittent hypoxia (CIH)-induced hypertension rat model that mimics the pathogenesis of OSA-related hypertension in humans. The model involved administering PPARγ agonist rosiglitazone (RSG), PPARγ antagonist GW9662, or normal saline, followed by regular monitoring of blood pressure and thoracic aorta analysis using staining and electron microscopy. Intriguingly, our results indicated that both RSG and GW9662 appeared to potently counteract CIH-induced hypertension. In silico study suggested that GW9662's antihypertensive effect might mediated through angiotensin II receptor type 1 (AGTR1). Our findings provide insights into the mechanisms of OSA-related hypertension and propose novel therapeutic targets.

The prevalence, relative risk factors and MTHFR C677T genotype of H type hypertension of the elderly hypertensives in Shanghai, China: a cross-section study : Prevalence of H type hypertension.

BACKGROUND: H type hypertension is defined as homocysteine (Hcy) ≥ 10 µmol/L in combination with primary hypertension. Studies demonstrated that the existence of hyperhomocysteine (HHcy) in hypertensive exacerbates the poor outcome of cardiocerebral incidents. This study was to investigate the current epidemic situation of H type hypertension and determine the risk factors in order to find intervention targets for H type hypertensives. METHODS: We conducted a cross-sectional study using cluster sampling design in Shanghai, China from July 2019 and April 2020. 23,652 patients with primary hypertension were enrolled in this study. Their medical information was recorded, and the level of Hcy concentrations and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms were detected. RESULTS: In total, 22,731 of 23,652 patients were recorded. The mean age was 68.9 ± 8.6 y and 43% were men. 80.0% of the enrolled patients had H type hypertension. The frequency of allele T was 40.9%, and the proportions of the CC, CT, and TT genotypes were 36.1%, 46.0%, and 17.9%, respectively. Compared with the TT genotype, the plasma Hcy concentration levels were lower in patients with the CC/CT genotype (18.96 ± 13.48 µmol/L vs. 13.62 ± 5.20/14.28 ± 5.36, F = 75.04, p < 0.01). The risk for H type hypertension was higher in elderly people. Men had ~ 5.55-fold odds of H type hypertension compared with women. Patients with CT genotype and TT genotype had ~ 1.36- and ~ 2.76-fold odds of H type hypertension compared with those with CC genotype, respectively. Smoking and diabetes were not significantly associated with H type hypertension. CONCLUSIONS: The prevalence of H type hypertension in patients with primary hypertension was 80.0%, which was higher than the 75% found in prior report in China. Age, gender, and MTHFR C677T polymorphisms rather than smoking and diabetes were independently associated with H type hypertension.

Particulate matter air pollution and reduced heart rate variability: How the associations vary by particle size in Shanghai, China.

BACKGROUND: It remains unclear which size of particles has the strongest effects on heart rate variability (HRV). OBJECTIVE: To explore the association between HRV parameters and daily variations of size-fractionated particle number concentrations (PNCs). METHODS: We conducted a longitudinal repeated-measure study among 78 participants with a 24-h continuous ambulatory Holter electrocardiographic recorder in Shanghai, China, from January 2015 to June 2019. Linear mixed-effects models were employed to evaluate the changes of HRV parameters associated with PNCs of 7 size ranges from 0.01 to 10 µm after controlling for environmental and individual confounders. RESULTS: On the concurrent day, decreased HRV parameters were associated with increased PNCs of 0.01-0.3 µm, and smaller particles showed greater effects. For an interquartile range increase in ultrafine particles (UFP, those < 0.1 µm, 2453 particles/cm3), the declines in very-low-frequency power, low-frequency power, high-frequency power, standard deviation of normal R-R intervals, root mean square of the successive differences between R-R intervals and percentage of adjacent normal R-R intervals with a difference ≥ 50 ms were 5.06% [95% confidence interval (CI): 2.09%, 7.94%], 7.65% (95%CI: 2.73%, 12.32%), 9.49% (95%CI: 4.64%, 14.09%), 5.10% (95%CI: 2.21%, 7.91%), 8.09% (95%CI: 4.39%, 11.65%) and 24.98% (95%CI: 14.70%, 34.02%), respectively. These results were robust to the adjustment of criteria air pollutants, temperature at different lags, and the status of heart medication. CONCLUSIONS: Particles less than 0.3 µm (especially UFP) may dominate the acute effects of particulate air pollution on cardiac autonomic dysfunction.

