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Thao P. Nguyen Ali A. Sovari Arash Pezhouman Shankar Iyer Hong Cao Christopher Y. Ko Aneesh Bapat Nooshin Vahdani Mostafa Ghanim Michael C. Fishbein Hrayr S. Karagueuzian 《The Journal of physiology》2016,594(6):1689-1707
Key points
- Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation.
- Whether hypertension in its early stage is associated with an increased risk of ventricular tachyarrhythmias is not known.
- Based on experiments performed at the cellular and whole heart levels, we show that, even early in chronic hypertension, the hypertrophied and fibrotic ventricles of spontaneously hypertensive rats aged 5 to 6 months have already developed increased stress‐induced arrhythmogenicity, and this increased susceptibility to ventricular arrhythmias is primarily a result of tissue remodelling rather than cellular electrophysiological changes.
- Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.
Abstract
Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress‐induced VT/VF increases. We compared the susceptibility of 5‐ to 6‐month‐old male spontaneously hypertensive rats (SHR) and age/sex‐matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2O2; 0.15 mmol l−1). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage‐calcium optical mapping of Langendorff‐perfused SHR hearts revealed that H2O2‐induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)‐mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.Abbreviations
- AP
- action potential
- APD
- action potential duration
- APD90
- action potential at 90% duration
- CaMKII
- calcium/calmodulin‐dependent protein kinase II
- CaT
- calcium transient
- CaTD90
- calcium transient at 90% duration
- CI
- confidence interval
- DBP
- diastolic blood pressure
- EAD/DAD
- early/delayed after‐depolarization
- HR
- heart rate
- ICC
- interclass correlation
- ICa,L
- L‐type calcium current
- IKs
- slow delayed rectifier potassium current
- INa
- sodium current
- Ito
- transient outward potassium current
- IVS(d,s) interventricular septum thickness (during diastole
- during systole)
- LV
- left ventricle
- LVEF
- left ventricular ejection fraction
- LVFS
- left ventricular fractional shortening
- LVH
- left ventricular hypertrophy
- LVID(d,s) left ventricular internal diameter (during diastole
- during systole)
- MV
- mitral valve
- NR
- normotensive rats
- PA peak vel
- pulmonary artery peak velocity
- (P)CL
- (pacing) cycle length
- PW
- posterior wall
- P‐ECG
- pseudo‐electrocardiogram
- RV
- right ventricle
- RWT
- relative wall thickness
- SHR
- spontaneously hypertensive rats
- SHHF
- spontaneously hypertensive heart failure
- SBP
- systolic blood pressure
- VT/VF
- ventricular tachycardia and fibrillation
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A Aljada H Ghanim P Mohanty D Hofmeyer D Tripathy P Dandona 《The Journal of clinical endocrinology and metabolism》2001,86(12):5988-5991
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Ajay Chaudhuri MD Husam Ghanim PhD Pradeep Arora MD 《Diabetes, obesity & metabolism》2022,24(3):365-376
Based on global estimates, almost 10% of adults have diabetes, of whom 40% are estimated to also have chronic kidney disease (CKD). Almost 2 decades ago, treatments targeting the renin-angiotensin system (RAS) were shown to slow the progression of kidney disease. More recently, studies have reported the additive benefits of antihyperglycaemic sodium-glucose co-transporter-2 inhibitors in combination with RAS inhibitors on both CKD progression and cardiovascular outcomes. However, these recent data also showed that patients continue to progress to kidney failure or die from kidney- or cardiovascular-related causes. Therefore, new agents are needed to address this continuing risk. Overactivation of the mineralocorticoid (MR) receptor contributes to kidney inflammation and fibrosis, suggesting that it is an appropriate treatment target in patients with diabetes and CKD. Novel, selective non-steroidal MR antagonists are being studied in these patients, and the results of two large recently completed clinical trials have shown that one such treatment, finerenone, significantly reduces CKD progression and cardiovascular events compared with standard of care. This review summarizes the pathogenic mechanisms of CKD in type 2 diabetes and examines the potential benefit of novel disease-modifying agents that target inflammatory and fibrotic factors in these patients. 相似文献
48.
The whitefly Bemisia tabaci is a major pest to agriculture. Adults are able to fly for long distances and to colonize staple crops, herbs and ornamentals, and to vector viruses belonging to several important taxonomic groups. During their early development, whiteflies mature from eggs through several nymphal stages (instars I to IV) until adults emerge from pupae. We aim at reducing whitefly populations by inhibiting the emergence of adults from nymphs. Here we targeted dystrophin, a conserved protein essential for the development of the muscle system in humans, other animals and insects. We have exploited the fact that whitefly nymphs developing on tomato leaves feed from the plant phloem via their stylets. Thus, we delivered dystrophin‐silencing double‐stranded RNA to nymphs developing on leaves of tomato plantlets with their roots bathing in the silencing solution. Downregulation of dystrophin expression occurred mainly in pupae. Dystrophin silencing induced also the downregulation of the dystrophin‐associated protein genes actin and tropomyosin, and disrupted F‐actin. Most significantly, the treatment inhibited the emergence of adults from pupae, suggesting that targeting dystrophin may help to restrain whitefly populations. This study demonstrates for the first time the important role of dystrophin in the development of a major insect pest to agriculture. 相似文献
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S S Mosko M J Dickel T Paul T LaTour S Dhillon A Ghanim J F Sassin 《Journal of the American Geriatrics Society》1988,36(6):502-508
The elderly have a high incidence of sleep complaints. A high incidence of sleep apnea (SA) and sleep-related periodic leg movements (PLMs) is also suspected. The relationship between the incidence and severity of SA and PLMs and sleep complaints has not, however, been determined in terms of symptomatology and physiologic abnormality. In a group of 46 community resident seniors (60 to 95 years old), the incidence of SA and PLMs was correlated with subjective sleep-wake complaints. Sixty-one percent of subjects had SA and/or PLMs. Apneas/hypopneas were associated with an average oxygen desaturation of less than 5% and an average change in heart rate of less than 10 beats per minute. While subjects with SA or PLMs had clear evidence of objective sleep disturbance, only one quarter of them admitted to any subjective sleep complaints or daytime sleepiness. Furthermore, severity of SA or PLMs failed to predict sleep-wake complaints, and vice versa. This study confirms that typically mild SA and PLMs are widespread in the elderly but tend not to be manifested in sleep-wake complaints and probably go untreated as a result. Further research is needed to determine any long-term medical significance. 相似文献