Calcium Channel Blocker Treatment Research Articles

Ankle ulcer as a complication of systemic lupus erythematosus: A case report

Background: In 10-20% of cases, Raynaud’s Phenomenon (RP) is an initial manifestation of underlying connective tissue disease such as systemic lupus erythematosus (SLE), then Raynaud’s Phenomenon on SLE called secondary RP. Case presentation: A 26-year-old female came with pain in the fingers and toes. Pain aggravated by activity and cold temperatures. there are black-coloured changes at the tips of the toes, pale and bluish at bilateral fingertips. History of systemic lupus erythematosus since last 3 months. Physical examination revealed bilateral pale and cyanotic fingers, Black-colored sores on the right lateral malleolus, 1st and 5th toe of the right foot, 2nd and 3rd toes of the left foot. There is tenderness and pitting oedema. Peripheral pulses are not palpable. The antinuclear Antibody (ANA) profile is positive. Multislice computed tomography (MSCT) Angiography of the bilateral lower extremity was performed where there is stenosis proximal right dorsalis pedis artery, stenosis right plantar pedis artery, stenosis 1/3 medial left tibial posterior artery, and stenosis 1/3 distal left tibial anterior artery. The patient was diagnosed with secondary RP because of SLE and we performed debridement of the wound, then treated the patient with calcium channel blocker, prostacyclin analogue, antiplatelet and non-pharmacological treatment included avoiding cold exposure. Symptom resolution and ANA titer reduction are obtained at intervals of two- and six-months post-treatment. Conclusion: RP in this case is a manifestation of systemic lupus erythematous. Ulcer in the lateral malleolus area is a complication of secondary RP.

Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious diseases by the World Health Organization due to its high fatality of 12%-50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.

Abstract 237: Identifying the Transcriptome Signature of Calcium Channel Blocker in Human iPSC-Derived Cardiomyocytes

Calcium channel blockers (CCBs) are important in treating cardiovascular diseases and the acute pharmacological actions of CCBs in the hearts have been extensively studied. However, we lack the knowledge of the drug-specific effect on human cardiomyocyte transcriptome and potential physiological change after long-term exposure as patients are usually prescribed with these medications for their lifetime after diagnosis. Thus, we aimed to simulate chronic CCB treatment in human cardiomyocytes and subsequently examine both the functional and transcriptomic alterations. We differentiated cardiomyocytes from three human induced pluripotent stem cell (iPSC) lines and exposed them to four different CCBs—nifedipine, amlodipine, diltiazem, and verapamil—at their physiological serum concentrations for two weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line specific inhibition on calcium kinetics and contractility. While all four CCBs exerted comparable inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By examining cardiomyocyte transcriptome after treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction related genes, such as myosin heavy chain and troponin I, consistent with its depressive effects on contractile function. Moreover, the alterations in these gene may help explain how HCM patients respond to verapamil in relieving outflow tract obstruction. In conclusion, we identified the distinct transcriptome signatures of different CCBs in human cardiomyocytes, suggesting that although the four inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology. The application of iPSC platform and transcriptomic findings may allow us to identify responders to verapamil treatment.

PULMONARY ARTERY VASOREACTIVITY IN PATIENTS WITH CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION AFTER BALLOON PULMONARY ANGIOPLASTY

Objective: To demonstrate the recovery of pulmonary vasoreactivity in patients with chronic thromboembolic pulmonary hypertension (CTEPH) after series of balloon pulmonary angioplasty (BPA). Design and method: A 49-years old woman was admitted to pulmonary hypertension department with shortness of breath during minimal exertion, dizziness, syncope episodes, leg swelling. The patient had a history of pulmonary embolism 2 years ago, and then regularly took anticoagulants. According to the results of standard clinical examination diagnosis of CTEPH, WHO-FC III was established. The data of right heart catheterization (RHC) was: mean pulmonary artery pressure (PAPm) 50 mmHg, pulmonary artery wedge pressure 6 mmHg, cardiac output (CO) 3.8 l/min, pulmonary vascular resistance (PVR) 11.5 WU. Acute vasoreactivity test (AVT) with iloprost was performed – negative response: PAPm 48 mmHg, CO 3.7 l/min. Multidisciplinary team considered the patient suitable for BPA due to the distal type of lesions. 6 sessions of BPA with 3–4 week interval were performed: segmental and subsegmental arteries of C3-C8, C10 of the right lung and C8-C10 of the left lung. Results: At 1 month follow-up we found out regression of dyspnea, leg swelling, dizziness and syncope episodes, increased physical activity (increasing 6-minute walking distance from 400 to 583 m). RHC: decrease of PAPm to 29 mmHg and PVR to 5.2 WU, increase of CO to 4.4 l/min. AVT with iloprost was repeated: after the test PAPm – 21 mmHg, CO – 4.6 l/min. The patient had 2 of 3 criteria of positive response: PAPm <= 40 mmHg and increased or unchanged CO. The relative decrease of PAPm >= 10 mmHg wasn’t achieved. Conclusions: BPA in patients with CTEPH can improve pulmonary artery vasoreactivity, giving them chance to be considered for high-dose calcium channel blocker treatment.

