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1.  d,l-Sotalol at Therapeutic Concentrations Facilitates the Occurrence of Long-lasting Non-stationary Reentry During Ventricular Fibrillation in Isolated Rabbit Hearts 
Background
Effects of d,l-sotalol at therapeutic concentrations (≤10 mg/L) on wavefront dynamics during ventricular fibrillation (VF) and electrophysiological heterogeneity remain unclear.
Methods and Results
By using an optical mapping system, epicardial activation patterns of VF were studied in 6 Langendorff-perfused rabbit hearts at baseline, during 10 mg/L d,l-sotalol infusion, and after washout. An additional 4 hearts, action potential duration (APD), conduction velocity, and wavelength (WL) restitutions were determined. During d,l-sotalol infusion, VF was terminated in 3 of the 6 hearts. Only one experienced a transient ventricular tachycardia (VT). d,l-Sotalol reduced the number of phase singularities (i.e., wavebreak) during VF (p<0.05). d,l-Sotalol also increased the occurrence frequency (p<0.05) and life span (p<0.05) of epicardial reentry during VF. These reentries were non-stationary in nature and did not anchor on anatomical structures. Restitution data showed that d,l-Sotalol flattened APD restitution. Furthermore, APD dispersion and spatial heterogeneity of restitutions were not enhanced by d,l-sotalol.
Conclusions
d,l-Sotalol at therapeutic concentrations decreased wavebreak and facilitated the occurrence of long-lasting non-stationary reentry during VF. However, VT rarely occurred. The related mechanisms include: (1) APD restitution flattening without enhancement of spatial heterogeneity of electrophysiological properties causes wavefront organization, and (2) WL prolongation prevents a steady anchoring of reentry.
PMCID: PMC3060151  PMID: 19008631
d,l-sotalol; reentry; ventricular fibrillation
2.  Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20 
PLoS Medicine  2008;5(3):e64.
Background
Rituximab is used in the treatment of CD20+ B cell lymphomas and other B cell lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising antilymphoma effects. The objective of this study was to evaluate the influence of statins on rituximab-induced killing of B cell lymphomas.
Methods and Findings
Complement-dependent cytotoxicity (CDC) was assessed by MTT and Alamar blue assays as well as trypan blue staining, and antibody-dependent cellular cytotoxicity (ADCC) was assessed by a 51Cr release assay. Statins were found to significantly decrease rituximab-mediated CDC and ADCC of B cell lymphoma cells. Incubation of B cell lymphoma cells with statins decreased CD20 immunostaining in flow cytometry studies but did not affect total cellular levels of CD20 as measured with RT-PCR and Western blotting. Similar effects are exerted by other cholesterol-depleting agents (methyl-β-cyclodextrin and berberine), but not filipin III, indicating that the presence of plasma membrane cholesterol and not lipid rafts is required for rituximab-mediated CDC. Immunofluorescence microscopy using double staining with monoclonal antibodies (mAbs) directed against a conformational epitope and a linear cytoplasmic epitope revealed that CD20 is present in the plasma membrane in comparable amounts in control and statin-treated cells. Atomic force microscopy and limited proteolysis indicated that statins, through cholesterol depletion, induce conformational changes in CD20 that result in impaired binding of anti-CD20 mAb. An in vivo reduction of cholesterol induced by short-term treatment of five patients with hypercholesterolemia with atorvastatin resulted in reduced anti-CD20 binding to freshly isolated B cells.
Conclusions
Statins were shown to interfere with both detection of CD20 and antilymphoma activity of rituximab. These studies have significant clinical implications, as impaired binding of mAbs to conformational epitopes of CD20 elicited by statins could delay diagnosis, postpone effective treatment, or impair anti-lymphoma activity of rituximab.
Jakub Golab and colleagues found that statins significantly decrease rituximab-mediated complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against B cell lymphoma cells.
Editors' Summary
Background.
Lymphomas are common cancers of the lymphatic system, the tissues and organs that produce and store the white blood cells (lymphocytes) that fight infections. In healthy people, the cells in the lymph nodes (collections of lymphocytes in the armpit, groin, and neck) and other lymphatic organs divide to form new cells only when the body needs them. Lymphomas form when a T or B lymphocyte starts to divide uncontrollably. The first sign of lymphoma is often a painless swelling in the armpit, groin, or neck caused by lymphocyte overgrowth in a lymph node. Eventually, the abnormal (malignant) lymphocytes, which provide no protection against infectious diseases, spread throughout the body. Treatments for lymphoma include chemotherapy (drugs that kill rapidly dividing cells) and radiotherapy. In addition, a drug called rituximab was recently developed for the treatment of some types of B cell lymphoma. Rituximab is a monoclonal antibody, a laboratory-produced protein. It binds to a protein called CD20 that is present on the surface of both normal and malignant B lymphocytes and induces cell killing through processes called “complement-dependent cytotoxity” (CDC) and “antibody-dependent cellular cytotoxity” (ADCC).
Why Was This Study Done?
