To Stent or Not? A Critical Decision
Reporter: Aviva Lev-Ari, PhD, RN
VIEW VIDEO – Short Overview [1:45 minutes]
VIEW VIDEO – Clinical Results [44-54 minutes]
Clinical Summary
Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease
(The FAME II Study)
A Multicenter, Randomized Prospective Study in Consecutive Patients.
This study is sponsored by St. Jude Medical.
Coordinating Clinical Investigator: Bernard De Bruyne, OLV Ziekenhuis, Aalst, Belgium
Fractional Flow Reserve–Guided PCI versus Medical Therapy in Stable Coronary Disease
Bernard De Bruyne, M.D., Ph.D., Nico H.J. Pijls, M.D., Ph.D., Bindu Kalesan, M.P.H., Emanuele Barbato, M.D., Ph.D., Pim A.L. Tonino, M.D., Ph.D., Zsolt Piroth, M.D., Nikola Jagic, M.D., Sven Möbius-Winkler, M.D., Gilles Rioufol, M.D., Ph.D., Nils Witt, M.D., Ph.D., Petr Kala, M.D., Philip MacCarthy, M.D., Thomas Engström, M.D., Keith G. Oldroyd, M.D., Kreton Mavromatis, M.D., Ganesh Manoharan, M.D., Peter Verlee, M.D., Ole Frobert, M.D., Nick Curzen, B.M., Ph.D., Jane B. Johnson, R.N., B.S.N., Peter Jüni, M.D., and William F. Fearon, M.D. for the FAME 2 Trial Investigators
N Engl J Med 2012; 367:991-1001 September 13, 2012DOI: 10.1056/NEJMoa1205361
BACKGROUND
The preferred initial treatment for patients with stable coronary artery disease is the best available medical therapy. We hypothesized that in patients with functionally significant stenoses, as determined by measurement of fractional flow reserve (FFR), percutaneous coronary intervention (PCI) plus the best available medical therapy would be superior to the best available medical therapy alone.
METHODS
In patients with stable coronary artery disease for whom PCI was being considered, we assessed all stenoses by measuring FFR. Patients in whom at least one stenosis was functionally significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy (PCI group) or the best available medical therapy alone (medical-therapy group). Patients in whom all stenoses had an FFR of more than 0.80 were entered into a registry and received the best available medical therapy. The primary end point was a composite of death, myocardial infarction, or urgent revascularization.
RESULTS
Recruitment was halted prematurely after enrollment of 1220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical-therapy group (1.6% vs. 11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P<0.001); in particular, in the PCI group, fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography (hazard ratio, 0.13; 95% CI, 0.04 to 0.43; P<0.001). Among patients in the registry, 3.0% had a primary end-point event.
CONCLUSIONS
In patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization. In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01132495.)
Supported by St. Jude Medical.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on August 28, 2012, and updated on October 18, 2012, at NEJM.org.
SOURCE INFORMATION
From the Cardiovascular Center Aalst, Onze-Lieve-Vrouw Clinic, Aalst, Belgium (B.D.B., E.B.); Department of Cardiology, Catharina Hospital, and Department of Biomedical Engineering, Eindhoven University of Technology — both in Eindhoven, the Netherlands (N.H.J.P., P.A.L.T.); Division of Clinical Epidemiology and Biostatistics, Institute of Social and Preventive Medicine and Clinical Trials Unit Bern, University of Bern, Bern, Switzerland (B.K., P.J.); Hungarian Institute of Cardiology, Budapest (Z.P.); Clinical Center Kragujevac, Kragujevac, Serbia (N.J.); Heart Center Leipzig, Leipzig, Germany (S.M.-W.); Cardiovascular Hospital, Lyon, France (G.R.); Södersjukhuset, Stockholm (N.W.), and Karolinska Institutet at Örebro University Hospital, Örebro (O.F.) — both in Sweden; Department of Internal Medicine and Cardiology, University Hospital Brno, Brno, Czech Republic (P.K.); King’s College Hospital, London (P.M.), Golden Jubilee National Hospital, Glasgow (K.G.O.), Royal Victoria Hospital, Belfast (G.M.), and Department of Cardiology, Southampton University Hospital Trust, Southampton (N.C.) — all in the United Kingdom; Department of Cardiology, Rigshospitalet University Hospital, Copenhagen (T.E.); Atlanta Veterans Affairs Medical Center, Atlanta (K.M.); Northeast Cardiology Associates, Bangor, ME (P.V.); St. Jude Medical, Plymouth, MN (J.B.J.); and Stanford University Medical Center, Stanford, CA (W.F.F.).
