This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.
Clinically, chronic atrial dilatation is associated with an increased incidence of atrial fibrillation (AF), but the underlying mechanism is not clear. We have investigated atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation (MR).
Methods and Results
Thirteen control and 19 MR dogs (1 month after partial mitral valve avulsion) were studied. Dogs in the MR group were monitored using echocardiography and Holter recording. In open-chest follow-up experiments, electrode arrays were placed on the atria to investigate conduction patterns, effective refractory periods, and inducibility of AF. Alterations in tissue structure and ultrastructure were assessed in atrial tissue samples. At follow-up, left atrial length in MR dogs was 4.09±0.45 cm, compared with 3.25±0.28 at baseline (P<0.01), corresponding to a volume of 205±61% of baseline. At follow-up, no differences in atrial conduction pattern and conduction velocities were noted between control and MR dogs. Effective refractory periods were increased homogeneously throughout the left and right atrium. Sustained AF (>1 hour) was inducible in 10 of 19 MR dogs and none of 13 control dogs (P<0.01). In the dilated MR left atrium, areas of increased interstitial fibrosis and chronic inflammation were accompanied by increased glycogen ultrastructurally.
Chronic atrial dilatation in the absence of overt heart failure leads to an increased vulnerability to AF that is not based on a decrease in wavelength.
fibrillation; electrophysiology; tissue
An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.
albuminuria; ambulatory blood pressure; direct renin inhibitor; left ventricular hypertrophy; hypertension (kidney)
To demonstrate the benefit of the combination amlodipine/valsartan 5/160 mg over amlodipine 10 mg, in producing a lower incidence of peripheral oedema for a comparable mean sitting systolic blood pressure (MSSBP) reduction.
After a 4-week amlodipine 5 mg run-in phase, inadequately controlled hypertension patients (aged ≥ 55 years, MSSBP ≥ 130 and ≤ 160 mmHg) were randomised to receive amlodipine/valsartan 5/160 mg or amlodipine 10 mg for 8 weeks, followed by amlodipine/valsartan 5/160 mg for 4 weeks for all patients. Primary variables were MSSBP change from baseline to week 8 and incidence of peripheral oedema reported as an AE. Resolution of peripheral oedema was assessed 4 weeks after switching patients from amlodipine 10 mg to amlodipine/ valsartan 5/160 mg.
At week 8, MSSBP showed greater reduction with amlodipine/valsartan 5/160 mg than amlodipine 10 mg (least square mean: −8.01 vs.−5.95 mmHg, p<0.001 for non-inferiority and p=0.002 for superiority). Systolic control, overall BP control and systolic response rate at week 8 were significantly higher with combination than amlodipine 10 mg (34 vs. 26%; 57 vs. 50%; 36.57 vs. 27.77%, respectively). Incidence of peripheral oedema was significantly lower with the combination than amlodipine 10 mg (6.6 vs. 31.1%, p<0.001). Peripheral oedema resolved in 56% patients who switched from amlodipine 10 mg to the combination, without the loss of effect on BP reduction.
In non-responders to amlodipine 5 mg, treatment with amlodipine/valsartan 5/160 mg induced significantly less peripheral oedema than amlodipine 10 mg for similar BP reduction. Peripheral oedema resolved in > 50% patients switching from amlodipine 10 mg to the combination.
This study evaluated the effects on blood pressure (BP) of valsartan 160 mg or losartan 100 mg addition to amlodipine 5 mg in hypertensive patients.
221 patients with inadequately controlled BP (DBP ≥ 90 mmHg) after 4 weeks of treatment with amlodipine 5 mg were randomized to receive losartan/amlodipine combination therapy or valsartan/amlodipine combination therapy for 4 weeks in a cross-over study design. At the end of the wash-out period and of each treatment period, clinic and ambulatory BP measurements were recorded.