The acute effects of temperature variability on heart rate variability: A repeated-measure study.

BACKGROUND: The impacts of temperature variability on cardiac autonomic function remain unclear. OBJECTIVE: To explore the short-term associations between daily temperature variability and parameters of heart rate variability (HRV). METHODS: This is a repeated-measure study among 78 eligible participants in Shanghai, China. We defined temperature variability as diurnal temperature range (DTR), the standard-deviation of temperature (SDT) and temperature variability (TV). We evaluated 3 frequency-domain HRV parameters (VLF, LF and HF) and 4 time-domain parameters (SDNN, SDANN, rMSSD and pNN50). We used linear mixed-effect models to analyze the data after controlling for environmental and individual confounders. RESULTS: Temperature variability was significantly associated with decreased HRV, especially on the concurrent day. The exposure-response relationships were almost inversely linear for most parameters. Every one interquartile range (IQR) increase of DTR was associated with a decrease of 3.92% for VLF, 6.99% for LF, 5.88% for HF, 3.94% for rMSSD and 1.30% for pNN50. Each IQR increase of SDT was associated with a decline of 6.48% for LF, 5.91% for HF, 4.26% for rMSSD and 1.87% for pNN50. Every IQR increase of SDT was associated with a decrease of 4.39% for VLF, 7.67% for LF, 6.52% for HF, 3.22% for SDNN, 2.98% for SDANN, 4.05% for rMSSD, and 1.41% for pNN50. The decrements in HRV associated with temperature variability were more prominent in females. CONCLUSION: Temperature variability on the concurrent day could significantly decrease cardiac autonomic function, especially in females.

A novel risk assessment model of contrast-induced nephropathy after percutaneous coronary intervention in patients with diabetes.

The purpose of our study was to develop a simple clinical pre-procedure risk model based on clinical characteristics for the prediction of contrast-induced nephropathy (CIN) and major adverse cardiac events (MACEs) after percutaneous coronary intervention (PCI) in patients with diabetes. A total of 1113 patients with diabetes who underwent PCI with contrast exposure were randomized into a development group (n = 742) and a validation group (n = 371) in a 2:1 ratio. CIN was defined as an increase of either 25% or 0.5 mg/dL (44.2 µmol/L) in serum creatinine within 72 hours after contrast infusion. A simple CIN risk score based on independent predictors was established. Four variables were identified for our risk score model: LVEF < 40%, acute coronary syndrome (ACS), eGFR < 60, and contrast volume > 300 mL. Based on this new CIN risk score, the incidence of CIN had a significant trend with increased predicting score values of 5.9%, 32.9% and 60.0%, corresponding to low-, moderate- and high-risk groups, respectively. The novel risk assessment exhibited moderate discrimination ability for predicting CIN, with an AUC of 0.759 [95% CI 0.668-0.852, P = .001] in the validation cohort. It also had similar prognostic values for one-year follow-up MACE (C-statistic: 0.705 and 0.606 for new risk score and Mehran score, respectively). This novel risk prediction model could be effective for preventing nephropathy in diabetic patients receiving contrast media during surgical procedures.

Size-fractionated particulate air pollution and myocardial infarction emergency hospitalization in Shanghai, China.

