Calcium Channel Alpha Research Articles

Hypertension in Older Frail Adults in an Integrated Care Hub -What is the Guidance for Management in this Cohort?

Abstract Background The current European Society of Hypertension (ESH, 2023) guidelines suggest specific recommendations for very old or frail patients; to maintain an office systolic blood pressure (OSBP) between 140 to 150 mmHg. A reduction of treatment could be considered in these patients with a low OSBP (<120 mmHg) or in the presence of severe orthostatic hypotension or a high frailty level. Methods We completed a retrospective chart review of patients 80 years and older, who were referred for frailty and a falls assessment, from November 2021 to April 2024. During the chart review we examined the OSBP recordings for these patients to examine our practice. We explored the medication profile of patients who had an OSBP <120mmHg and >150mmHg. The agents used were ACE inhibitors, Angiotensin Receptor Blockers, Calcium Channel Blockers, Beta Blockers, Diuretics and Alpha Blockers. Results The charts for 52 patients met the criteria and were retrieved for review. The average age was 87 years (range 80-96). 3/52(6%) had a SBP < 120mmHg. 27/52(52%) had OSBP between 120 and 149 mmHg. 22/52(42%) had an OSBP >150mmHg. We examined the medication profile of those patients who had an OSBP <120 mmHg. 2/3 patients were on three agents and 1/3 patient was on two agents. Looking at the OSBP profile of those patients who had an OSBP >150mmHg. 6/22(27%) patients were on three agents, 3/22(14%) were on two agents, 12/22(54%) were on one agent and 1/22(5%) were on no antihypertensive treatment. Conclusion From our data we found 6% of our patients were over treated for blood pressure while 42% had uncontrolled OSBP readings. We are conscious of deprescribing in older fallers, but further prescribing may be necessary to achieve published targets as per the ESH guidelines. Further research needs to examine the prevalence of white coat hypertension in our cohort.

Drug repositioning for Alzheimer’s disease and related dementias: Network meta‐analysis using individual participant data

AbstractBackgroundAlzheimer’s disease and related dementias (AD/ADRD) are chronic neurodegenerative pathology and bring a growing public health concern worldwide; particularly, treatments for AD/ADRD remain limited. Drug repositioning has alternate potential to provide an opportunity to accelerate newly identified treatments for individuals with AD/ADRD. Like, some studies have investigated effects of antihypertensive medications on dementia risk, but inconsistent results are reported. In this study, we aim to determine whether existing or approved drugs, including antihypertensive drugs and hormone replacement therapy, enable to reduce the risk of dementia or cognitive impairment.MethodWe searched PubMed, MEDLINE and EMBASE for published trials up to December 31, 2020. The primary outcome of interest was incident dementia or incident cognitive decline. We examined the following candidate repurposed drugs, including hormone replacement therapy and antihypertensive drug classes: diuretics, beta blockers (BB), angiotensin‐converting enzyme inhibitors (ACE‐I), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), alpha blockers, central agonists, vasodilators, and aldosterone blockers. We conducted a random‐effects network meta‐analysis using individual participant data to identify both direct and indirect evidence from the include trials.ResultFour trials, including 19,632 participants and 10 candidate repurposed drugs, met the eligibility criteria, as shown in Figure 1. The results of network meta‐analysis were presented as a league table in Figure 2. We found that aldosterone blockers (OR = 2.32; 95% CI: 1.41 to 3.81), ARB (OR = 1.31; 95% CI: 1.07 to 1.60) and hormone therapy (OR = 1.36; 95% CI: 1.08 to 1.71) were less effective in reducing dementia risk when compared with ACE‐I. Moreover, all the other drugs reduced dementia risk statistically significantly compared with aldosterone blockers (ORs ranging from 0.46 (95% CI: 0.27 to 0.79) for alpha blockers to 0.59 (95% CI: 0.35 to 0.99) for hormone replacement therapy).ConclusionOur findings showed some classes of antihypertensive drugs may have more potential to prevent the incidence of dementia or cognitive decline than the other classes. However, further research for validation of our results is needed.