166 patients completed the study. Both combination treatments induced a greater ambulatory BP reduction than did monotherapy. However, the further mean reductions in BP versus monotherapy were significantly greater with the valsartan/amlodipine combination (SBP/DBP: −7.9 ± 3.4/−6.5 ± 2.6 mmHg for 24-hour, −8.0 ± 3.4/−6.6 ± 2.7 mmHg for daytime; −7.7 ± 3.3/−6.4 ± 2.7 mmHg for nighttime) than with the losartan/amlodipine combination (SBP/DBP: −5.5 ± 2.8/−4.2 ± 2.1 mmHg for 24-hour, −5.7 ± 2.9/−4.4 ± 2.2 mmHg for daytime; −4.8 ± 2.8/−3.7 ± 2.2 mmHg for nighttime; P < 0.01 vs valsartan/amlodipine). The incidence of adverse events with valsartan/amlodipine (8%) and losartan/amlodipine (9%) was lower than that observed with amlodipine monotherapy (17%; P < 0.05 vs combinations).
Valsartan 160 mg plus amlodipine 5 mg produced greater BP reductions than losartan 100 mg plus amlodipine 5 mg.
angiotensin receptor blocker; ambulatory blood pressure monitoring; valsartan; losartan; amlodipine; combination therapy
The aim of this study was to compare the effects of olmesartan combined with either azelnidipine or amlodipine on central blood pressure (CBP) and left ventricular mass index (LVMI) in hypertensive patients.
Patient and methods:
Patients with brachial systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg received olmesartan monotherapy (20 mg daily) for 12 weeks. The patients were then randomly assigned to fixed-dose add-on therapy with azelnidipine (16 mg daily) or amlodipine (5 mg daily) (25 patients/group) for a further 24 weeks. CBP and LVMI were measured at baseline and at the end of the study.
Baseline characteristics were similar in both groups. The decrease in brachial BP was similar in both groups. CBP and LVMI decreased significantly in both groups (both, P < 0.001). However, the decreases in CBP and LVMI were significantly greater with olmesartan/azelnidipine than with olmesartan/amlodipine (CBP, P < 0.001; LVMI, P = 0.002).
These findings indicate that olmesartan/azelnidipine had greater effects on CBP and LVMI than did olmesartan/amlodipine, even though the reduction in brachial BP was similar in both groups. These differential effects on CBP and LVMI may have important implications for cardiovascular risk reduction.
central blood pressure; left ventricular mass index; augmentation index; brachial-ankle pulse wave velocity; olmesartan/azelnidipine
The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap. The permeability of b-lap was greatest in the large intestinal segments. Compared with SLS micelles, the effective permeability coefficient values measured with mixed micelles were 5- to 23-fold higher depending on the intestinal segment. Our data suggest that b-lap should be delivered to the large intestine using a mixed micellar system for improved absorption.
Beta-lapachone; Mixed micelles; Permeability; Single-pass intestinal perfusion
Background. Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that theoretically believed to improve cardiac output by lowering right atrial pressure. However, hemodynamic parameters have never been formally assessed. Methods. Seven healthy swine were intubated and sedated. A baseline assessment of conventional ventilation (assist control) and positive end-expiratory pressure (PEEP) of
5 cm H2O was initiated. Ventilator mode was changed to APRV with incremental elevations of CPAP-high from 10 to 35 cm H2O. After a 3-to-5-minute stabilization period, measurements of hemodynamic parameters (PCWP, LAP, and CVP) were recorded at each level of APRV pressure settings. Results. Increasing CPAP caused increased PCWP and LAP measurements above their baseline values. Mean PCWP and LAP were linearly related (LAP = 0.66∗PCWP + 4.5 cm H2O,
R2 = 0.674, and P < .001) over a wide range of high and low CPAP values during APRV. With return to conventional ventilation, PCWP and LAP returned to their baseline values. Conclusion. PCWP is an accurate measurement of LAP during APRV over variable levels of CPAP. However, PCWP and LAP may not be accurate measurements of volume when CPAP is utilized.