BACKGROUND: Fine particulate matter (PM2.5) air pollution has been associated with increased risks of acute myocardial infarction (AMI), but it remains unknown about the potentially differentiated effects of size-fractionated particulate matter on AMI risk. OBJECTIVE: To identify the specific size ranges that dominate the effects of particulate matter on AMI onset. METHODS: We conducted a time-series study in Shanghai, China from January 2014 to December 2018. We evaluated particle size distribution of 0.01 µm to 2.5 µm from an environmental supersite and AMI emergency hospitalizations from the largest cardiovascular hospital in Shanghai. We used over-dispersed generalized additive models to estimate the associations of size-fractionated particle number concentrations (PNC) with AMI and its types. RESULTS: We identified a total of 4720 AMI emergency hospitalizations. PM2.5 was significantly associated with increased AMI risk on the concurrent day. The associations were significant only for PNC < 0.3 µm. For an IQR increase of PNCs for size ranges 0.01-0.03 µm, 0.03-0.05 µm, 0.05-0.10 µm and 0.10-0.30 µm, AMI hospitalizations increased by 6.68% (95% CI: 2.77%, 10.74%), 6.53% (95% CI: 2.08%, 11.17%), 5.78% (95% CI: 0.92%, 10.88%) and 5.92% (95% CI: 1.31%, 10.74%), respectively. The associations of PNC < 0.05 µm remained significant when adjusting for other air pollutants. There were consistently much stronger associations of particles with ST-segment elevation AMI than those with non-ST-segment elevation AMI. CONCLUSIONS: This epidemiological investigation suggested that ultrafine particles, especially those <0.05 µm, may be mainly responsible for the acute AMI risk induced by PM2.5.

Fine particulate matter constituents and heart rate variability: A panel study in Shanghai, China.

BACKGROUND: Short-term exposure to fine particulate matter (PM2.5) has been associated with reduced heart rate variability (HRV), an established indicator of cardiac autonomic function, but it remains uncertain which specific constituents of PM2.5 had key impacts. OBJECTIVE: To examine the short-term associations between various PM2.5 constituents and HRV measures. METHODS: We conducted a retrospective panel study among 78 participants who received repeated 24-h electrocardiogram testing in Shanghai, China from 2015 to 2019. We obtained daily concentrations of 14 main chemical constituents of PM2.5 from a fixed-site monitor. During 3 or 4 rounds of follow-ups, we measured 6 HRV parameters, including 3 frequency-domain parameters (power in very low frequency, low frequency and high frequency) and 3 time-domain parameters (standard deviation of normal-to-normal intervals, root mean square successive difference and percent of adjacent normal R-R intervals with a difference ≥50 msec). We used linear mixed-effects models to analyze the data after controlling for time trends, environmental and individual risk factors. RESULTS: The average daily PM2.5 exposure was 45.8 µg/m3 during the study period. The present-day exposure to PM2.5 had the strongest negative influences on various HRV indicators. These associations attenuated greatly on lag 1 d or lag 2 d. Elemental carbon, organic carbon, nitrate, sulfate, arsenic, cadmium, chromium and nickel were consistently associated with reduced HRV parameters in both single-constituent models and constituent-PM2.5 models. CONCLUSION: Our study highlighted the key roles of traffic-related components of PM2.5 in inhibiting cardiac autonomic function.

Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson's disease.

The mitochondria are the most important cytoplasmic organelles in determining cell survival and death. Mitochondrial dysfunction leads to a wide range of disorders, including neurodegenerative diseases. The central events in the mitochondrial­dependent cell death pathway are the activation of the mitochodrial permeability transition pore (mPTP) and the disruption of mitochondrial membrane potential, which cause the release of apoptogenic molecules and finally lead to cell death. This is thought to be at least partly responsible for the loss of dopaminergic neurons in Parkinson's disease (PD); thus, the attenuation of mitochondrial dysfunction may contribute to alleviating the severity and progression of this disease. Guanosine is a pleiotropic molecule affecting multiple cellular processes, including cellular growth, differentiation and survival. Its protective effects on the central nervous system and and on several cell types by inhibiting apoptosis have been shown in a number of pathological conditions. This study aimed to analyze the ability of guanosine to protect neuronal PC12 cells from the toxicity induced by 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which mediates selective damage to dopaminergic neurons and causes irreversible Parkinson-like symptoms in humans and primates. Our results demonstrated that the apoptosis of PC12 cells induced by MPP+ was significantly prevented by pre-treatment for 3 h with guanosine. In addition, guanosine attenuated the MPP+-induced collapse of mitochondrial transmembrane potential and prevented the sebsequent activation of caspase-3, thereby protecting dopaminergic neurons against mitochondrial stress-induced damage.