THU529 Challenges In The Management Of Biochemically Silent Paraganglioma

Abstract Disclosure: S. Dewan: None. A. Farooqi: None. J. Jun: None. Biochemically silent Pheochromocytoma and Paraganglioma (PPGL) are rare neuro-endocrine tumors because of which there is low quality evidence and insufficient guidelines for their management. 74-year-old Female was referred to our Endocrine clinic for incidentally discovered Retroperitoneal mass on MRI. On evaluation patient reported having concerns of escalating anxiety, difficult to control HTN and episodic flushing after physical activity in the last one year. A CT abdomen and pelvis with contrast was ordered which showed 1.7 x 1.8 cm mass anterior to the L5 vertebral body just caudal to the aortic bifurcation. The biochemical work up including 24-hour urine Metanephrines (104 ug/24 hr; n 52-341), Normetanephrines (479 ug/24 hr; n 88-444), Total Metanephrines (583 ug/24 hr; n 88-444), 3 Methoxytyramine (166 mcg/24 hr; n <242) was inconclusive. For further evaluation PET CT DOTATATE scan was ordered which showed the lesion to be DOTATAE somatostatin analogue avid, consistent with somatostatin receptor positive neuroendocrine tumor. Patient was scheduled for surgery in 2 weeks and was started on Terazosin in addition to her anti HTN medications Amlodipine, Losartan and HCTZ. The surgery had to be rescheduled due to inadequate blood pressure control. Her amlodipine and Terazosin dosage were gradually increased while the procedure was rescheduled. Eventually she underwent Laparotomy exploration and resection of the lesion. Patient tolerated the procedure well and had no major intra or post operative fluctuations in her blood pressure, heart rate or blood glucose. According to the Endocrine Surgery team, the tumor could not be sufficiently removed since it was immovable during surgery and could not be delineated from the spine. The post-operative CT scan showed nodular lesion at aortic bifurcation slightly increased in soft tissue component from prior CT scan. After discussions with surgery and oncology team, patient opted for imaging surveillance for now and will consider genetic counseling and/or radiation therapy if the tumor increases in size. Untreated PPGL carries a high risk of cardiovascular morbidity and mortality, and some may also be malignant with a propensity to cause mass effects and metastasis. Currently, there are scarce evidence-based studies comparing treatment options in biochemically silent PPGL, and there is no consensus for the most appropriate peri-operative management of biochemically silent PPGL. This case adds to the literature on how a combination of calcium channel blocker and alpha blocker can be used to achieve peri-operative blood pressure and heart rate control with no major side effects. It also demonstrates the importance of functional imaging, especially in clinically or radiologically suspected PPGL, even with a normal biochemical work up. We suggest multi-disciplinary evaluation and individualized management to ensure positive outcomes. Presentation: Thursday, June 15, 2023

Association between antihypertensive medicine use and risk of ovarian cancer in women aged 50 years and older

BackgroundEpithelial ovarian cancer (EOC) has few modifiable risk factors. There is evidence that some antihypertensive medicines may have cancer preventive and/or therapeutic actions; therefore, we assessed the associations between use of different antihypertensive medicines and risk of specific EOC histotypes. MethodsOur nested case-control study of linked administrative health data included 6070 Australian women aged over 50 years diagnosed with EOC from 2004 to 2013, and 30,337 matched controls. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between ever use of each antihypertensive medicine group, including beta-adrenergic blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, and alpha blockers, and the risk of EOC overall and separately for the serous, endometrioid, mucinous, clear cell and other histotypes. ResultsWe found that most antihypertensive medicines were not associated with risk of EOC. However, women who used calcium channel blockers had a reduced risk of serous EOC (OR= 0.89, 95 % CI:0.81,0.98) and use of combination thiazide and potassium-sparing diuretics was associated with an increased risk of endometroid EOC (OR= 2.09, 95 % CI:1.15,3.82). ConclusionOur results provide little support for a chemo-preventive role for most antihypertensives, however, the histotype-specific associations we found warrant further investigation.