Monitoring of HF (heart failure) with intracardiac pressure, intrathoracic impedance and/or natriuretic peptide levels has been advocated. We aimed to investigate possible differences in the response patterns of each of these monitoring modalities during HF decompensation that may have an impact on the potential for early therapeutic intervention. Six sheep were implanted with a LAP (left atrial pressure) sensor and a CRT-D (cardiac resynchronization therapy defibrillator) capable of monitoring impedance along six lead configuration vectors. An estimate of ALAP (LAP from admittance) was determined by linear regression. HF was induced by rapid ventricular pacing at 180 and 220 bpm (beats/min) for a week each, followed by a third week with daily pacing suspensions for increasing durations (1–5 h). Incremental pacing induced progressively severe HF reflected in increases in LAP (5.9 ± 0.4 to 24.5 ± 1.6 mmHg) and plasma atrial (20 ± 3 to 197 ± 36 pmol/l) and B-type natriuretic peptide (3.7 ± 0.7 to 32.7 ± 5.4 pmol/l) (all P<0.001) levels. All impedance vectors decreased in proportion to HF severity (all P<0.001), with the LVring (left ventricular)-case vector correlating best with LAP (r2=0.63, P<0.001). Natriuretic peptides closely paralleled rapid acute changes in LAP during alterations in pacing (P<0.001), whereas impedance changes were delayed relative to LAP. ALAP exhibited good agreement with LAP. In summary, impedance measured with an LV lead correlates significantly with changes in LAP, but exhibits a delayed response to acute alterations. Natriuretic peptides respond rapidly to acute LAP changes. Direct LAP, impedance and natriuretic peptide measurements all show promise as early indicators of worsening HF. ALAP provides an estimate of LAP that may be clinically useful.
haemodynamics; heart failure; implantable monitor; intrathoracic impedance; left atrial pressure; natriuretic peptide; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; bpm, beats/min; CRT-D, cardiac resynchronization therapy defibrillator; HF, heart failure; ICU, intensive care unit; LAP, left atrial pressure; ALAP, LAP from admittance; LV, left ventricular; LVEDV, LV end-diastolic volume; MR, mitral valve regurgitation; PAM™, Patient Advisor Module; RA, right atrial; RV, right ventricular; Z, intrathoracic impedance
An implantable left atrial pressure (LAP) monitoring system for guiding the management of patients with advanced heart failure has the potential to require extraction, particularly in the setting of infection. The LAP sensor lead was designed to be suitable for ease of percutaneous extraction using standard techniques for extracting pacemaker and defibrillator leads. The clinical experience, to date, with percutaneous extraction of the LAP sensor lead is presented.
A total of 82 patients underwent successful implantation of the LAP sensor lead using transseptal catheterization. Five patients of the 82 patients during a cumulative follow-up period of 267 patient-years (median of 2.9 years/patient) underwent percutaneous extraction using manual traction with a locking stylet and/or an excimer laser sheath to bore through adhesions. The distal fixation anchors of the LAP sensor lead are designed to fold forward during extraction so that the sensor module can easily separate from the interatrial septum.
Percutaneous extraction of the LAP sensor lead was accomplished successfully in all five patients with no embolic events, vascular tears, perforations, or other complications requiring surgical intervention. Manual traction alone was sufficient to detach the LAP sensor lead from the interatrial septum in all cases. Use of the excimer laser sheath was needed in selected cases to bore through scar tissue within the venous insertion site, but not within the heart.
The extraction of the LAP sensor lead was accomplished safely using standard techniques and equipment for percutaneously extracting pacemaker and defibrillator leads.
lead extraction; pacemaker infection; left atrial pressure monitoring
The efficacy and safety of the novel calcium antagonist Amlodipine (Pfizer Laboratories, New York, New York) and hydrochlorothiazide were evaluated and compared in a randomized, single-blind, parallel group study in black Africans with essential hypertension. Twenty Nigerians with newly diagnosed mild to moderate essential hypertension were randomized to receive ascending doses of Amlodipine (5 mg and 10 mg) or hydrochlorothiazide (25 mg or 50 mg), and blood pressure and heart rate were measured at baseline and at 2, 4, and 6 weeks of therapy. Both Amlodipine and hydrochlorothiazide significantly reduced supine and erect blood pressure. Supine blood pressure on Amlodipine fell from a mean of 190/104 mm Hg to 150/79 mm Hg, and on thiazide from 180/103 mm Hg to 141/84 mm Hg. There was, however, no significant difference between both drugs in antihypertensive efficacy. Neither drug induced a reflex increase in heart rate. The fall in blood pressure on both agents was associated with an increase in plasma urea. Amlodipine induced no change in plasma potassium, but hydrochlorothiazide caused hypokalemia. Both agents were well tolerated, and Amlodipine should undergo further study in the treatment of hypertension in blacks.