Address reprint requests to Dr. De Bruyne at the Cardiovascular Centre Aalst, OLV-Clinic, Moorselbaan 164, B-9300 Aalst, Belgium, or atbernard.de.bruyne@olvz-aalst.be.
The investigators in the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial are listed in the Supplementary Appendix, available at NEJM.org.
Conclusions
The FAME II study results show that FFR-guided PCI compared to medical management alone significantly reduces patients’ risk for unplanned hospital readmission with urgent revascularization.
The new data support the paradigm of “Functionally Complete Revascularization,” that is, stenting of ischemic lesions and medical treatment of non-ischemic ones.
Routine Use of Ffr Significantly Improves the Outcome of Treatment in Stable CAD Patients. St. Jude Medical is focused on reducing risk by continuously finding ways to put more control into the hands of those who save and enhance lives.
SUMMARY OF KEY FINDINGS
FFR significantly improves outcome of treatment in stable patients. The results of FAME II, a St. Jude Medical sponsored clinical trial, show a significant benefit in using FFR-guided intervention. In patients with stable coronary artery disease undergoing PressureWireTM-guided intervention, PCI plus medical therapy was found to improve outcomes compared to medical therapy alone.
FFR Significantly Reduces Risk of Unplanned Hospital Readmission for Urgent Revascularization
Background
In patients with clinically stable coronary disease, PCI has not been shown to affect clinical outcomes such as death, nonfatal myocardial infarction and the need for urgent revascularization. In previous trials on revascularization, treatment has been guided by the angiographic appearance of the lesions. It is likely that in all previous trials dealing with patients with nonacute coronary artery disease (CAD), a sizable proportion of patients did not have ischemia.
Objectives
The overall purpose of the FAME II study was to compare the clinical outcomes of FFR-guided contemporary PCI plus medical therapy versus medical therapy alone in patients with stable coronary disease.
Methods
The FAME II trial is a prospective, multicenter randomized clinical trial with an all comers design. All consecutive patients with stable clinical condition and angiographically defined one-, two- or three-vessel coronary artery disease and amenable for PCI were screened and considered for participation in the study. Patients with at least one hemodynamically significant lesion were randomized into PCI (drug-eluting stents [DES] were recommended) plus medical therapy or medical therapy alone. It was expected that in approximately 20% of patients no stenoses would be hemodynamically significant.
Patients without hemodynamically significant lesions were enrolled in the registry portion of the study and treated with medical therapy. For prospectively collected data in the randomized study and the registry, an independent clinical events committee (CEC) adjudicated all clinical endpoints.
Key Exclusion Criteria
Prior coronary artery bypass grafting (CABG)
Left ventricular ejection fraction (LVEF) <30%
Left main (LM) stenosis
For patients with one or more significant lesions, there was an 86% relative reduction in the risk for unplanned hospital readmission with urgent revascularization for patients who received FFR-guided PCI plus medical therapy.
These findings support FFR-guided PCI compared to medical management alone to improve outcomes in the treatment of stable patients with single-vessel or multivessel coronary artery disease.
Study Endpoints
Original FAME II Study Flow Chart Primary Endpoint Composite of:
all-cause death
nonfatal myocardial infarction
unplanned hospitalization with urgent revascularization
As adjudicated by an independent CEC.