Although rituximab lengthens the lives of patients with some types of B cell lymphoma, it is not a cure—the lymphoma usually recurs. Researchers are trying to increase the effectiveness of rituximab by combining it with other anticancer agents. One group of drugs that might be combined with rituximab is the “statins,” drugs that reduce the risk of heart disease by lowering the level of cholesterol (a type of fat) in the blood. In laboratory experiments, statins kill some cancer cells, in part by altering the fat composition of their outer (plasma) membrane. In addition, some population-based studies suggest that statin treatment might slightly decrease the risk of developing some kinds of cancer, including lymphoma. Statins are already undergoing clinical evaluation in combination with chemotherapy for the treatment of lymphoma, but in this study, the researchers investigate the influence of statins on rituximab-induced killing of B cell lymphomas.
What Did the Researchers Do and Find?
When the researchers tested the ability of rituximab and statin combinations to kill B cell lymphoma cells growing in dishes, they found that statins decreased rituximab-dependent CDC and ADCC of these cells. Statin treatment, they report, did not alter the total amount of CD20 made by the lymphoma cells or the amount of CD20 in their plasma membranes, but it did reduce the binding of another anti-CDC20 monoclonal antibody to the cells. Because both this antibody and rituximab bind to a specific three-dimensional structure in CD20 (a “conformational epitope”), the researchers hypothesized that statins might alter rituximab-induced killing by affecting the shape of the CD20 molecule on the lymphoma cell surface. To test this idea, they used two techniques—atomic force microscopy and limited proteolysis. The data obtained using both approaches confirmed that statins induce shape changes in CD20. Finally, the researchers took B cells from five patients who had taken statins for a short time and showed that this treatment had reduced the amount of anti-CD20 monoclonal antibody able to bind to these cells.
What Do These Findings Mean?
These findings indicate that statins change the shape of the CD20 molecules on the surface of normal and malignant B lymphocytes, probably by changing the amount of cholesterol in the cell membrane. This effect of statins has several clinical implications, which means that cancer specialists should check whether patients with known or suspected B cell lymphoma are taking statins to treat high cholesterol. First, the impaired binding of monoclonal antibodies to conformational epitopes of CD20 in patients being treated with statins might delay the diagnosis of B cell lymphomas (CD20 binding to lymphocytes is used during the diagnosis of lymphomas). Second, some patients with B cell lymphoma may receive an incorrect diagnosis and may not be offered rituximab. Finally, because statins impair the anti-lymphoma activity of rituximab, a possibility that needs to be investigated in clinical studies, cancer specialists should check that patients with B cell lymphoma are not taking statins before prescribing rituximab.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050064.
The MedlinePlus has an encyclopedia page on lymphoma and a list of links to other sources of information on lymphoma (in English and Spanish)
The US National Cancer Institute provides information about lymphoma and about statins and cancer prevention (in English and Spanish)
The UK charity Cancerbackup provides information for patients and caregivers on different types of B-cell lymphoma and on rituximab
The US Leukemia and Lymphoma Society also provides information for patients and caregivers about lymphoma
doi:10.1371/journal.pmed.0050064
PMCID: PMC2270297  PMID: 18366248
3.  Simvastatin Activates the PPARγ-Dependent Pathway to Prevent Left Ventricular Hypertrophy Associated with Inhibition of RhoA Signaling 
Texas Heart Institute Journal  2013;40(2):140-147.
Left ventricular hypertrophy is an independent risk factor for major adverse cardiovascular events. Statins have positive effects on this condition; however, the mechanisms are incompletely understood. In this study, we examined whether the effect of simvastatin on left ventricular hypertrophy can be mediated with the peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway in rabbits with nonischemic heart failure (HF).
We induced aortic insufficiency and constriction in 48 rabbits and divided them equally into control, HF, and HF with simvastatin therapy (HF-SIM) groups. The HF-SIM group was given 10 mg/kg/d of simvastatin. We echocardiographically measured baseline and 8-week cardiac structure and function, and we used Western blot, polymerase chain reaction, and electrophoretic analytic techniques to evaluate messenger RNA expression and protein expression and activity. In comparison with the HF group, the HF-SIM rabbits had an increased ejection fraction and decreased left ventricular mass index, interventricular septal thickness, ventricular posterior-wall thickness, and collagen volume fraction. Moreover, the messenger RNA and protein expression of PPARγ in the HF-SIM rabbits were significantly higher than those in the HF rabbits; and the activity and expression of nuclear factor-κB subunit p65, RhoA, and Rho GTPase were significantly lower. Our results indicate that simvastatin therapy attenuates the PPARγ-dependent pathway in association with the inhibition of RhoA and Rho GTPase signaling to inhibit nuclear factor-κB activation, thus preventing the development of left ventricular hypertrophy and fibrosis in rabbits with nonischemic heart failure.