Identifying the Transcriptome Signatures of Calcium Channel Blockers in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Calcium channel blockers (CCBs) are an important class of drugs in managing cardiovascular diseases. Patients usually rely on these medications for the remainder of their lives after diagnosis. Although the acute pharmacological actions of CCBs in the hearts are well-defined, little is known about the drug-specific effects on human cardiomyocyte transcriptomes and physiological alterations after long-term exposure. This study aimed to simulate chronic CCB treatment and to examine both the functional and transcriptomic changes in human cardiomyocytes. We differentiated cardiomyocytes and generated engineered heart tissues from 3 human induced pluripotent stem cell lines and exposed them to 4 different CCBs-nifedipine, amlodipine, diltiazem, and verapamil-at their physiological serum concentrations for 2 weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line-specific inhibition on calcium kinetics and contractility. While all 4 CCBs exerted similar inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By profiling cardiomyocyte transcriptome after CCB treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction-related genes, such as MYH (myosin heavy chain) and troponin I, consistent with its depressive effects on contractile function. The reduction of these contraction-related genes may also explain the responsiveness of patients with hypertrophic cardiomyopathy to verapamil in managing left ventricular outflow tract obstruction. This is the first study to identify the transcriptome signatures of different CCBs in human cardiomyocytes. The distinct gene expression patterns suggest that although the 4 inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology.

The association of calcium channel blockers with β-cell function in type 2 diabetic patients: A cross-sectional study.

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess β-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3hours after glucose intake were measured. Homa-β was computed by Homeostasis Model Assessment model to evaluate β-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P=0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P=0.084 for fasting C-peptide levels; P≤0.024 for C-peptide levels at 1, 2, and 3hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P≥0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β-cell function.

A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers.

Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs).We included 5064 subjects (age: 40–82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP.All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P < .05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (Val158Met) in COMT was significantly associated with lower SBP in participants treated with CCBs (P = .009) with an especially strong impact in elderly individuals (age ≥ 70) alone (Δ = −14.08 mm Hg, P = .0005).These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.

Clinical Study of Acute Vasoreactivity Testing in Patients with Chronic Thromboembolic Pulmonary Hypertension.