This was a pilot study to determine the effectiveness of low-dose imatinib therapy for hemodynamic disturbances, including pulmonary arterial hypertension (PAH), and clinical manifestations caused by chronic heart failure in dogs. Six client-owned dogs with PAH were administered imatinib mesylate orally, 3 mg/kg body weight q24h, for 30 d. Physical examination, blood biochemical tests, radiography, and Doppler echocardiography were performed prior to imatinib administration and again 30 days after administration. Clinical scores were significantly reduced after imatinib treatment. Systolic pulmonary arterial pressure, heart rate, maximum tricuspid regurgitation velocity, left atrium/aorta ratio, right and left ventricular Tei indexes, early diastolic transmitral flow wave/mitral annulus velocity ratio, and plasma atrial natriuretic peptide concentration decreased significantly after therapy. Diastolic blood pressure, stroke volume, cardiac output, and left ventricular fractional shortening increased significantly after therapy. These results indicate that low-dose imatinib therapy was effective for heart failure in dogs with PAH.
Ankle edema is a common adverse effect of amlodipine, an L-type calcium channel blocker (CCB). Cilnidipine is a newer L/N-type CCB, approved for treatment of essential hypertension.
This study was designed to determine whether cilnidipine can produce resolution of amlodipine-induced edema while maintaining adequate control of hypertension.
Materials and Methods:
A prospective study was performed on 27 patients with essential hypertension with amlodipine-induced edema. Concomitant nephropathy, cardiac failure, hepatic cirrhosis, or other causes of edema, and secondary hypertension were excluded by appropriate tests. Amlodipine therapy was substituted in all the cases with an efficacy-equivalent dose of cilnidipine. Clinical assessment of ankle edema and measurement of bilateral ankle circumference, body weight, blood pressure, and pulse rate were performed at onset of the study and after 4 weeks of cilnidipine therapy.
At completion of the study, edema had resolved in all the patients. There was a significant decrease in bilateral ankle circumference and body weight (P < 0.001). There was no significant change in mean arterial blood pressure and pulse rate.
Therapy with cilnidipine resulted in complete resolution of amlodipine-induced edema in all the cases without significant worsening of hypertension or tachycardia. Cilnidipine is an acceptable alternative antihypertensive for patients with amlodipine-induced edema.
Ankle edema; Calcium channel blocker; Cilnidipine; Hypertension; L/N-type calcium channel
The effects on myocardial mechanics of acute, artificial aortic and mitral regurgitation were studied in the dog to determine the manner in which the changes in load induced by valvular regurgitation alter ventricular performance. With mitral and aortic regurgitant volumes of approximately the same magnitude as the forward stroke volume, immediate increases occurred in total stroke volume, left ventricular enddiastolic pressure, and peak ejection velocity, whereas contractility remained unchanged. Although calculated myocardial fiber tension rose, the rate of decline of tension during ejection was accelerated with regurgitation due to the more rapid decrease in ventricular size. Average tension therefore decreased relative to average pressure. As a consequence of the increased fiber length and this unloading, contractile element velocity, work, and power were increased. Despite unchanged contractility of the myocardium, the ejection fraction rose with both aortic and mitral regurgitation.
When regurgitant beats were compared with control beats at a constant end-diastolic volume, ventricular stroke volume, work, power, and ejection fraction, as well as contractile element velocity, work, and power consistently increased. Thus, reduction of instantaneous impedance to ejection allowed the ventricle to empty further, reducing ventricular wall tension with a resultant increase in the velocity of shortening. External energy output was increased despite unchanged contractility and diastolic fiber length. It is concluded that the impedance to ejection and myocardial fiber tension during ejection govern the velocity and extent of contractile element shortening, and hence affect stroke volume, peak aortic flow rate, and ejection fraction. The alterations of ventricular function accompanying valvular regurgitation can be explained by an evaluation of the effects of these lesions on the instantaneous impedance to left ventricular ejection.
The objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.
In this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group (36.5 mmHg vs. 31.6 mmHg; p = 0.0117). The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks (52.1% vs. 33.3%; p = 0.0213) but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.