PMCID: PMC3649785  PMID: 23678211
Disease models, animal; heart failure/drug therapy; heart ventricles/drug effects; hypertrophy, left ventricular/physiopathology/prevention & control; NF-kappa B/metabolism; PPAR gamma/drug effects/metabolism; rhoA GTP-binding protein; simvastatin; ventricular function, left/drug effects
4.  Optical Mapping of Electrical Heterogeneities in the Heart During Global Ischemia 
Real-time optical registration of electrical activity in the heart allows the study of arrhythmogenic mechanisms, in particular due to global ischemia. It is known that global ischemia increases electrical heterogeneity in the heart. However, inter-ventricular differences between the right (RV) and left ventricle (LV) during ischemia and their relationship to arrhythmogenesis remains poorly understood. We used high resolution optical mapping (di-4-ANEPPS, excitation at 532nm, emission at 640±50 nm) of Langendorff-perfused rabbit hearts to quantify inter-ventricular heterogeneity in the heart during periodic pacing and ventricular fibrillation. Two fast CCD cameras were used to record electrical activity from the RV and LV during control, global ischemia (20 min), and reperfusion. Hearts were paced at progressively reduced (from 300 ms to 100 ms) basic cycle lengths and ventricular fibrillation was induced by burst pacing and recorded before the global ischemia, and after the reperfusion. The action potential durations (APD), maximum slopes of APD restitution curves (Smax), and mean dominant frequency (DF) of ventricular fibrillation were measured for both LV and RV surfaces. No APD heterogeneity was observed in control hearts. Global ischemia induced inter-ventricular heterogeneity in APDs (RV: 109±21 ms, LV: 89±23 ms; p<0.01) that was abolished upon reperfusion. However, Smax was uniformly decreased in both RV (control: 0.94±0.25, ischemia: 0.36±0.12; p<0.01) and LV (control: 0.99±0.24, ischemia: 0.43±0.21; p<0.01) and did not recover upon reperfusion. In addition, the DF of ventricular fibrillation during reperfusion decreased significantly in RV (from 8.6±1.3 Hz to 6.2±1.1 Hz; p<0.05) but remained the same in LV (9.0±0.8 Hz vs 8.5±1.0 Hz). Thus, our results demonstrate that global ischemia induces inter-ventricular heterogeneity in APD during periodic pacing. Although this effect was abolished upon reperfusion, Smax did not recover, indicating the presence of residual changes in electrical properties of the heart. Therefore, reperfusion reveals the presence of inter-ventricular heterogeneities in the dynamics of ventricular fibrillation.
doi:10.1109/IEMBS.2009.5333176
PMCID: PMC2909844  PMID: 19964152
5.  Transmural Dispersion of Repolarization in Failing and Non Failing Human Ventricle 
Circulation research  2010;106(5):981-991.
Rationale
Transmural dispersion of repolarization has been shown to play a role in the genesis of ventricular tachycardia and fibrillation in different animal models of heart failure (HF). Heterogeneous changes of repolarization within the midmyocardial population of ventricular cells have been considered an important contributor to the HF phenotype. However, there is limited electrophysiological data from the human heart.
Objective
To study electrophysiological remodeling of transmural repolarization in the failing and non-failing human hearts.
Methods and Results
We optically mapped the action potential duration (APD) in the coronary-perfused scar-free posterior-lateral left ventricular free wall wedge preparations from failing (n=5) and non-failing (n=5) human hearts. During slow pacing (S1S1= 2,000ms), in the non-failing hearts we observed significant transmural APD gradient: subepicardial, midmyocardial, and subendocardial APD80 were 383±21ms, 455±20ms, and 494±22ms, respectively. In 60% of non-failing hearts (3 of 5), we found midmyocardial islands of cells that presented a distinctly long APD (537±40ms) and a steep local APD gradient (27±7ms/mm) compared with the neighboring myocardium. HF resulted in prolongation of APD80: 477±22ms, 495±29ms, and 506±35ms for the subepi-, mid- and subendocardium, respectively, while reducing transmural APD80 difference from 111±13ms to 29±6ms (p<0.005) and presence of any prominent local APD gradient. In HF, immunostaining revealed a significant reduction of Cx43 expression on the subepicardium.
Conclusions
We present for the first time direct experimental evidence of a transmural APD gradient in the human heart. HF results in the heterogeneous prolongation of APD, which significantly reduces the transmural and local APD gradients.
doi:10.1161/CIRCRESAHA.109.204891
PMCID: PMC2842469  PMID: 20093630
Heart failure; repolarization; transmural gradient; optical mapping; connexin43
6.  Simvastatin and Losartan Differentially and Synergistically Inhibit Atherosclerosis in Apolipoprotein E-/- Mice 
Korean Circulation Journal  2012;42(8):543-550.
Background and Objectives
Since statins and angiotensin receptor blockers are a frequently prescribed combination in patients with atherosclerotic cardiovascular diseases, we tested the interactive effects of simvastatin and losartan on atherosclerosis in apolipoprotein E (apoE)-/- mice.
Materials and Methods
Apolipoprotein E-/- mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks, with and without simvastatin (40 mg/kg) and/or losartan (20 mg/kg). The mice were divided into 5 groups and were fed as follows: regular chow (control diet, n=5), HFHC diet (n=6), HFHC diet with losartan (n=6), HFHC diet with simvastatin (n=6), and HFHC diet with both losartan and simvastatin (n=6).
Results
Losartan treatment in apoE-/- mice significantly decreased atherosclerotic lesion areas in whole aortic strips stained with Oil Red O. The plaque area measured at the aortic sinus level was reduced significantly by 17% (HFHC; 346830.9±52915.8 µm2 vs. HFHC plus losartan; 255965.3±74057.7 µm2, p<0.05) in the losartan-treated group. Simvastatin and simvastatin plus losartan treatments reduced macrophage infiltration into lesions by 33% (HFHC; 183575.6±43211.2 µm2 vs. HFHC plus simvastatin; 120556.0±39282.8 µm2, p<0.05) and 44% (HFHC; 183575.6±43211.2 µm2 vs. HFHC plus simvastatin and losartan; 103229.0±8473.3 µm2, p<0.001, respectively). In mice fed the HFHC diet alone, the smooth muscle cell layer in the aortic media was almost undetectable. In mice co-treated with losartan and simvastatin, the smooth muscle layer was more than 60% preserved (p<0.05). Given alone, losartan showed a slightly stronger effect than simvastatin; however, treatment with losartan plus simvastatin induced a greater inhibitory effect on atherosclerosis than either drug given alone. Serum lipid profiles did not differ significantly among the groups.