Background:The clinical significance of acute vasoreactivity testing (AVT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We analyzed changes in hemodynamics and oxygenation dynamics indices after AVT in patients with CTEPH using patients with pulmonary arterial hypertension (PAH) as controls.Methods:We analyzed retrospectively the results of AVT in 80 patients with PAH and 175 patients with CTEPH registered in the research database of Beijing Chao-Yang Hospital between October 2005 and August 2014. Demographic variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups. A long-term follow-up was conducted in patients with CTEPH. Between-group comparisons were performed using the independent-sample t-test or the rank sum test, within-group comparisons were conducted using the paired t-test or the Wilcoxon signed-rank test, and count data were analyzed using the Chi-squared test. Survival was estimated using the Kaplan-Meier method and log-rank test.Results:The rates of positive response to AVT were similar in the CTEPH (25/175, 14.3%) and PAH (9/80, 11.3%) groups (P > 0.05). Factors significantly associated a positive response to AVT in the CTEPH group were level of N-terminal pro-brain natriuretic peptide (≤1131.000 ng/L), mean pulmonary arterial pressure (mPAP, ≤44.500 mmHg), pulmonary vascular resistance (PVR, ≤846.500 dyn·s−1·m−5), cardiac output (CO, ≥3.475 L/min), and mixed venous oxygen partial pressure (PvO2, ≥35.150 mmHg). Inhalation of iloprost resulted in similar changes in mean blood pressure, mPAP, PVR, systemic vascular resistance, CO, arterial oxygen saturation (SaO2), mixed venous oxygen saturation, partial pressure of oxygen in arterial blood (PaO2), PvO2, and intrapulmonary shunt (Qs/Qt) in the PAH and CTEPH groups (all P > 0.05). The survival time in patients with CTEPH with a negative response to AVT was somewhat shorter than that in AVT-responders although the difference was not statistically significant (χ2 = 3.613, P = 0.057). The survival time of patients with CTEPH who received calcium channel blockers (CCBs) was longer than that in the group with only basic treatment and not shorter than that of patients who receiving targeted drugs or underwent pulmonary endarterectomy (PEA) although there was no significant difference between the four different treatment regimens (χ2 = 3.069, P = 0.381).Conclusions:The rates of positive response to AVT were similar in the CTEPH and PAH groups, and iloprost inhalation induced similar changes in hemodynamics and oxygenation dynamics indices. A positive response to AVT in the CTEPH group was significantly correlated with milder disease and better survival. Patients with CTEPH who cannot undergo PEA or receive targeted therapy but have a positive response to AVT might benefit from CCB treatment.

Replacement of Amlodipine and Lercanidipine by Barnidipine: Tolerability and Effectiveness in a Real-Life Study.

Hypertension is the leading cause of cardiovascular disease worldwide. Calcium channel blockers are an effective antihypertensive treatment, but frequently hypertension remains uncontrolled for many patients, partly due to tolerability issues. To assess the tolerability and effectiveness of barnidipine in mild to moderate hypertension patients switching treatment from other calcium channel blockers in daily practice. BASIC-HT, a prospective real life study, enrolled 20,479 hypertensive patients initiating barnidipine treatment. The present paper focuses on a subgroup of patients in BASIC-HT for whom the previous treatment with amlodipine or lercanidipine was replaced by barnidipine. Tolerability and effectiveness of barnidipine in these patients were assessed at two visits during a 3-month follow up. In 1710 mild to moderate hypertension patients switching treatment from amlodipine or lercanidipine to barnidipine monotherapy or in combination with other antihypertensive drug classes, mean blood pressure decreased during 3-month follow-up. The mean systolic blood pressure decreased from 153.15mmHg [95% CI 152.35-153.95] at baseline to 139.20mmHg [95% CI 138.58-139.82] at visit 3, after 3months. The mean diastolic blood pressure decreased from 88.85mmHg at baseline [95% CI 88.36-89.34], to 81.56 mmHg [95% CI 81.20-81.91] at visit 3. Among these patients, 65.4% replaced their initial calcium channel blocker treatment to barnidipine for tolerability reasons. During the follow-up, the main adverse event reported was edema (4.8%). The nature and frequency of events reported in this subgroup of switcher patients were in line with those reported by the total population in BASIC-HT. This real-life study suggests that replacement of other calcium channel blockers with barnidipine is a valuable therapeutic option, especially when tolerability is an issue.

Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough.

Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10-5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

Gene expression profiling of calcium-channel antagonists in the heart of hypertensive and normotensive rats reveals class specific effects