These results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.
hypertension; amlodipine; losartan
Jasmonate inducible plant leucine aminopeptidase (LAP) is proposed to serve as direct defense in the insect midgut. However, exact functions of inducible plant LAPs in the insect midgut remain to be estimated. In the present investigation, we report the direct defensive role of pigeon pea inducible LAP in the midgut of Helicoverpa armigera (Lepidoptera: Noctuidae) and responses of midgut soluble aminopeptidases and serine proteinases upon LAP ingestion. Larval growth and survival was significantly reduced on the diets supplemented with pigeon pea LAP. Aminopeptidase activities in larvae remain unaltered in presence or absence of inducible LAP in the diet. On the contrary, serine proteinase activities were significantly decreased in the larvae reared on pigeon pea LAP containing diet as compared to larvae fed on diet without LAP. Our data suggest that pigeon pea inducible LAP is responsible for the degradation of midgut serine proteinases upon ingestion. Reduction in the aminopeptidase activity with LpNA in the H. armigera larvae was compensated with an induction of aminopeptidase activity with ApNA. Our findings could be helpful to further dissect the roles of plant inducible LAPs in the direct plant defense against herbivory.
Objective—To assess the relative merits of transthoracic and transoesophageal echocardiography before balloon dilatation of the mitral valve.
Design—Transthoracic and transoesophageal echocardiograms were prospectively performed in 35 patients being considered for balloon dilatation of the mitral valve. Echocardiograms were analysed for image quality, the assessment of valve morphology, the detection of left atrial thrombus, and the assessment of mitral regurgitation and other valvar pathology.
Patients—35 consecutive patients with symptomatic dominant mitral stenosis.
Interventions—30 eventually underwent balloon dilatation of the mitral valve by the Inoue technique. Five patients had mitral valve replacement.
Main outcome measures—Echocardiographic and surgical detection of left atrial thrombus and successful, uncomplicated balloon dilatation of the mitral valve.
Results—Left atrial thrombus was detected in 1/35 patients by transthoracic studies compared with 6/35 from transoesophageal studies. Otherwise both techniques gave comparable results. Thrombus was confirmed at mitral valve replacement in five patients. Successful dilatation of the mitral valve was performed in 30 patients.
Conclusions—Transthoracic echocardiography is a useful screening procedure but transoesophageal echocardiography is mandatory before balloon dilatation of the mitral valve for the detection of left atrial thrombus.
Lamina-associated polypeptide (LAP) 2α is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2α in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2α by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2α-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2α COOH terminus directly bound Rb, and overexpressed LAP2α inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2α associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2α in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2α on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.
Latency Associated Peptide (LAP) binds TGF-β1, forming a latent complex.
Currently, LAP is presumed to function only as a sequestering agent for active
TGF-β1. Previous work shows that LAP can induce epithelial cell
migration, but effects on leukocytes have not been reported. Because of the
multiplicity of immunologic processes in which TGF-β1 plays a role, we
hypothesized that LAP could function independently to modulate immune responses.
In separate experiments we found that LAP promoted chemotaxis of human monocytes
and blocked inflammation in vivo in a murine model of the
delayed-type hypersensitivity response (DTHR). These effects did not involve
TGF-β1 activity. Further studies revealed that disruption of specific
LAP-thrombospondin-1 (TSP-1) interactions prevented LAP-induced responses. The
effect of LAP on DTH inhibition depended on IL-10. These data support a novel
role for LAP in regulating monocyte trafficking and immune modulation.
Amlodipine is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris. Toxic effects reported from amlodipine include hypotension, reflex tachycardia, metabolic acidosis, and pulmonary edema. We report a rare fatality in an infant after ingestion of amlodipine with benazepril, with postmortem blood concentrations.