Conclusion
Losartan displayed anti-atherosclerotic effects in apoE-/- mice that were equivalent to or greater than the effects of simvastatin. Combined treatment with these drugs had greater effect than either drug alone.
doi:10.4070/kcj.2012.42.8.543
PMCID: PMC3438264  PMID: 22977450
Atherosclerosis; Losartan; Simvastatin; Mice, knockout; Models, animal
7.  Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation 
Circulation  2011;123(25):2922-2930.
Background
The substrates for human atrial fibrillation (AF) are poorly understood but involve abnormal repolarization (action potential duration, APD). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF.
Methods and Results
In 33 subjects (12 persistent AF, 13 paroxysmal AF, 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths (CL) 600–500 ms (100–120 beats/min) to AF. APD alternans required progressively faster rates for patients with persistent AF, paroxysmal AF and controls (CL 411±94 vs 372±72 vs 218±33 ms; p<0.01). In AF patients, APD alternans occurred at rates as slow as 100–120 beats/min, unrelated to APD restitution (p=NS). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF and controls (CL: 316±99 vs 266±19 vs 177±16 ms; p=0.02). In paroxysmal AF, APD oscillations amplified prior to AF (p<0.001). In controls, APD alternans arose only at very fast rates (CL < 250 ms; p<0.001 vs AF groups) just prior to AF. In n=4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished.
Conclusions
Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes, and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.
doi:10.1161/CIRCULATIONAHA.110.977827
PMCID: PMC3135656  PMID: 21646498
Atrium; Fibrillation; Action Potentials; Electrophysiology; Remodeling; Alternans; Electrical Restitution
8.  Chronic myocardial infarction promotes atrial action potential alternans, afterdepolarizations, and fibrillation 
Cardiovascular Research  2013;99(1):215-224.
Aims
Atrial fibrillation (AF) is increased in patients with heart failure resulting from myocardial infarction (MI). We aimed to determine the effects of chronic ventricular MI in rabbits on the susceptibility to AF, and underlying atrial electrophysiological and Ca2+-handling mechanisms.
Methods and results
In Langendorff-perfused rabbit hearts, under β-adrenergic stimulation with isoproterenol (ISO; 1 µM), 8 weeks MI decreased AF threshold, indicating increased AF susceptibility. This was associated with increased atrial action potential duration (APD)-alternans at 90% repolarization, by 147%, and no significant change in the mean APD or atrial global conduction velocity (CV; n = 6–13 non-MI hearts, 5–12 MI). In atrial isolated myocytes, also under β-stimulation, L-type Ca2+ current (ICaL) density and intracellular Ca2+-transient amplitude were decreased by MI, by 35 and 41%, respectively, and the frequency of spontaneous depolarizations (SDs) was substantially increased. MI increased atrial myocyte size and capacity, and markedly decreased transverse-tubule density. In non-MI hearts perfused with ISO, the ICaL-blocker nifedipine, at a concentration (0.02 µM) causing an equivalent ICaL reduction (35%) to that from the MI, did not affect AF susceptibility, and decreased APD.
Conclusion
Chronic MI in rabbits remodels atrial structure, electrophysiology, and intracellular Ca2+ handling. Increased susceptibility to AF by MI, under β-adrenergic stimulation, may result from associated production of atrial APD alternans and SDs, since steady-state APD and global CV were unchanged under these conditions, and may be unrelated to the associated reduction in whole-cell ICaL. Future studies may clarify potential contributions of local conduction changes, and cellular and subcellular mechanisms of alternans, to the increased AF susceptibility.
doi:10.1093/cvr/cvt087
PMCID: PMC3687753  PMID: 23568957
Atrial fibrillation; Myocardial infarction; Action potential alternans; Afterdepolarization; β-Adrenergic stimulation; T-tubule; Calcium
9.  Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy 
Circulation  2003;108(7):839-843.
Background
Chronic heart failure is associated with inflammation and neurohormonal imbalance. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that short-term statin therapy may have beneficial effects in patients with nonischemic heart failure.
Methods and Results
Sixty-three patients with symptomatic, nonischemic, dilated cardiomyopathy were randomly divided into 2 groups. One group received simvastatin (n=24), and the other group received placebo (n=27). The initial dose of simvastatin was 5 mg/d, which was increased to 10 mg/d after 4 weeks. After 14 weeks, patients receiving simvastatin exhibited a modest reduction in serum cholesterol level compared with patients receiving placebo (130±13 versus 148±18, P<0.05). Patients treated with simvastatin had a lower New York Heart Association functional class compared with patients receiving placebo (2.04±0.06 versus 2.32±0.05, P<0.01). This corresponded to improved left ventricular ejection fraction in the simvastatin group (34±3 to 41±4%, P<0.05) but not in the placebo group. Furthermore, plasma concentrations of tumor necrosis factor-α, interleukin-6, and brain natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group.