Calcium channel blockers (CCB) differ in their effects on the cardiovascular system with diltiazem being less negatively ionotrop as compared to verapamil. Diltiazem is mainly used to treat supraventricular tachycardia, vasospastic angina and the Raynaud's syndrome. Little is known about the molecular effects of benzothiazepins on cardiac gene expression. We therefore investigated the effects of diltiazem on cardiac gene expression in normotensive and hypertensive rats with left ventricular hypertrophy and compared the results with our previous findings on verapamil and nifedipine. Spontaneously hypertensive (SHR) and normotensive Sprague Dawley (SD) rats were treated with 15mg/kg diltiazem b.i.d. for 3days. Total RNA was isolated from surgically removed hearts and the gene expression of ion channels, ion transporters and their associated partners, calcium handling proteins as well as stress and cellular differentiation markers was investigated by RT-PCR. Subsequently, hierarchical gene cluster analysis was performed to decode treatment effects of different classes of CCBs. CCB treatment of normotensive and hypertensive rats revealed class specific effects with diltiazem specifically repressing cardiac genes pertinent for ion homeostasis and excitation-contraction coupling in normotensive but not hypertensive rats. Conversely, verapamil and nifedipine caused predominantly repression of genes to affect ion homeostasis and contractile dysfunction in spontaneously hypertensive rats; nonetheless, genes coding for calcium-handling proteins were up-regulated. Unlike diltiazem treatment of normotensive rats with verapamil and/or nifedipine did not influence cardiac gene expression. The effects of diltiazem on cardiac gene expression provide a molecular rationale for its use in the treatment of vasospastic angina.

PP.22.03] 24-HOUR URINE ALPHA-1-MICROGLOBULIN AS A MARKER OF HYPERTENSION-INDUCED RENAL IMPAIRMENT AND ITS RESPONSE ON DIFFERENT BP-LOWERING DRUGS.

Objective: The purpose of this study was to assess the role of urine α1-microglobulin as a marker of hypertension-induced renal damage compared to the gold-standard markers (estimated glomerular filtration rate, eGFR; urine albumin and urine albumin-to-creatinine ratio, ACR). Its response on different BP-lowering drugs was also studied. Design and method: Sixty never-treated hypertensives (65.0% males, 46.9 years, 141.4/94.0 mmHg) were randomized to an angiotensin receptor blocker (ARB)- or non-dihydropyridine calcium channel blocker (CCB)-based regimen. Patients with diabetes, established cardiovascular or renal disease were excluded. Blood samples and 24-hour urine were analyzed at baseline and 6 months after pharmaceutical blood pressure (BP) normalization. Serum creatinine was measured and eGFR was calculated. Urine albumin, creatinine, and α1-microglobulin were measured and ACR was calculated. Results: Minor changes (p = NS) in eGFR were noted during follow-up in both groups (from 111.0 to 108.4 and from 111.3 to 114.0 ml/min/1.73 m2 in the ARB and CCB group, respectively). 24-hour urine indices were all significantly improved (P < 0.01) with ARB (albumin from 19.4 to 8.2 mg/l, ACR from 21.5 to 10.0 mg/g, α1-microglobulin from 5.06 to 3.64 mg/l) but not (P = NS) with CCB treatment (albumin from 15.6 to 13.9 mg/l, ACR from 17.6 to 17.1 mg/g, α1-microglobulin from 4.94 to 4.79 mg/l). These differences between groups remained significant (P < 0.05) after adjusting for office heart rate (HR) and BP. Alpha-1-microglobulin was significantly correlated (P < 0.05) to albumin and ACR both at baseline (r = 0.283 and 0.299, respectively) and at the end of follow-up (r = 0.432 and 0.465, respectively) but not (P = NS) to eGFR. It was also significantly related (P < 0.05) to cardiovascular risk scores (Framingham and HeartScore) both at baseline (r = 0.264 and 0.436, respectively) and at the end of follow-up (r = 0.308 and 0.472, respectively). Conclusions: Urine α1-microglobulin emerges as a potentially valuable marker of hypertension-induced renal impairment. Its kinetics and its response to treatment appears similar to that of albumin. ARBs emerge as superior to non-dihydropyridine CCBs at improving its excretion in urine, independently of HR/BP control.

LB03.07

OBJECTIVE: To explore if calcium channel blocker (CCB) treatment is associated with a different or lower risk of mood affective disorder hospital admissions compared to other antihypertensive drugs. DESIGN AND METHOD: Two cohorts were studied: the Glasgow Blood Pressure Clinic (GBPC) and a hospital cohort of admissions from two Glasgow hospitals from 1980 to March 2013. These cohorts included 17,610 and 525,046 patients respectively. Prescription refill data from 2004-2013 was used to create monotherapy groups for ACE inhibitors /angiotensin-receptor blockers (AA), beta blockers (BB) and CCB with duration >90 days and a control of no antihypertensive exposure in the hospital cohort. Only prescriptions started after the 1st of April 2004 were included to exclude prevalent use. In the GBPC and hospital cohort, patients were >18 years of age and 40-80 years respectively. Admissions were classified as ICD-10 F30-39 or ICD-9 295-7. RESULTS: There were 1,927 eligible patients with 31 incident admissions for mood disorders in the GBPC over 10 years and 144,087 with 302 admissions over 5 years in the hospital cohort. Mean ages were 58 and 56 respectively. After adjustment for age at prescription and sex in both cohorts and additional baseline demographics of blood pressure, height, weight, BMI, smoking and alcohol consumption, eGFR and cardiovascular disease in the GBPC, BB showed a higher risk of admission (HR: 3.2, [95% CI: 1.2-8.6], P = 0.017) compared to AA in the GBPC. In the hospital cohort compared to controls of no antihypertensive exposure BB (1.6[1.1-2.4], P = 0.009) and CCB (1.8[1.1-3.0], P = 0.014) showed higher risks (Figure 1).(Figure is included in full-text article.) CONCLUSIONS: : Calcium antagonists may exert similar effects on mood symptoms compared to beta blockers. This association has not been previously recognised

Interventions to Prevent Cognitive Decline and Dementia in Adults without Cognitive Impairment: A Systematic Review.

Without preventative strategies, the burden of dementia is likely to increase rapidly worldwide. Primary prevention approaches involve modifying risk factors before symptoms of cognitive impairment develop. This review systematically assesses Randomised Controlled Trials (RCTs) and reviews of RCTs for their effectiveness in primary prevention. We searched Medline, the Cochrane Library, Web of Science and Psych-Info for relevant studies using pre-determined keywords. Both non-pharmacological and pharmacological interventions were considered. Inclusion criteria were sample size greater or equal to 50, at least 6 months of follow-up, and participants with no cognitive impairment at baseline. Outcomes included dementia incidence, cognitive decline and cognitive function. Study quality was rated using the Jadad criteria. Thirty-nine studies, 17 non-pharmacological and 22 pharmacological, were included. Results were heterogeneous across interventions and studies, with few significant effects. Studies investigating physical activity and calcium channel blocker treatment demonstrated significant effects in preventing cognitive decline. There were no conclusive results demonstrating overall capacity of assessed interventions to reduce risk of dementia. The review provides an overview of the current literature, and identifies areas in need of further research.

The effect of postoperative medical treatment on left ventricular mass regression after aortic valve replacement

The study objective was to analyze factors associated with left ventricular mass regression in patients undergoing aortic valve replacement with a newer bioprosthesis, the Trifecta valve pericardial bioprosthesis (St Jude Medical Inc, St Paul, Minn). A total of 444 patients underwent aortic valve replacement with the Trifecta bioprosthesis from 2007 to 2009 at 6 US institutions. The clinical and echocardiographic data of 200 of these patients who had left ventricular hypertrophy and follow-up studies 1 year postoperatively were reviewed and compared to analyze factors affecting left ventricular mass regression. Mean (standard deviation) age of the 200 study patients was 73 (9) years, 66% were men, and 92% had pure or predominant aortic valve stenosis. Complete left ventricular mass regression was observed in 102 patients (51%) by 1 year postoperatively. In univariate analysis, male sex, implantation of larger valves, larger left ventricular end-diastolic volume, and beta-blocker or calcium-channel blocker treatment at dismissal were significantly associated with complete mass regression. In the multivariate model, odds ratios (95% confidence intervals) indicated that male sex (3.38 [1.39-8.26]) and beta-blocker or calcium-channel blocker treatment at dismissal (3.41 [1.40-8.34]) were associated with increased probability of complete left ventricular mass regression. Patients with higher preoperative systolic blood pressure were less likely to have complete left ventricular mass regression (0.98 [0.97-0.99]). Among patients with left ventricular hypertrophy, postoperative treatment with beta-blockers or calcium-channel blockers may enhance mass regression. This highlights the need for close medical follow-up after operation. Labeled valve size was not predictive of left ventricular mass regression.

Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine.

Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4±4.9% of control in the presence of 20nmoll(-1) nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.

Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

Augmentation area index: a novel approach to disease severity and outcome in patients with WHO group I and group III pulmonary hypertension (1089.2)

Background: Pulmonary hypertension (PH) has a poor outcome overwhelmingly related to right ventricular (RV) failure. Augmentation area index (AI) could capture hemodynamic effects of vessel stiffening on this processes. We studied AI’s relationship to other hemodynamic measures and to clinical outcomes.Methods: This is a retrospective, exploratory clinical and hemodynamic data analysis of PH patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) or chronic obstructive pulmonary disease (COPD) who were catheterized at UPMC Presbyterian Hospital from 1/1/2006 to 3/26/2012. AI was calculated in a blinded fashion from RV pressure wave‐forms using validated image analysis software. We used linear regression to study the relationships between AI and hemodynamic parameters, multiple regression to study the primary outcome of time to death or transplantation, and logistic regression to study secondary outcome of being World Health Organization functional category 1 or 2 versus 3 or 4.Results: Clinical and hemodynamic data were analyzed for 63 patients. Mean age was 56.3 years (SD 15.0) and 67% were female. There was a positive correlation between AI and PVR (R2=.16 t=2.85 p=0.007) and a negative correlation between AI and CI (R2=.07, t=‐2.04, p=0.046). When adjusted for calcium channel blocker treatment and pulse pressure, AI was a significant predictor of time to death or transplant (R2=0.67, F(3,16)=11, p&lt;.001). Logistic regression testing of AI as the primary predictor of clinical function adjusted for systemic hypertension, tobacco use, prostacyclin treatment, body‐surface area and peripheral vascular resistance, yielded an odds ratio of 1.12 (p=.001, partial p= 0.014).Conclusion: In patients with different etiologies of PH, AI could be a significant predictor of clinical outcome. A novel approach to the pulmonary system, it correlates with other hemodynamic values previously shown to be significant markers of disease progression.Grant Funding Source: NIH TPPG

Long-term effects of antihypertensive medications on bone mineral density in men older than 55 years.

IntroductionIn this study, we investigated the effects of long-term antihypertensive treatment with calcium channel blockers or beta blockers on the bone mineral density of maxilla, as determined by cone-beam computed tomography (CBCT).Material and methodsThis retrospective study was conducted on CBCT images of men older than 55 years who had received different dental indications. Data were grouped into three categories according to the antihypertensive medication history of the patients: group A included patients who had been taking beta-blocker treatment for more than 5 years, group B included patients who had been taking calcium channel blocker treatment for more than 5 years, and the control group included patients who had never used any hypertensive medications before.ResultsStatistically significant differences were observed between the beta blocker and calcium channel blocker groups.ConclusionIn hypertension treatment, beta blockers may be preferred to calcium channel blockers in patients at high risk for osteoporosis and bone resorption.

Radiofrequency Catheter Ablation of Ventricular Tachycardia in a Military Parachuter

Premature ventricular contractions (PVCs) presenting as isolated complexes are insignificant, but if they present as salvos they are considered indicators of high risk for potentially fatal arrhythmias. We present the case of a 39-yr-old male military parachuter with PVCs and ventricular tachycardia that were incidentally detected on ECG and treated with radiofrequency catheter ablation (RFCA). He had no significant past medical history. Physical examination and biochemical tests were normal. Transthoracic echocardiography showed no structural heart disease. Due to frequent ventricular extrasystoles (VES) detected on his ECG, 24-h Holter monitoring was conducted and revealed VES, including 13,351 isolated PVCs, 1427 episodes of bigeminy, 397 of trigeminy, 30 couplets, and 4 salvo periods. After beta-blocker and calcium channel blocker treatment for 1 mo, his repeat 24-h Holter monitoring showed 18,414 isolated PVCs, 819 episodes of bigeminy, 181 of trigeminy, and 6 couplet VES, but no episodes of salvos. Electrophysiological studies (EPS) were performed and the baseline measurements were: basic cycle length: 890 ms; atrium His interval: 78 ms; and ventricular His interval: 54 ms. VES were found to orginate from the right ventricular outflow tract and were terminated by RFCA. Medical treatment was stopped. Repeat Holter showed no VES. The parachuter was qualified for full duties. As the patient is an aircrew member and further usage of antiarrhythmic agents will interfere with his flying status, instead of initiating a drug therapy again, we performed EPS and RFCA as an effective and dependable method in order to treat and to determine his fitness.