Secondary Endpoints
Individual components of the primary endpoint*
Cardiac death*
Nonurgent revascularization procedures*
Angina class
*As adjudicated by an independent CEC.
Stable patients scheduled for 1, 2 or 3 vessel DES stenting
RANDOMIZED TRIAL REGISTRY
FFR in all target lesions
Randomization 1:1
PCI + medical therapy medical therapy
Follow-up after 1, 6 months, 1, 2, 3, 4 and 5 years
At least 1 stenosis with FFR ≤ 0.80 When all FFR > 0.80
Medical Therapy
Aspirin
Beta blocker
Calcium blocker and/or nitrate as necessary
Statin
ACE inhibitor (or ARB)
Diabetes treatment guided by a specialist
FFR-guided PCI
FFR measured during hyperemia
PCI only if FFR ≤ 0.80 and randomized to PCI
2nd generation drug-eluting stents (recommended)
Fractional Flow Reserve Measurements Intracoronary pressure measurements were obtained with a guiding catheter (fluid-filled) and the St. Jude Medical PressureWire CertusTM or AerisTM guidewire.
Results
The independent Data and Safety Monitoring Board recommended halting patient recruitment due to a significantly increased patient risk of major adverse cardiac events among patients randomized to medical therapy alone compared to patients randomized to medical therapy plus PCI.
The enrollment goal in FAME II was approximately 1,800 patients (randomized study and registry combined). The data sample presented here is the same data on which the decision to halt enrollment was based (January 15, 2012).
A total of 888 (73%) patients with ischemic lesions had been successfully randomized, and an additional 332 (27%) patients were enrolled in the registry because no ischemic lesions were detected. In total, 1,220 patients were enrolled in the FAME II trial, including 1,054 who were assigned to follow-up.
Medical Therapy
Actual FAME II Study Flow Chart
* Note that 6 patients had total occlusions supplying akinetic myocardium and were therefore not considered for PCI; 1 patient had 2 FFR negative lesions and was therefore included in the registry, however, a subsequently detected total occlusion was eventually treated with DES.
Randomized (n = 888)
Underwent FFR (n = 1220)
FFR >0.80 in all lesions included in registry
(n = 332)*
Allocated to medical therapy alone (n = 441)
Received allocated intervention (n = 439)
Did not receive allocated intervention (n = 2)
Erroneously received DES (n = 2)
Randomly selected to receive follow-up (n = 166)
Received medical therapy alone (n = 165)
Received DES (n = 1)
Allocated to PCI+medical therapy (n = 447)
Received allocated intervention (n = 435)
Did not receive allocated intervention (n = 12)
Treated with balloon angioplasty (n = 3)
Underwent CABG rather than PCI (n = 4)
Received medical therapy, planned for staged
procedure (n = 3)
Received medical therapy, unsuccessful PCI (n = 1)
Received medical therapy, FFR >0.8 (n = 1)
Follow-up information for primary endpoint
available until Jan 15, 2012 (n = 446)
Followed up and alive (n = 445)
Deceased (n = 1)