Medical Therapy to Facilitate Urinary Stone Passage

Background: Urinary stones are now a worldwide problem due to a rise in occurrence over the past few decades. All racial and cultural groups have experienced this. Complex metabolic and environmental risk factors are both involved in the pathogenetic pathways of stone production. This disease affects roughly 12% of the world's population. Its recurrence rate is about 70% in men and 47% in women. Urinary stones have significantly increased in prevalence over the past 20 years, becoming a global disease. Aim: This review covers literature on the medical therapy of urolithiasis to facilitate urinary stone passage and their mechanism of action in the light of the new data on the diagnosis and different types of urinary tract stones. Method: A preliminary search of related articles was obtained from three online databases PubMed, Sci.hub and Google scholar whichwere used to conduct a systematic evaluation of the literature. Inclusion and exclusion criteria screened the initial search results, and 67 papers were chosen to be appropriate for this literature review following careful reading, analysis, and evaluation. Results: Different methods of medical therapy (phosphodiesterase-5 inhibitors, alpha blockers, calcium blockers, non-steroidal anti-inflammatory drugs and different types of surgical procedures (extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy,ureteroscopy)were thoroughly reviewed but among all of them the expulsion rate to remove the urinary stone was found to be larger and faster in calcium channel blocker (CI 1.33-1.66) and alpha blockers(CI 1.152–7.45). Practical implications: Medical therapies facilitate the urinary-stone passagebut these therapies are not generally used. The choices for treating urinary stones are expanded by these techniques. Patients with big ureteral stones have had better results with medical expulsive therapy.Removing the urinary stones also decreases the chances of other diseases which happened as a result of urinary stone. There are many benefits of medical expulsive therapy which are diverse in nature andthis therapy minimizes the exposure to anesthesia and radiations. Conclusion: Different surgical procedures are used to remove the stones from the urinary passage. Despite of surgical procedures, medical expulsive therapy are more helpful. Alpha-blockers and calcium channel blockers are the main medical expulsive therapies for primary evacuation of urinary tract stones. Keywords: Urolithiasis, Urinary tract stones, Medical expulsive treatment.

Parallel changes in the promoter methylation of voltage-gated T-type calcium channel alpha 1 subunit G and histone deacetylase activity in the WAG/Rij model of absence epilepsy

Objective: In the last two decades, research on epigenetic mechanisms has expanded dramatically. Recent studies demonstrated that epigenetic mechanisms regulate epilepsy and epileptogenic pathologies. In this study, we aimed to investigate changes in the promoter methylation status of the voltage-gated T-type calcium channel alpha 1 subunit G (CACNA1G) gene and total histone deacetylase activity in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is one of the commonly used genetic absence rat models of epilepsy in the three different age groups (3, 6, and 9 months old) on both sexes. 
 Material and Method: Evaluation of changes in the spike-wave discharges (SWDs) was performed with electrocorticography (ECoG). The promoter methylation status of the CACNA1G gene was determined by methylation-specific PCR (MSP), and histone deacetylase (HDAC) activity was determined spectrophotometrically. 
 Results: Our results demonstrated that the number of SWDs increased time-dependent in WAG/Rij. Additionally, it was observed that CACNA1G promoter methylation decreased, and total HDAC activity increased with age in both sexes. 
 Conclusion: Our results provide further support for epigenetic regulation in the absence epilepsy phenotype and suggest that the underlying mechanism behind the increase in the number of SWDs with age in the WAG/Rij animals might be regulated by CACNA1G promoter methylation or HDAC activity.

Comparison of the different isoforms of vitamin e against amyloid beta-induced neurodegeneration.