An 11-month-old, 10.88-kg boy ingested 10 to 45 mg amlodipine with 40 to 180 mg benazepril. No action was taken initially because the parents believed only one or two capsules had been ingested. A later count revealed a maximum of nine capsules missing. The child was observed at home and vomited once with possible capsule fragments. Forty-five minutes post-ingestion, the child was noted to be suddenly unresponsive and was brought the local emergency department by a private vehicle. Upon arrival (90 min post-ingestion), the child was unresponsive with the following vital signs HR 133 bpm, BP 67/42 mmHg, respiratory rate 40/min, and temperature 97.5°F. Pertinent abnormal laboratory values were HCO3 13 mmol/l and glucose 302 mg/dl. The child was placed on oxygen via a non-rebreather mask and was intubated 45 min post-arrival. The patient became progressively bradycardic, and 55 min after arrival, the patient was in asystole with no palpable blood pressure. Resuscitation measures included chest compressions, epinephrine atropine, sodium bicarbonate, and calcium gluconate. Rescue insulin therapy was begun with 4 units IVP followed by 10 units per hour. Resuscitation efforts persisted for 1 h without success. An autopsy revealed pulmonary edema and no gross or microscopic evidence of natural disease. Stomach contents revealed food matter with small white fragments. Analysis of postmortem heart blood showed amlodipine 1,300 ng/ml (therapeutic <20 ng/ml). Benazepril levels were not available.
We believe this is the first reported fatality in an infant from amlodipine. While benazepril may have contributed, ACE inhibitors have not been previously associated with rapid cardiovascular collapse.
Small doses of amlodipine (0.9 to 4.1 mg/kg) may produce rapid and fatal cardiovascular collapse in an infant.
Amlodipine; Postmortem; Infant; Overdose
The prevalence of hypertension increases with advancing age. The management of hypertension especially in the elderly has its own limitations. Verapamil is not recommended in the elderly on account of high incidences of troublesome constipation. Amlodipine has become very popular with the cardiologists and general physicians. Survey of literature has not yielded any citation where the troublesome effect of amlodipine on the gastrointestinal tract has been reported. In an experimental study on isolated rabbit intestine we have demonstrated that amlodipine dose-dependently inhibit the spontaneous activity of the intestinal tract. With this background the present observational study was planned. A total of 100 hypertensive patients were included in the present study. Fifty patients were on amlodipine alone and 50 patients on combination of amlodipine and atenolol. The main parameter analyzed was the frequency and consistency of stool before and after intake of drug. The relative risk (RR) of developing constipation was 4.00 with 95% CI 0.8930 to 17.917 in amlodipine alone group. From this study it can be concluded that the relative risk of developing constipation is 4 times more in patients who are taking amlodipine alone as compared to those patients who are on combination of amlodipine and atenolol.
Microalbuminuria can be present in 25–100% of patients with essential hypertension and is associated with increased incidence of cardiovascular events. Our goal was to evaluate the effect of a commonly used calcium channel blocker, amlodipine, and an angiotensin converting enzyme inhibitor, lisinopril on urinary albumin excretion in patients with mild to moderate essential hypertension. We screened 324 patients with essential hypertension for microalbuminuria and documented it in 120 patients. These 120 patients with microalbuminuria were randomly divided into two groups of 60 each, matched for age, sex, arterial pressure, creatinine clearance, and urinary albumin excretion so as to receive amlodipine or lisinopril. We prospectively measured their urinary albumin excretion and creatinine clearance prior to treatment and, four and eight weeks after treatment with amlodipine or lisinopril. Mean arterial pressure (mean ± SD) at baseline, after four weeks, and after eight weeks was 113.01 ± 4.38,104.93 ± 3.12, and 98.89 ± 1.75 mmHg (P < 0.0000); and 114.13 ± 7.11, 106.52 ± 3.50, and 100.89 ± 2.80 mmHg (P < 0.0000) in amlodipine and lisinopril groups, respectively. Urinary albumin excretion (mean ± SEM) at baseline, after four, and after eight weeks was 79.30 ± 3.74, 62.03 ± 3.61, and 52.02 ± 3.05 (P < 0.0000); and 73.96 ± 4.10, 72.39 ± 3.74, 66.12 ± 3.94 (P = 0.1742) in lisinopril and amlodipine groups, respectively. Lisinopril but not amlodipine, reduced the urinary albumin excretion significantly despite their similar antihypertensive efficacy. The clinical and prognostic significance of these observations need to be established.
Angiotensin converting enzyme inhibitors; calcium channel blockers; hypertension; microalbuminuria
Monocytic differentiation is orchestrated by complex networks that are not fully understood. This study further elucidates the involvement of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ). Initially, we demonstrated a marked increase in nuclear C/EBPβ-liver-enriched activating protein* (LAP*)/liver-enriched activating protein (LAP) levels and LAP/liver-enriched inhibiting protein (LIP) ratios in phorbol 12-myristate 13-acetate (PMA)-treated differentiating THP-1 premonocytic cells accompanied by reduced proliferation. To directly study C/EBPβ effects on monocytic cells, we generated novel THP-1-derived (low endogenous C/EBPβ) cell lines stably overexpressing C/EBPβ isoforms. Most importantly, cells predominantly overexpressing LAP* (C/EBPβ-long), but not those overexpressing LIP (C/EBPβ-short), exhibited a reduced proliferation, with no effect on morphology. PMA-induced inhibition of proliferation was attenuated in C/EBPβ-short cells. In C/EBPβWT macrophage-like cells (high endogenous C/EBPβ), we measured a reduced proliferation/cycling index compared with C/EBPβKO. The typical macrophage morphology was only observed in C/EBPβWT, whereas C/EBPβKO stayed round. C/EBPα did not compensate for C/EBPβ effects on proliferation/morphology. Serum reduction, an independent approach known to inhibit proliferation, induced macrophage morphology in C/EBPβKO macrophage-like cells but not THP-1. In PMA-treated THP-1 and C/EBPβ-long cells, a reduced phosphorylation of cell cycle repressor retinoblastoma was found. In addition, C/EBPβ-long cells showed reduced c-Myc expression accompanied by increased CDK inhibitor p27 and reduced cyclin D1 levels. Finally, C/EBPβ-long and C/EBPβWT cells exhibited low E2F1 and cyclin E levels, and C/EBPβ overexpression was found to inhibit cyclin E1 promoter-dependent transcription. Our results suggest that C/EBPβ reduces monocytic proliferation by affecting the retinoblastoma/E2F/cyclin E pathway and that it may contribute to, but is not directly required for, macrophage morphology. Inhibition of proliferation by C/EBPβ may be important for coordinated monocytic differentiation.
C/EBP Transcription Factor; Cell Differentiation; E2F Transcription Factor; Macrophage; Retinoblastoma (Rb); C/EBP beta; Cyclin E; Monocyte; Morphology; Proliferation
Left ventricular diastolic dysfunction, with secondary atrial pressure elevation, is a well-known concept. On the contrary, effect of left atrial compliance on pulmonary pressure is rarely considered.
We report the echocardiographic case of a 9-year-old child who presented severe rheumatic mitral valve regurgitation with a giant left atrium, in contrast to a normal artery pulmonary pressure, testifying of the high left atrial compliance.
Left atrial compliance is an important determinant of symptoms and pulmonary artery pressure in mitral valve disease.
We found that β-lapachone (β-lap), a novel bioreductive drug, caused rapid apoptosis and clonogenic cell death in A549 human lung epithelial cancer cells in vitro in a dose-dependent manner. The clonogenic cell death caused by β-lap could be significantly inhibited by dicoumarol, an inhibitor of NAD(P)H:quinone oxido-reductase (NQO1), and also by siRNA for NQO1, demonstrating that NQO1-induced bioreduction of β-lap is an essential step in β-lap-induced cell death. Irradiation of A549 cells with 4 Gy caused a long-lasting upregulation of NQO1, thereby increasing NQO1-mediated β-lap-induced cell deaths. Although the direct cause of β-lap-induced apoptosis is not yet clear, β-lap treatment reduced the expression of p53 and NF-κB, whereas it increased cytochrome C release, caspase-3 activity, and γH2AX foci formation. Importantly, β-lap treatment immediately after irradiation enhanced radiation-induced cell death, indicating that β-lap sensitizes cancer cells to radiation, in addition to directly killing some of the cells. The growth of A549 tumors induced in immunocompromised mice could be markedly suppressed by local radiation therapy when followed by β-lap treatment. This is the first study to demonstrate that combined radiotherapy and β-lap treatment can have a significant effect on human tumor xenografts.
NQO1; radiation; β-lapachone; A549 cells; Bioreductive drug