Follow-up at Jan 15, 2012 unavailable (n = 1)
Withdrew (n = 1)
Lost to follow-up (n = 0)
Follow-up information for primary endpoint
available until Jan 15, 2012 (n = 439)
Followed up and alive (n = 436)
Deceased (n = 3)
Follow-up at Jan 15, 2012 unavailable (n = 2)
Withdrew (n = 2)
Lost to follow-up (n = 0)
Follow-up information for primary endpoint
available until Jan 15, 2012 (n = 163)
Followed up and alive (n = 163)
Deceased (n = 0)
Follow-up at Jan 15, 2012 unavailable (n = 3)
Withdrew (n = 1)
Lost to follow-up (n = 2)
Analyzed on primary clinical endpoint (n = 166)
Censored at time of lost to follow-up
or withdrawal (n = 3)
Analyzed on primary clinical endpoint (n = 441)
Censored at time of lost to follow-up
or withdrawal (n = 2)
Analyzed on primary clinical endpoint (n = 447)
Censored at time of lost to follow-up
or withdrawal (n = 1)
Patients n = 447 n = 441 n = 166
Age in years, mean±SD 63.52 ± 9.35 63.86 ± 9.62 63.58 ± 9.75 0.90
Men, n (%) 356 (79.6) 338 (76.6) 113 (68.1) 0.005
BMI, mean±SD 28.29 ± 4.27 28.44 ± 4.55 27.83 ± 3.94 0.14
Family history of coronary artery disease, n (%) 216 (48.3) 207 (46.9) 76 (45.8) 0.65
Current smoking, n (%) 89 (19.9) 90 (20.4) 35 (21.1) 0.79
Hypertension, n (%) 347 (77.6) 343 (77.8) 136 (81.9) 0.23
Hypercholesterolemia, n (%) 330 (73.9) 348 (78.9) 118 (71.1) 0.15
Diabetes mellitus, n (%) 123 (27.5) 117 (26.5) 42 (25.3) 0.65
Insulin requiring diabetes, n (%) 39 (8.7) 39 (8.8) 10 (6.0) 0.24
Renal insufficiency (Creatinine > 2.0 mg/dL), n (%) 8 (1.8) 12 (2.7) 7 (4.2) 0.14
Peripheral vascular disease, n (%) 43 (9.6) 47 (10.7) 8 (4.8) 0.065
History of stroke/TIA, n (%) 33 (7.4) 28 (6.3) 10 (6.0) 0.69
History of MI, n (%) 164 (37.2) 165 (37.8) 60 (36.6) 0.83
History of PCI in target vessel, n (%) 80 (17.9) 76 (17.2) 34 (20.5) 0.37
Angina Class, n (%) 0.64
Asymptomatic 53 (11.9) 46 (10.5) 17 (10.2) .
CCS class I 82 (18.3) 98 (22.3) 42 (25.3) .
CCS class II 204 (45.6) 197 (44.8) 74 (44.6) .
CCS class III 80 (17.9) 65 (14.8) 23 (13.9) .
CCS IV, stabilized 28 (6.3) 34 (7.7) 10 (6.0) .
Silent Ischemia, n (%) 73 (16.3) 73 (16.6) 27 (16.3) 0.96
Left ventricular ejection fraction<50%, n (%) 83 (19.6) 56 (13.7) 27 (18.0) 0.69
Classification of patients according to angiography
No. of significant lesions per patient, mean±SD 1.87 ± 1.05 1.73 ± 0.94 1.32 ± 0.59 <0.001
No. of vessels per patient with at least one significant lesion, n (%) <0.001
1 251 (56.2) 261 (59.2) 136 (81.9) .
2 156 (34.9) 146 (33.1) 26 (15.7) .
3 40 (8.9) 34 (7.7) 4 (2.4) .
Proximal or mid LAD stenosis (%) 65.1 62.6 44.6 <0.001
Classification of patients according to FFR
No. of significant lesions per patient according to FFR, mean±SD 1.52 ± 0.78 1.42 ± 0.73 0.03 ± 0.17 <0.001
No. of vessels with significant lesions by FFR, n (%) 1.00
1 331 (74.0) 343 (77.8) 3.0
2 102 (22.8) 85 (19.3) 0 (0)
3 14 (3.1) 13 (2.9) 0 (0)
Proximal or mid LAD stenosis (%) 62.4 59.6 0.6 <0.001
Lesions n = 890 n = 815 n = 241
Classification of lesions according to angiography .