Conclusions
Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy. These findings suggest that statins may have therapeutic benefits in patients with heart failure irrespective of serum cholesterol levels or atherosclerotic heart disease.
doi:10.1161/01.CIR.0000084539.58092.DE
PMCID: PMC2665260  PMID: 12885745
heart failure; statins; cholesterol; endothelium; inflammation
10.  Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet 
Background
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.
Results
The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.
Conclusions
We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.
doi:10.1186/1476-511X-10-8
PMCID: PMC3031258  PMID: 21241519
11.  Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts 
INTRODUCTION
This study compared the effects of ATP-regulated potassium channel (KATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles.
METHODS
We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the KATP targets Kir6.1, Kir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts.
RESULTS
In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by −21±3% and −27±13%, p<0.01) and ventricles (by −28±7% and −28±4%, p<0.01). Diazoxide did not change APD (0±5%) in NF atria. Pinacidil significantly decreased APDs in both atria (−46 to - 80%, p<0.01) and ventricles (−65 to −93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4±6.1 Hz and 17.5 ±5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP targets were correlated to functional observations.
CONCLUSION
Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.
doi:10.1016/j.yjmcc.2011.04.016
PMCID: PMC3124600  PMID: 21586291
human heart; IKATP; ischemic heart disease; heart failure; arrhythmias; optical mapping
12.  Role of the Alternans of Action Potential Duration and Aconitine-Induced Arrhythmias in Isolated Rabbit Hearts 
Journal of Korean Medical Science  2011;26(12):1576-1581.
Under conditions of Na+ channel hyperactivation with aconitine, the changes in action potential duration (APD) and the restitution characteristics have not been well defined in the context of aconitine-induced arrhythmogenesis. Optical mapping of voltage using RH237 was performed with eight extracted rabbit hearts that were perfused using the Langendorff system. The characteristics of APD restitution were assessed using the steady-state pacing protocol at baseline and 0.1 µM aconitine concentration. In addition, pseudo-ECG was analyzed at baseline, and with 0.1 and 1.0 µM of aconitine infusion respectively. Triggered activity was not shown in dose of 0.1 µM aconitine but overtly presented in 1.0 µM of aconitine. The slopes of the dynamic APD restitution curves were significantly steeper with 0.1 µM of aconitine than at baseline. With aconitine administration, the cycle length of initiation of APD alternans was significantly longer than at baseline (287.5 ± 9.6 vs 247.5 ± 15.0 msec, P = 0.016). The functional reentry following regional conduction block appears with the progression of APD alternans. Ventricular fibrillation is induced reproducibly at pacing cycle length showing a 2:1 conduction block. Low-dose aconitine produces arrhythmogenesis at an increasing restitution slope with APD alternans as well as regional conduction block that proceeds to functional reentry.
doi:10.3346/jkms.2011.26.12.1576
PMCID: PMC3230017  PMID: 22147994
Aconitine; Optical mapping; APD restitution; APD alternans
13.  Effect of statin treatments on highly pathogenic avian influenza H5N1, seasonal and H1N1pdm09 virus infections in BALB/c mice 
Future virology  2012;7(8):801-818.
Statins are used to control elevated cholesterol or hypercholesterolemia, but have previously been reported to have antiviral properties.
Aims
To show efficacy of statins in various influenza virus mouse models.
Materials & methods
BALB/c mice were treated intraperitoneally or orally with several types of statins (simvastatin, lovastatin, mevastatin, pitavastatin, atorvastatin or rosuvastatin) at various concentrations before or after infection with either influenza A/Duck/ MN/1525/81 H5N1 virus, influenza A/Vietnam/1203/2004 H5N1 virus, influenza A/ Victoria/3/75 H3N2 virus, influenza A/NWS/33 H1N1 virus or influenza A/CA/04/09 H1N1pdm09 virus.
Results
The statins administered intraperitoneally or orally at any dose did not significantly enhance the total survivors relative to untreated controls. In addition, infected mice receiving any concentration of statin were not protected against weight loss due to the infection. None of the statins significantly increased the mean day of death relative to mice in the placebo treatment group. Furthermore, the statins had relatively few ameliorative effects on lung pathology or lung weights at day 3 and 6 after virus exposure, although mice treated with simvastatin did have improved lung function as measured by arterial saturated oxygen levels in one experiment.
Conclusion
Statins showed relatively little efficacy in any mouse model used by any parameter tested.
doi:10.2217/fvl.12.71
PMCID: PMC3571729  PMID: 23420457
anti-inflammatory; atorvastatin; BALB/c mouse; influenza virus; lovastatin; mevastatin; pitavastatin; rosuvastatin; simvastatin; statin
14.  Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial 
BMC Research Notes  2012;5:251.
Background
Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia.
Methods
This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks.
Results
At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments.
Conclusion
Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing.
Trial registration
Registered at ClinicalTrials.gov: NCT00652327
doi:10.1186/1756-0500-5-251
PMCID: PMC3403927  PMID: 22621316
Ezetimibe; Simvastatin; Atorvastatin; Pravastatin
15.  Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles 
Circulation research  2011;108(8):971-979.
Rationale
Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF).
Objective
We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles.
Methods and Results
A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002).
Conclusions
Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.
doi:10.1161/CIRCRESAHA.110.238386
PMCID: PMC3086382  PMID: 21350217
arrhythmia; intracellular calcium; ion channels; ventricular fibrillation
16.  Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices 
BMJ : British Medical Journal  2003;326(7391):689.
Objective
To compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations.
Design
Cross sectional study.
Setting
17 practices within 17 primary care groups in Trent region, United Kingdom.
Participants
Patients aged 35 years or over taking lipid lowering drugs and with at least two serum cholesterol concentrations recorded on computer.
Main outcome measures
Proportion of patients achieving serum cholesterol concentration of ⩽5 mmol/l and mean percentage reduction in serum cholesterol concentration.
Results
1353 of 2469 (54.8%) patients receiving lipid lowering treatment had a last recorded serum cholesterol concentration of ⩽5 mmol/l. Significantly more patients taking statins achieved the target value for serum cholesterol (5 mmol/l) than those taking fibrates (1307 (57%) v 46 (26%); P<0.0001). Atorvastatin and simvastatin were the most effective drugs in achieving the target. Significant differences were found between lipid lowering drugs for the pretreatment serum cholesterol concentration, the most recent cholesterol concentration, and the associated percentage reduction. Atorvastatin and simvastatin achieved the greatest percentage reduction in serum cholesterol concentrations (30.1%, 95% confidence interval 28.8% to 31.4%, and 28.0%, 26.7% to 29.3%, respectively). Although the mean serum cholesterol concentrations in this unselected population tended to be higher than those in clinical trials, the percentage reduction was consistent with the trials.
Conclusion
The ability of individual statins to lower serum cholesterol concentration varied, with atorvastatin and simvastatin being the most effective. The percentage reductions agreed with those of randomised controlled trials indicating likely benefits in unselected patients in primary care. As the initial serum cholesterol concentrations were higher than those in randomised controlled trials, target serum cholesterol values of ⩽5 mmol/l may be unrealistic even for patients taking the most efficacious drugs. Also, the higher initial levels could mean that the absolute reduction in cardiovascular risk in primary care patients is greater than thought.
What is already known on this topicStatins in patients with coronary heart disease help reduce further cardiovascular events and improve survivalThis seems to be a class effect of statins, although there may be important differences in effectiveness between themLess than half of patients in the community who take lipid lowering drugs achieve target serum cholesterol valuesWhat this study addsStatins vary in their ability to lower serum cholesterol concentration, with atorvastatin and simvastatin achieving the best resultsThe percentage reductions agreed with those found in randomised controlled trialsSince the initial serum cholesterol concentrations were higher than in trials, absolute risk reductions in primary care patients may be greater than thoughtTarget values of ⩽5 mmol/l may be unrealistic even for patients on the most efficacious drugs, because the initial mean cholesterol values of primary care patients are higher than those of patients in trials
PMCID: PMC152367  PMID: 12663406
17.  Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling? 
Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings.
doi:10.1016/j.trsl.2010.09.003
PMCID: PMC2990975  PMID: 21078495
Statin; HMG-CoA reductase; mevalonate; asthma; goblet cell hyperplasia; arginase; hydroxyproline; TGFβ1; nitric oxide; remodeling
18.  Statin and Resveratrol in Combination induces Cardioprotection against Myocardial Infarction in Hypercholesterolemic Rat 
Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide dependent mechanism. Therefore the present study was undertaken to determine whether combination therapy with statin and resveratrol are more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed rats with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1mg/kg bw/day) and resveratrol (20mg/kg bw/day) for 2 weeks. The rats were assigned to: 1) Control (C) 2) HC 3) HCR 4) HCS and 5) HCRS. The hearts, subjected to 30 min global ischemia followed by 120 min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt) was found to be significantly better in the HCRS (1926±43), HCR (1556±65) and HCS (1635±40) compared to HC group (1127±16). The infarct size in the HCRS, HCS and HCR groups were 37±3.6, 43±3.3 and 44±4.2 respectively compared to 53±4.6 in HC. The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In-vivo rat myocardial infarction (MI) model subjected to one week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased β-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, anti-hyperlipidemic and anti-apoptotic effects and long term effects may be caused by increased neovascularization of the MI zone leading to less ventricular remodeling.
doi:10.1016/j.yjmcc.2006.10.018
PMCID: PMC1857339  PMID: 17188708
statin; resveratrol; cholesterol; myocardium; Akt; eNOS; VEGF; β-catenin
19.  Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism 
Background
Microvascular injury plays a key role in normal tissue radiation responses. Statins, in addition to their lipid-lowering effects, have vasculoprotective properties that may counteract some effects of radiation on normal tissues. We examined whether administration of simvastatin ameliorates intestinal radiation injury, and whether the effect depends on protein C activation.
Methods
Rats received localized, fractionated small bowel irradiation. The animals were fed either regular chow or chow containing simvastatin from 2 weeks before irradiation until termination of the experiment. Groups of rats were euthanized at 2 weeks and 26 weeks for assessment of early and delayed radiation injury by quantitative histology, morphometry, and quantitative immunohistochemistry. Dependency on protein C activation was examined in TM mutant mice with deficient ability to activate protein C.
Results
Simvastatin administration was associated with lower radiation injury scores (p<0.0001), improved mucosal preservation (p=0.0009), and reduced thickening of the intestinal wall and subserosa (p=0.008 and p=0.004), neutrophil infiltration (p=0.04), and accumulation of collagen I (p=0.0003). The effect of simvastatin was consistently more pronounced for delayed than for early injury. Surprisingly, simvastatin reduced intestinal radiation injury in TM mutant mice, indicating that the enteroprotective effect of simvastatin after localized irradiation is unrelated to protein C activation.
Conclusions
Simvastatin ameliorates the intestinal radiation response. The radioprotective effect of simvastatin after localized small bowel irradiation does not appear to be related to protein C activation. Statins should undergo clinical testing as a strategy to minimize side effects of radiation on the intestine and other normal tissues.
doi:10.1016/j.ijrobp.2007.03.036
PMCID: PMC2000701  PMID: 17674978
Endothelium; Intestine; Radiation injuries; Hydroxymethylglutaryl-CoA reductase inhibitors
20.  IMPACT OF CHRONIC ANTI-CHOLESTEROL THERAPY ON DEVELOPMENT OF MICROVASCULAR RAREFACTION IN THE METABOLIC SYNDROME 
Object
The obese Zucker rat (OZR) model of the metabolic syndrome is partly characterized by moderate hypercholesterolemia in addition to other contributing co-morbidities. Previous results suggest that vascular dysfunction in OZR is associated with chronic reduction in vascular nitric oxide (NO) bioavailability and chronic inflammation, both frequently associated with hypercholesterolemia. As such, we evaluated the impact of chronic cholesterol reducing therapy on the development of impaired skeletal muscle arteriolar reactivity and microvessel density in OZR and its impact on chronic inflammation and NO bioavailability.
Materials and Methods
Beginning at 7 weeks of age, male OZR were treated with gemfibrozil, probucol, atorvastatin or simvastatin (in chow) for 10 weeks. Subsequently, plasma and vascular samples were collected for biochemical/molecular analyses, while arteriolar reactivity and microvessel network structure were assessed using established methodologies after 3, 6 and 10 weeks of drug therapy
Results
All interventions were equally effective at reducing total cholesterol, although only the statins also blunted the progressive reductions to vascular NO bioavailability, evidenced by greater maintenance of acetylcholine-induced dilator responses, an attenuation of adrenergic constrictor reactivity, and an improvement in agonist-induced NO production. Comparably, while minimal improvements to arteriolar wall mechanics were identified with any of the interventions, chronic statin treatment reduced the rate of microvessel rarefaction in OZR. Associated with these improvements was a striking statin-induced reduction in inflammation in OZR, such that numerous markers of inflammation were correlated with improved microvascular reactivity and density. However, using multivariate discriminant analyses, plasma RANTES, IL-10, MCP-1 and TNF-α were determined to be the strongest contributors to differences between groups, although their relative importance varied with time.
Conclusions
While the positive impact of chronic statin treatment on vascular outcomes in the metabolic syndrome are independent of changes to total cholesterol, and are more strongly associated with improvements to vascular NO bioavailability and attenuated inflammation, these results provide both a spatial and temporal framework for targeted investigation into mechanistic determinants of vasculopathy in the metabolic syndrome.
doi:10.3109/10739680903133722
PMCID: PMC3335395  PMID: 19905967
regulation of skeletal muscle perfusion; vascular remodeling; vascular reactivity; rodent models of obesity; nitric oxide bioavailability; chronic inflammation
21.  Effect of Simvastatin on Burn Induced Alterations in Tissue Specific Glucose Metabolism: Implications for Burn Associated Insulin Resistance 
In addition to their primary role in lowering plasma cholesterol, statins have a variety of other actions. In this report we studied the effect of simvastatin treatment on burn injury induced changes in regional glucose metabolism. Groups of six CD-1 mice (male, ~25 g) were subjected to full thickness 30% total body surface area (TBSA) burn injury. Seven days later the animals were treated with simvastatin at various doses (0.02, 0.2 and 2.0 μg/kg, i.p.). On the following morning, the mice were injected with 18FDG (50 μCi) via tail vein. Approximately 60 minutes after tracer injection, the animals were sacrificed and biodistribution was measured. A sub-set burned and sham-control animals was injected with a larger dose of 18FDG (~1.0 mCi) and tracer distribution was evaluated by μPET. In heart and brown adipose tissue (BAT), burn injury produced a highly significant increase in 18FDG accumulation (p<0.01), whereas tracer accumulation in brain was markedly reduced (p<0.01). In heart and BAT, simvastatin treatment produced dose dependent reductions in 18FDG accumulation. In contrast, simvastatin did not affect 18FDG accumulation in brain. There was no effect of simvastatin treatment on 18FDG accumulation in heart, BAT or brain of sham treated mice. Less pronounced effects were detected in other tissues that were studied. All animals had normal plasma glucose levels (~90 mg/dl). Our results indicate that simvastatin reverses burn induced increases in 18FDG accumulation by heart and BAT in a dose dependant manner but does not affect burn induced reductions of 18FDG accumulation by brain. These findings suggest that statins may exert some of their effects by tissue specific modulation of glucose metabolism.
PMCID: PMC4090513  PMID: 20664945
Burn; Glucose; 18FDG; Insulin resistance; Brown Adipose Tissue; Simvastatin; Sepsis
22.  Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo 
European journal of pharmacology  2010;650(1):309-316.
Transgenic rabbits expressing loss-of-function pore mutants of the human gene KCNQ1 (KvLQT1-Y315S) have a Long QT-Syndrome 1 (LQT1) phenotype. We evaluated for the first time the effect of nicorandil, an opener of ATP-sensitive potassium channels, and of isoproterenol on cardiac action potential duration and heart rate dependent dispersion of repolarisation in transgenic LQT1 rabbits.
In vivo LQT1 and littermate control were subjected to transvenous electrophysiological studies; in vitro monophasic action potentials were recorded from explanted Langendorff-perfused hearts.
In vivo ventricular effective refractory periods (VERP) at the right ventricular base were significantly prolonged in LQT1 as compared to littermate control, resulting in a more pronounced VERP dispersion in LQT1. This difference in VERP dispersion between LQT1 and littermate control disappeared after infusion of nicorandil. In vitro, mean action potential durations (APD75 and APD90) of LQT1 were significantly prolonged compared to littermate control at baseline. Nicorandil decreased APD75 and APD90 in LQT1 and littermate control at all stimulated heart rates. After adding nicorandil, the APD90 at all hearts rates and the APD75 at high heart rates were no longer different. Dispersion of repolarisation (ΔAPD75 and ΔAPD90) was heart rate dependently decreased after nicorandil at all tested stimulation cycle lengths only in LQT1.
We demonstrated phenotypic differences of LQT1 and littermate control in vivo and in vitro. Nicorandil 20 μmol/l improved repolarisation abnormalities and heterogeneities in transgenic LQT1 rabbits.
doi:10.1016/j.ejphar.2010.10.016
PMCID: PMC2997896  PMID: 20959120
Long QT-Syndrome; polymorphic ventricular tachycardia; transgenic rabbit model; electrophysiological studies; nicorandil; dispersion of repolarisation
23.  Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia 
BMC Microbiology  2012;12:73.
Background
Recent studies suggest that the reported protective effects of statins (HMG-CoA reductase inhibitors) against community-acquired pneumonia (CAP) and sepsis in humans may be due to confounders and a healthy user-effect. To directly test whether statins are protective against Streptococcus pneumoniae, the leading cause of CAP, we examined the impact of prolonged oral simvastatin therapy at physiologically relevant doses in a mouse model of pneumococcal pneumonia. BALB/c mice were placed on rodent chow containing 0 mg/kg (control), 12 mg/kg (low simvastatin diet [LSD]; corresponds to 1.0 mg/kg/day), or 120 mg/kg (high simvastatin diet [HSD]; corresponds to 10 mg/kg/day) simvastatin for four weeks, infected intratracheally with S. pneumoniae serotype 4 strain TIGR4, and sacrificed at 24, 36, or 42 h post-infection for assessment of lung histology, cytokine production, vascular leakage and edema, bacterial burden and bloodstream dissemination. Some mice received ampicillin at 12-h intervals beginning at 48 h post-infection and were monitored for survival. Immunoblots of homogenized lung samples was used to assess ICAM-1 production.
Results
Mice receiving HSD had reduced lung consolidation characterized by less macrophage and neutrophil infiltration and a significant reduction in the chemokines MCP-1 (P = 0.03) and KC (P = 0.02) and ICAM-1 in the lungs compared to control mice. HSD mice also had significantly lower bacterial titers in the blood at 36 (P = 0.007) and 42 (P = 0.03) hours post-infection versus controls. LSD had a more modest effect against S. pneumoniae but also resulted in reduced bacterial titers in the lungs and blood of mice after 42 h and a reduced number of infiltrated neutrophils. Neither LSD nor HSD mice had reduced mortality in a pneumonia model where mice received ampicillin 48 h after challenge.
Conclusions
Prolonged oral simvastatin therapy had a strong dose-dependent effect on protection against S. pneumoniae as evidenced by reduced neutrophil infiltration, maintenance of vascular integrity, and lowered chemokine production in the lungs of mice on HSD. Statin therapy also protected through reduced bacterial burden in the lungs. Despite these protective correlates, mortality in the simvastatin-receiving cohorts was equivalent to controls. Thus, oral simvastatin at physiologically relevant doses only modestly protects against pneumococcal pneumonia.
doi:10.1186/1471-2180-12-73
PMCID: PMC3438118  PMID: 22587610
24.  Caveolin Contributes to the Modulation of Basal and β-Adrenoceptor Stimulated Function of the Adult Rat Ventricular Myocyte by Simvastatin: A Novel Pleiotropic Effect 
PLoS ONE  2014;9(9):e106905.
The number of people taking statins is increasing across the globe, highlighting the importance of fully understanding statins' effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (‘pleiotropic effects’). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 µM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2+]i) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16 and troponin I at Ser23/24 was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered β-adrenoceptor signalling. In addition, as caveolin is ubiquitously expressed and has myriad tissue-specific functions, the impact of statin-dependent changes in caveolin is likely to have many other functional sequelae.
doi:10.1371/journal.pone.0106905
PMCID: PMC4161364  PMID: 25211146
25.  Effects of 4-week administration of simvastatin in different doses on heart rate and blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats 
Introduction
Statins and β1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on β-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats.
Material and methods
The experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally.
Results
Simvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min−1 vs. 374.41±13.32 min−1; p<0.05). In rats receiving simvastatin during the 4-week period after metoprolol injection, heart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone.
Conclusions
Simvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.
doi:10.5114/aoms.2012.27275
PMCID: PMC3309431  PMID: 22457669
rats; simvastatin; metoprolol; heart rate; blood pressure

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