Neurodegeneration is the progressive loss of structure or function of neurons. Amyloid beta oligomers and aggregates have been linked to neurodegeneration. While previous studies have suggested that dietary α-tocopherol intake can prevent amyloid beta aggregation and protect the brain against neurotoxicity, other research, however, indicated that tocotrienol forms might be used as an alternate agent against this kind of degeneration. In the presented research, we compared the in vitro protective effects of α-tocopherol and α-tocotrienol. In this context, we formed an in vitro neurodegeneration model with primary isolated neurons and measured α-tocopherol's and α-tocotrienol's protective effects. As a result, α-tocopherol and α-tocotrienol prevent the degeneration of neurons. Moreover, α-tocopherol and α-tocotrienol regulated the neuron's calcium channels mechanism by decreasing the expression of the calcium channel alpha 1C subunit. We also observed that the amount of amyloid beta accumulation in the extracellular matrix decreased with the application of these isoforms. In specific time points, α-tocopherol and α-tocotrienol differ in terms of protective effects. In conclusion, it could be interpreted that, in more extended periods, α-tocotrienol could be a significant protective agent against amyloid beta-induced neurodegeneration, and it can be used as an alternative to other protective agents, especially α-tocopherol.

ASSESSMENT OF WHOQOL BREF DOMAINS AND ANTIHYPERTENSIVES PRESCRIPTION PATTERN IN HEMODIALYSIS PATIENTS

Background: ESRD is considered as an important cause of mortality worldwide. Patients with CKD on Hemodialysis treatment is very complex requires additional importance in prescribing antihypertensives and also patients on Hemodialysis have effects on functional state and quality of life (QOL). Objectives: The study aimed to assess prescribing pattern of antihypertensives and to demonstrate QOL in different domains of patients with ESRD underdoing hemodialysis. Materials and Methods: Study comprised of 85 patients with ESRD under hemodialysis conducted in multi-speciality hospital between September 2019 to February 2020.The data was collected from the records and by interviewing patients. Results: The mean age of the study population was 54.76±14.32, 72% were males, hypertension is the common cause of ESRD. Calcium channel blockers are the most commonly prescribed drugs followed by alpha blockers, diuretics, beta blockers, vasodilators etc. Comparing the four domains of ESRD patients, environmental domain was the highest with a mean score of 64.56±19.86while the physical health domain was the lowest with a mean score of55.6±12.60. Conclusion: Calcium channel blockers and alpha blockers are most commonly prescribed antihypertensives. The four domains were signicantly and positively interrelated with moderate to strong relationships

Beneficial effect of walnuts on vascular tone is associated with Akt signalling, voltage-dependent calcium channel LTCC and ATP-sensitive potassium channel Kv1.2

Consumption of walnuts is beneficial for cardiovascular health. To study walnut effects on proteins involved in vascular tone regulation, control and fructose-fed rats were subjected to walnut diet for 6 weeks. In contrast with increased energy intake and body mass gain, aortic protein level of L-type calcium channel alpha subunit was decreased and the level of SUR2B subunit of ATP-sensitive K + channel was increased in healthy rats subjected to walnuts, together with improved Akt phosphorylation. Upon the walnut diet in rats subjected to fructose overload, the rise in energy intake and body mass gain, was followed by an increase in blood insulin. Although SUR2B level was elevated, the level of sodium-calcium exchanger NCX1 and inducible nitric oxide synthase were reduced and increased, respectively. In summary, walnut consumption was accompanied with moderate beneficial vascular effect in healthy rats, while an effect of walnut in rats with metabolic disturbances was rather controversial.