No. of significant lesions (diameter stenosis>50%), n (%) 837 (94.0) 764 (93.7) 219 (90.9) 0.13
Percent diameter stenosis, n (%) <0.001
<50% 53 (6.0) 51 (6.3) 22 (9.1)
50-69% 317 (35.6) 331 (40.6) 176 (73.0)
70-90% 383 (43.0) 331 (40.6) 38 (15.8)
>90% 101 (11.3) 80 (9.8) 0 (0)
Total occlusions 36 (4.0) 22 (2.7) 5 (2.1)
Classification of lesions according to FFR
No. of significant lesions (FFR≤0.80), n (%) 679 (76.3) 625 (76.7) 5* (2.1) <0.001
FFR in significant lesions, mean±SD 0.68 ± 0.10 0.68 ± 0.15 0.50 ± 0.00 0.013
Randomized Trial Registry p-value for
Trial vs. Registry
PCI+medical therapy medical therapy alone
**Differences between the two randomized groups were not significant with the exception of left ventricular ejection fraction<50% (p<0.05). Data are mean±SD or number of patients assessed (%). P-value using chi square test;
when cells are small Fisher’s test is used. Data for ejection fraction were available for 423 in PCI&medical therapy, 410 in medical therapy and 150 in registry. Data for history of MI were available for 442 in PCI&medical therapy,
436 in medical therapy and 295 in registry. CCS=Canadian Cardiovascular Society functional classification of angina pectoris; Data available in 447 in PCI&medical therapy, 440 in medical therapy, and 166 in registry. **5 totally
occluded arteries supplied infarcted areas and therefore not considered for revascularization using PCI. In patient level analysis p-value calculated using chi-square test, in case of cells <15 Fisher’s test. In lesion level analysis,
mixed maximum-likelihood logistic regression models were used for comparisons between groups for dichotomous variables and mixed maximum-likelihood linear regression models for continuous variables to account for the
correlation of multiple lesions within patients.
Conclusions
The FAME II study results show that FFR-guided PCI compared to medical management alone significantly reduces patients’ risk for unplanned hospital readmission with urgent revascularization.
The new data support the paradigm of “Functionally Complete Revascularization,” that is, stenting of ischemic lesions and medical treatment of non-ischemic ones.
Routine Use of Ffr Significantly Improves the Outcome of Treatment in Stable CAD Patients. St. Jude Medical is focused on reducing risk by continuously finding ways to put more control into the hands of those who save and enhance lives.
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ATRIAL FIBRILLATION CARDIAC RHYTHM MANAGEMENT CARDIOVASCULAR NEUROMODULATION
The content of this clinical summary is based on:
De Bruyne, B., et al. Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Versus Medical Treatment in Stable Coronary Disease,
N Engl J Med 2012; published online ahead of print August 28, 2012.
http://www.Clinicaltrials.gov. FAME II Study Identifier: NCT01132495.
FAME II study protocol (on file, St. Jude Medical).
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+1 651 756 4470
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+46 18 161099 Fax
SOURCE:
http://www.sjmprofessional.com/fame2?utm_source=fameii&utm_medium=vanity&utm_campaign=fame2
This looks like a problem with tables. I’m not sure if a reference is sufficient.
WATCH THE TWO VIDEOS. The reference looks the same.
GO TO
Fractional Flow Reserve–Guided PCI versus Medical Therapy in Stable Coronary Disease
Bernard De Bruyne, M.D., Ph.D., Nico H.J. Pijls, M.D., Ph.D., Bindu Kalesan, M.P.H., Emanuele Barbato, M.D., Ph.D., Pim A.L. Tonino, M.D., Ph.D., Zsolt Piroth, M.D., Nikola Jagic, M.D., Sven Möbius-Winkler, M.D., Gilles Rioufol, M.D., Ph.D., Nils Witt, M.D., Ph.D., Petr Kala, M.D., Philip MacCarthy, M.D., Thomas Engström, M.D., Keith G. Oldroyd, M.D., Kreton Mavromatis, M.D., Ganesh Manoharan, M.D., Peter Verlee, M.D., Ole Frobert, M.D., Nick Curzen, B.M., Ph.D., Jane B. Johnson, R.N., B.S.N., Peter Jüni, M.D., and William F. Fearon, M.D. for the FAME 2 Trial Investigators
N Engl J Med 2012; 367:991-1001September 13, 2012DOI: 10.1056/NEJMoa1205361
[…] http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/ […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette