Intravascular Stimulation of Autonomics: A Letter from Dr. Michael Scherlag
Letter received by Aviva Lev-Ari, PhD, RN on September 1, 2012
Michael Scherlag
To the Editor:
After doing a Google search, I came across your well written article which lacked any references to my research. It would be easy to do a Google search for intravascular stimulation of autonomics to find our work.
The topic of renal denervation is fascinating and holds tremendous promise for the treatment of a plethora of diseases (besides hypertension) which are most likely due to an imbalance of autonomic tone. Rather than referring to the technique by the misnomer of renal artery denervation, I prefer the name “cardiac sympathetic denervation”. As I will outline, the ablation of autonomics in the renal artery has more of an effect on the heart than it does on the kidneys.
The possibility that parasympathetic or sympathetic nerves running on blood vessels could be stimulated or ablated from inside the vasculature was initially demonstrated using basket electrode catheters in a series of experimental studies (1-6) and formally patented in 1999 (7).
Our experiments noted changes in heart rate which have also been reported in SYMPLICITY HTN-1 and SYMPLICITY HTN-2 (8-9). The SYMPLICITY HTN-2 study demonstrated profound bradycardia in 13% of patients that was treated with atropine.
The intra-procedure effect on heart rate during renal artery denervation documented in the SYMPLICITY trials is also manifest long term by measuring heart rate variability (10).
Indeed, cardiac effects would be expected with autonomic modulation. Besides the two example above showing that cardiac sympathetic denervation effects heart rate, there are many more that are just beginning to be reported in the literature.
This article discusses the effect of renal sympathetic denervation on atrial fibrillation.http://www.ncbi.nlm.nih.gov/pubmed/22585944
These articles shows the effects of renal denervation on heart rate. http://www.ncbi.nlm.nih.gov/pubmed/1735574
http://www.ncbi.nlm.nih.gov/pubmed/8777835
A Cleveland Clinic review article states: “Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.”
http://www.ccjm.org/content/79/7/501.full
“Brandt reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.” (Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012; 59:901–909)
“Ukena reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.” (Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-in man experience. Clin Res Cardiol 2012; 101:63–67)
The most recent data from Europe shows the following effects on heart failure: http://www.eurekalert.org/pub_releases/2012-08/esoc-rdg082712.php
http://www.theheart.org/article/1364267.do
Nearly ten examples of the effects of “CARDIAC SYMPATHETIC DENERVATION” and what are the effects on the kidney? No change in GFR. No change in creatinine. My question to you is why does Dr. Esler refuse to cite our work? Clearly, we were the first to stimulate/ablate autonomic nerves effecting the heart from the intravascular space. If you doubt that, please see the patent. Maybe, it is his conflict of interest with funding and consulting fees coming from Ardian/Medtronic. I have sent emails and requests to Dr. Esler and other Symplicity investigators to cite our work, yet they refuse.
I do not use the term plagiarism lightly. It is my hope that you will ask Dr. Esler and his cohort of Symplicity investigators why they refuse to cite our work.
I would also, respectively, ask that you cite our work.
Sincerely,
Michael Scherlag, MD
Interventional Cardiologist
Oklahoma Heart Hospital
References:
1. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Transvenous parasympathetic cardiac nerve stimulation: an approach for stable sinus rate control. J Electrophysiol. 1999 Nov;10(11):1517-24.
2. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Ventricular rate control during atrial fibrillation by cardiac parasympathetic nerve stimulation: a transvenous approach. J Am Coll Cardiol. 1999 Dec;34(7):2043-50.
3. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000 Nov 28;102(22):2774-80.
4. Scherlag MA, Scherlag BJ, Yamanashi W, Schauerte P, Goli S, Jackman WM, Reynolds D, Lazzara R. Endovascular neural stimulation via a novel basket electrode catheter: comparison of electrode configurations. J Interv Card Electrophysiol. 2000 Apr;4(1):219-24.
5. Scherlag BJ, Yamanashi WS, Schauerte P, Scherlag M, Sun YX, Hou Y, Jackman WM, Lazzara R. Endovascular stimulation within the left pulmonary artery to induce slowing of heart rate and paroxysmal atrial fibrillation. Cardiovasc Res. 2002 May; 54(2):470-5.
6. Hasdemir C, Scherlag BJ, Yamanashi WS, Lazzara R, Jackman WM. Endovascular stimulation of autonomic neural elements in the superior vena cava using a flexible loop catheter. Jpn Heart J. 2003 May;44(3):417-27.
7. Webster W Jr, Scherlag BJ, Scherlag MA, Schauerte P. Method and apparatus for transvascular treatment of tachycardia and fibrillation. US Patent 6,292,695. Filed June 17, 1999.
8. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.
9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.
10. Frank Himmel MD, Joachim Weil MD, Michael Reppel MD, Kai Mortensen MD, Klaas Franzen, Leidinger Ansgar MD, Heribert Schunkert MD, Frank Bode MD. Improved Heart Rate Dynamics in Patients Undergoing Percutaneous Renal Denervation. Letter to the Editor. JCH. 31 MAY 2012.1751-7176.
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[…] http://pharmaceuticalintelligence.com/2012/09/02/intravascular-stimulation-of-autonomics-a-letter-fr… […]
I think that this is a very important letter format of post. I can understand an oversight undetected by the peer review process, and then missed by the Editor. It is very hard for this to happen because the reviewer today has full access to related publications. If the wording is looked at carefully, then questions about plagiarism do arise. This is more likely to happen in a review than in an original article.
Dr. Larry,
Please go to my posed called
Renal Denervation and see his comment and my comment,
I decided to post his comment as a Post which will be accessible to the search engine, comments are not
I believe, Dr. Scherlag is attributing plagiarism to Dr. Esler.
I believe that he wishes us to get involve in asking Esler to correct the record.
“It is my hope that you will ask Dr. Esler and his cohort of Symplicity investigators why they refuse to cite our work.”
I believe that he requests me to cite his work which was not included in my post which focused only on Medical Devices and HTN.
I believe that if the entire world label a procedure Renal Arterial Denervation (RAD) and he labels it Intravascular Stimulation of Autonomics (ISA) THEN in a literature survey based on key word search engine results, search done for RAS no entries on ISA will come out.
Go to Google and search for Intravascular Stimulation of Autonomics (ISA) you will not get to his work. If you search for Michael Scherlag, you will get to his work.
I searched for Renal Arterial Denervation RAD — than none of his work came up. The focus of my post was on Medical devices for refractory hypertension !!
I sent you and e-mail, I created another post on additional benefits of ISA beside HTN which I fully covered in my post.
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.