145 Antihypertensive Medications and Falls in the Older Person

Abstract Background There have always been concerns about the increased risk of falls in the older person taking antihypertensive medications. This retrospective study is aimed to determine whether different classes and number of antihypertensive medication used were associated with increased risk of falls in the older person. Methods Data was obtained from the geriatric clinic database in HKL from 2015-2018. The data for fallers were extracted from the Falls Clinic while data for the control group of non-fallers were extracted from the General Geriatric clinic. Socio-demographic details, types of falls, types of medications, and risk factors of falls were analysed. Results 117 of the cases who were fallers and 39 cases of non-fallers were analysed. Univariate logistic regression revealed that age, Parkinson’s disease and hypertension to have significant association with falls. The fallers were then analysed to assess falls risk with the use of antihypertensive medications. Those on one anti-hypertensive medication had an increased risk of recurrent falls (AOR = 3.16; 95% CI: 1.47–6.82) compared to those without antihypertensive medications (AOR = 0.37; CI: 0.13-1.03) and those with two or more antihypertensive medications (AOR = 0.56; CI: 0.27-1.16). Multivariate logistic regression also revealed that the use of all antihypertensive classes were not associated with recurrent falls and injuries from falls. However, patients who were on diuretics had significant odds of admission for falls (AOR 3.05; 95% CI 1.14-8.21) compared to ACE inhibitors or angiotensin receptor blockers (AOR 0.88; CI 0.38-2.10), beta blockers (AOR 0.88; CI 0.35-2.24), calcium channel blockers (AOR 0.96; CI 0.42-2.23) or alpha blockers (AOR 0.41; CI 0.09-1.99). Conclusion Older person with advanced age and Parkinson’s disease should be screened for risk of falling. In addition, all older people on antihypertensive medications especially diuretics should also be monitored for increased risk of falls.

A meta-analysis of analgesic efficacy of opioids in the treatment of neuropathic pain

Background: Neuropathic pain is the most common form of chronic pain often associated with impaired quality of life due to its poor management. Tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors and calcium channel alpha 2 ligand agonist are preferred as first line therapy for neuropathic pain. Lignocaine patches and transdermal patches of capsaicin are used as second line agents. Moderate efficacy opioids like tramadol and strong opioids are recommended as second line and third line therapy for neuropathic pain respectively. Previous meta-analysis and systematic review shows inconsistent data and lacks reliability in getting conclusive results in opioids use in neuropathic pain. So, author conducted a meta-analysis to reanalyse the analgesic efficacy of opioid agonist for the treatment of neuropathic pain.Methods: Author searched Oxford pain relief data base, Google web, Embase, Medline and Cochrane library from February 2001 to November 2017 for articles related to analgesic efficacy of opioid agonist in neuropathic pain based on author’s selection criteria. Reference list of reviews were retrieved using Prisma Algorithm and analysed using REVIEW MANAGER 5 software.Results: Among 1108 publications searched, only 5 trials met the inclusion criteria. Primary outcome measure was proportion of participants reporting 50% of pain relief or better. In five trials, 305 patients treated with opioids and placebo/standard treatment for neuropathic pain, the number per treatment group ranges from 31 to 170 (median 50±5). The overall point estimate of risk difference was 0.17 (95% CI 0.02 to 0.33, P=0.026) translating to number needed to treat (Benefit) of 5.9 (3.0 to 50.0).Conclusions: In this meta-analysis, opioid agonist efficacy trials shown consistent analgesic efficacy and benefit over placebo/standard treatment in reducing neuropathic pain.

SU70 - DNA METHYLATION CHANGES IN THE RAT STRIATUM DUE TO L-DOPA TREATMENT IN A TIC ANIMAL MODEL

Background Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. The cause of TS remains elusive but dopamine (DA) has a central role within the cortico-striatal pathway. TS has high heritability and a complex genetic background, but environmental factors also play an important role in the development of the disorder. These factors often operate via epigenetic mechanisms (i.e. covalent chromatin modifications). Methods We used a rodent tic model to test the epigenetic alterations in the striatum. Juvenile male Wistar Kyoto rats were injected with 6-OH-dopamine in the left medial forebrain bundle resulting in degeneration of nigrostriatal dopaminergic neurons. Chronic application of L-DOPA after consolidation of the lesion leads to motor tics due to the striatal hypersensitivity to DA. We studied genome-wide DNA methylation by Reduced Representation Bisulfite Sequencing technique (RRBS) in 3 groups: animals undergoing lesion only, animals treated with L-DOPA after the lesion and animals co-treated with L-DOPA and riluzole (medication used in TS) after the lesion. Results Surprisingly, by investigating the striata we detected only a few DNA methylation changes between the lesioned and control sides of the brain in each group. However, when we compared the control or the lesioned striata of the three groups of animals we more abundant methylation differences. L-DOPA treatment brought about statistically significant DNA hypermethylation at over 1000 CpG sites and hypomethylation at around 300 sites genome-wide. Several dozens of genes were identified in the vicinity of hypermethylated sites, while considerably less were hypomethylated. Some of the relevant hits include genes coding for neurotransmitter transporters, such as SLC6A2 (Norepinephrine transporter), Cacna1h (Calcium channel alpha 1 h subunit), Tnfrsf8 (TNF receptor superfamily member 8), HAT1 (histone acetyltransferase 1), plus several microRNA genes. Discussion This project is a methylome study on a Tourette Syndrome animal model that may provide novel candidate genes and a better understanding of the molecular mechanisms behind the pathophysiology of TS.

Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking

Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein-protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3 protein-protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3 protein-protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1 Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein-protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

Profil Penggunaan Obat Antihipertensi di RSUD Mas Amsyar Kasongan Kabupaten Katingan

Hypertension or high blood pressure is one of the lead causes of death. Hypertension can cause various complications with another disease, even the cause of heart disease, stroke, and kidney disorders. Hypertension is the second rank of the most diseases in Kabupaten Katingan. The purpose of this research is to know the profile of antihypertensive medicines in RSUD Mas Amsyar Kasongan. Method of this research was a descriptive method with saturation sampling used retrospective data on all prescription drugs in 2017. The results of this research based on the patient characteristic were found 43.3% men and 56.7% women, meanwhile 45.8% age < 45 years old and 54.2% for age > 45 years old. The antihypertensive drug items used are propranolol, telmisartan, amlodipine, lisinopril, furosemide, ramipril, valsartan, candesartan, irbesartan, and bisoprolol, meanwhile based on the classification of antihypertensive drugs. are angiotensin II receptor blockers (ARB), diuretics, angiotensin converting enzyme Inhibitors (ACEI), Calcium Channel Blockers (CCB) and alpha 2 adrenergic agonists. Based on the result, it can be concluded that hypertension patient in RSUD Mas Amsyar Kasongan is mostly female (56.7%) and age of hypertension patient is > 45 years old (54.2%). The most antihypertensive prescribed is monotherapy (72%) and the most item of the drug is amlodipine. (38%).

Alterations of L-type voltage dependent calcium channel alpha 1 subunit in the hippocampal CA3 region during and after pilocarpine-induced epilepsy

Voltage-dependent calcium channels (VDCC) have been shown to regulate neuronal excitability and their antagonists have been used clinically for the control of seizures. While functional studies of VDCC in epileptogenesis in the CA1 area of hippocampus or the dentate gyrus have been done, few studies were carried out in the CA3 area. Given the bursting characteristics of the CA3 neurons, we speculated that VDCC in the CA3 area might play an important role in the epileptogenesis. In the present study in the mouse pilocarpine model of temporal lobe epilepsy, we investigated the alterations of alpha 1 subunits of L-type VDCC in the CA3 area of the hippocampus at different stages of epileptogenesis, i.e., acute stage from 10 min to 1 day during and after pilocapine-induced status epilepticus (SE), latent period at 1 week, and chronic stage with spontaneous recurrent seizures at 2 months after SE. We found that an immediate redistribution of alpha 1 subunits in the CA3 area occurred during SE which might be involved in the seizure occurrence indicated by the Racine score record. Alterations of alpha 1 subunits were also demonstrated in the latent period and chronic stage, which might be related to the epileptogenesis and occurrence of epilepsy. Cav1.3, but not Cav1.2, was expressed in reactive astrocytes of the CA3 area, indicating the involvement of Cav1.3 in the modulation of astrocytic Ca2+ homeostasis during epileptogenesis.

The cardiac L-type calcium channel alpha subunit is a target for direct redox modification during oxidative stress-the role of cysteine residues in the alpha interacting domain.

Cardiovascular disease is the leading cause of death in the Western world. The incidence of cardiovascular disease is predicted to further rise with the increase in obesity and diabetes and with the aging population. Even though the survival rate from ischaemic heart disease has improved over the past 30years, many patients progress to a chronic pathological condition, known as cardiac hypertrophy that is associated with an increase in morbidity and mortality. Reactive oxygen species (ROS) and calcium play an essential role in mediating cardiac hypertrophy. The L-type calcium channel is the main route for calcium influx into cardiac myocytes. There is now good evidence for a direct role for the L-type calcium channel in the development of cardiac hypertrophy. Cysteines on the channel are targets for redox modification and glutathionylation of the channel can modulate the function of the channel protein leading to the onset of pathology. The cysteine responsible for modification of L-type calcium channel function has now been identified. Detailed understanding of the role of cysteines as possible targets during oxidative stress may assist in designing therapy to prevent the development of hypertrophy and heart failure.

Astragalus Granule Prevents Ca2+ Current Remodeling in Heart Failure by the Downregulation of CaMKII.

Background Astragalus was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from Astragalus, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca2+ current (ICa-L) in HF mice by the downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). Methods HF mice were induced by thoracic aortic constriction (TAC). After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP) and ICa-L. The expressions of L-type calcium channel alpha 1C subunit (Cav1.2), CaMKII, and phosphorylated protein kinase A (p-PKA) were examined by western blot. Results The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered ICa-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG-related shortened repolarization time, decreased peak ICa-L, accelerated ICa-L inactivation, and positive frequency-dependent ICa-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart. Conclusion AG treatment protected the failing heart against electrical remodeling and ICa-L remodeling by downregulating CaMKII.

OP.8B.06] HYPOTENSIVE THERAPY IN PATIENTS WITH OBSTRUCTIVE SLEEP APNOEA

Objective: Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder. Individuals with OSA are at increased risk of cardiovascular diseases such as arterial hypertension (HTN), heart failure, stroke and pulmonary hypertension. Detailed data regarding hypotensive therapy and its effectiveness in patients with HTN and OSA are lacking. The aim of the study was to characterize in details hypotensive therapy in patients with HTN and OSA. Design and method: We retrospectively analyzed 1270 patients who were treated in our outpatient sleep apnea clinic. All patients underwent polysomnography. 795 patients with diagnosed HTN were included in further analysis. In the next step we divided patients in 2 subgroups with and without OSA. Local ethics committee gave consent to conduct the study. Results: In our study population mean age was 60.1 ± 11.4 years, 69.4% were male, 64.9% were smokers, 63% were obese, 65% had hyperlipidemia, 59.9% reported snoring, and 83.4% had the diagnosis of OSA (average supine AHI 46,8 ± 35,2). Patients with OSA were statistically significantly older (p = 0.033), were more frequently male (p < 0.001), obese (p < 0.001) and more often had hyperlipidemia (p < 0.001). Regarding details of hypotensive therapy patients with OSA significantly more frequently took ACEi, ARBs, betablockers, thiazides and loop diuretics, aldosteron antagonists, calcium channel blockers and alpha blockers (p < 0.01 for all medication groups). We found no statistically significant differences in respect of potassium sparing diuretics and hypotensive drugs acting centrally. We found no statistically significant differences between patients with and without OSA if analyzing use of different medication within each class of hypotensive drugs. Conclusions: There are significant differences in antyhypertensive therapy in patients with HTN and with or without OSA. Since HTN is one of the most recognized comorbidity in patients with OSA further studies are needed in order to assess effectiveness of hypotensive therapy in this population.

Band-like Acral Osteolysis in Limited Cutaneous Scleroderma

Abstract: Acral osteolysis is a well-recognized manifestation of scleroderma. Scleroderma is characterized by abnormal deposition of collagen and other extra cellular matrix macromolecules leading to vascular damage, inflammation and tissue fibrosis. Acral osteolysis in scleroderma occurs due to digital ischemia resulting from the vasculopathy. Treatment is directed towards providing symptomatic relief and prevention of complications. Here we present a case of band-like acral osteolysis seen in a patient of limited cutaneous scleroderma. Keywords: Osteolysis; Acral osteolysis; Scleroderma; Systemic sclerosis Introduction:Scleroderma is a multisystem connective tissue disorder that is characterised by abnormal deposition of collagen and other connective tissue macromolecules in the skin and multiple internal organs leading to inflammation and fibrosis. The exact etiology is unknown. Various genetic, infectious, and environmental factors have been implicated in the pathogenesis of scleroderma leading to vascular injury, fibrosis, and immune activation. The pathological pathways include vasculopathy and abnormalities in both humoral and cellular immunity. Osteolysis is a well-recognized manifestation of scleroderma. Here we report a case of band-like acral osteolysis seen in a patient of scleroderma. Clinical Presentation: A 25 years old female presented with a history of progressive tightening of the skin over her fingers and face for 3 years associated with phasic changes in skin colour (white, blue and red) typical of Raynaud’s phenomenon. On physical examination, the skin over her face appear stretched out, tight and shiny. The skin over the distal part of most her fingers also appear tight and stretched out. The tips of most of her fingers appear shortened (Figure 1). A test for antinuclear antibodies was positive with a titre of 1: 1280. Her Anticentromere antibodies were positive. A radiograph of both hands showed symmetrical band-like osteolysis of the diaphysis of distal phalanges suggestive of acral osteolysis (Figure 2). Echocardiography revealed a normal study. Further test were done that ruled out other organ systems involvement. Discussion: Acral osteolysis in scleroderma is thought to result from impaired blood flow due to vasculopathy resulting in digital ischemia and subsequent damage to the terminal phalanges [1]. It may also be a result of pressure changes due to the induration and tightening of the skin. Acral osteolysis can also be seen in various other pathological conditions such as diabetes mellitus, tabes dorsalis, leprosy, psoriasis, rheumatoid arthritis, exposure to vinyl chloride, following trauma or in association with hyperparathyroidism [2]. Treatment options are limited and is focused on providing symptomatic relief and preventing complications. Patients should avoid prolonged cold exposure and avoid digital or skin trauma. Calcium channel blockers and alpha receptor blockers may reduce the ischemia by promoting vasodilatation. Phosphodiesterase-5 inhibitors such as sildenafil may also help provide symptomatic relieve. The disease is, however, progressive in nature and currently there are no approved therapy aimed at retarding the vascular damage, fibrosis and altered immunological response. Current experimental therapies are based on immune-suppression and immune-modulation and include drugs like methotrexate, mycophenolate mofetil, D-penicillamine and rituximab. Tocilizumab, an interleukin-6 (IL-6) receptor antagonist was recently granted breakthrough therapy designation status for systemic sclerosis by the United States Food and Drug Administration (USFDA) [3]. Various other possible immune-inflammatory therapies are currently under study, including modulators of the profibrotic pathways [4]. The safety and possible toxicity of these agents remain a cause for concern.

T-type Calcium Channel Regulation of Neural Tube Closure and EphrinA/EPHA Expression.

A major class of human birth defects arise from aberrations during neural tube closure (NTC). We report on a NTC signaling pathway requiring T-type calcium channels (TTCCs) that is conserved between primitive chordates (Ciona) and Xenopus. With loss of TTCCs, there is a failure to seal the anterior neural folds. Accompanying loss of TTCCs is an upregulation of EphrinA effectors. Ephrin signaling is known to be important in NTC, and ephrins can affect both cell adhesion and repulsion. In Ciona, ephrinA-d expression is downregulated at the end of neurulation, whereas, with loss of TTCC, ephrinA-d remains elevated. Accordingly, overexpression of ephrinA-d phenocopied TTCC loss of function, while overexpression of a dominant-negative Ephrin receptor was able to rescue NTC in a Ciona TTCC mutant. We hypothesize that signaling through TTCCs is necessary for proper anterior NTC through downregulation of ephrins, and possibly elimination of a repulsive signal.