Preventing Heart Attacks with Ouabain
Reversing Heart Disease Part Five
by Jeffrey Dach MD
Our previous articles in this series, Parts one, two, three and four have made the case for the “clogged artery” filled with atherosclerotic plaque as the cause for heart attacks. Indeed, imaging studies and autopsy studies show extensive arterial plaque formation in the unfortunate victims of heart attacks. Above left image Strophanthus Flower source for Ouabain, Cardiac Drug. Courtesy of wikimedia commons.
The Plumbing Approach to Heart Disease
Recognizing the “clogged artery” as the cause of heart attacks, we have built an entire medical industry devoted to unclogging them with the “plumbing approach”. Heroic doctors serve as glorified plumbers, advancing catheters, angioplasty balloons and stents into the patient to open up these clogged arteries. If the catheters, balloons, and stents fail, the open-heart bypass operation is next. For those patients who escape the attention of the invasive cardiologist with their heroic plumbing procedures, there is “medical treatment” with cardiac drugs such as Statins, Beta Blockers, Calcium Channel blockers, Nitrates, Aspirin, blood thinners etc . Left image: Cardiac Bypass Operation, opening up clogged arteries with a bypass.
What Causes Heart Attacks ?
According to mainstream cardiology, heart attacks are caused by obstruction of the coronary artery shutting off oxygen supply to a segment of the heart muscle which then undergoes “infarction”, a word meaning cell death from lack of oxygen. No doubt this does happen in most but not all cases. Above Left Image : Plumber Opening Clogged Pipe similar to our current medical procedures. Courtesy of Wikimedia Commons.
Heart Attack with Normal Coronary Arteries –
Clogged Arteries with No Heart Attack
We know that in some cases, heart attacks occur with completely normal coronary arteries as demonstrated by angiography or autopsy examination.(25-31).
Not only that, autopsy studies on young trauma victims show left main or multivessel disease in 20%, yet heart attacks are rare in this age-group.
Autopsy studies of hospitalized patients who die of non-cardiac causes show 41% have critical stenosis or occlusion of at least one major vessel. Why didn’t they die of a heart attack first ? Clearly there must be other factors at work. Clogged arteries are quite common and some people seem to do Ok with it. We will pick up this idea later. Left Image: Coronary arteries courtesy of wikimedia commons.
Coronary Artery Theory
In the Coronary Artery Theory of Heart Attacks, the arterial plaque continues to enlarge causing narrowing of the arterial lumen (stenosis). This stenosis is like closing a water faucet reducing blood flow down to a trickle. Finally, the “ruptured plaque” is the final event triggering thrombosis and total obstruction of the coronary artery. Downstream from the blocked artery, the heart segment undergoes cell death from lack of oxygen. This is called a myocardial infarction, or heart attack.
The Zipper Club
This Coronary Artery Theory is the working hypothesis of the mainstream cardiologist who would never question it, and happily goes about his job as a glorified pumber, searching out all the clogged arteries with imaging in the cath lab. His job is to inject radiographic dye into the coronary arteries looking for the stenosis. If a severely narrowed artery is discovered, the invasive cardiologist will promptly perform a plumbing procedure, the angioplasty or stent to open the narrowed artery. If this is proves to be unsuccessful, the patient may be sent next door to the surgical department. They may wake up in the recovery room after a “Cabbage” , a (CABG) Coronary Artery Bypass Graft. This is also called the “Big Zipper” and Zipper Club tee shirts are available (left image courtesy of Mended Little Hearts of Winchester.)
A massive medical industry has been built on the Coronary Artery Theory of heart disease. Your local hospital might very well be in an expansion phase, building larger facilities to do all this.
Left Image: Construction Cranes over Hospital expansion courtesy of wikimedia commons.
How to Reduce Plaque : Track Your Plaque
Atheroscleorosis is a bad thing. How do we prevent it ? How do we halt progression of all these atherosclerotic plaques in our arteries? Should we use drugs, diet or lifestyle modifications ? This is where the “Track Your Plaque Program ” comes in, devoted to halting progression of plaque formation with diet and lifestyle changes.
Rather than re-invent the wheel, we have adopted the William Davis MD program called “Track Your Plaque“. With this program we can estimate heart attack risk by measuring plaque size and growth with serial calcium scores. The program also uses the advanced lipoprotein profile as another way to monitor response to diet and lifestyle modification. This is all discussed in part one.
A Differing Viewpoint – The Plumbers Are Wrong
Dr. Thomas Cowan in the May 2014 Townsend Letter begs to differ and proposes an alternate theory called the Myogenic Theory. A .pdf of the May 2014 article can be read by clicking here: Thomas_Cowan_What_Causes_Heart_Attacks.
Although arterial plaque is a bad thing, Dr Cowan says the Plumbing approach to clogged arteries is all wrong, and for the most part a futile exercise.
Left image: Diagram showing Coronary Stenting Procedure Courtesy of NIH and Wikimedia Commons.
In agreement with Dr. Cowan is Howard H. Wayne, M.D. who lists 39 studies published in the mainstream cardiology literature proving the futility of the Plumbing approach. Dr. Wayne says (quote)
“almost every single study….clearly and unequivocally demonstrates that invasive treatment, be it bypass surgery or angioplasty, fail to reduce heart attacks and mortality when compared to patients who have been conservatively treated with medication. In addition, there is a clear increase in mortality….in the invasively treated patients. (End Quote Dr Wayne)
Of course, the favorite study quoted is the large 2003 Mayo Clinic study which concludes that bypass relieves chest pain but does not prevent further heart attacks, and that those who benefit from bypass surgery are the high risk patients whose lives are in acute danger.
Problems with the Plumbing Approach
The “plumbing approach” to coronary artery disease with stents and bypass operations has been a disappointment with no reduction in mortality compared to medical treatment for the patient with chronic stable angina. However, there is a plumbing benefit, as mentioned above, for the high risk patient. We will now look into this to find out why.
With the exception of the bypass or stent for the “high risk patient” such as the left main coronary artery lesion, also known as the “Widow Maker“, cardiac “plumbing” procedures have been a disappointment. In the stable angina patient, benefits of plumbing procedures are about the same as medical treatment. Why is that?
Formation of Collateral Circulation
A 1976 study from the dog lab is illustrative. When the dog’s coronary artery is suddenly occluded, the dog suffers a heart attack and could die. However, if the dog’s coronary artery is gradually occluded over four days, the dog’s heart develops extensive collateral vessels which prevent myocardial infarction. The collateral vessels have done their job. This dog has a completed occluded coronary artery with no heart attack nor cardiac damage.
Quote from study: “When the time to complete occlusion was 4 days, myocardial infarction was prevented due to growth-transformation of pre-existing collaterals.” Quote from Dr. Schaper Circ 1976.
The formation of well developed collaterals has “survival benefit” protects us from heart attacks, serving as our own personal bypass operation courtesy of mother nature. This explains the value of medical treatment with Beta-Blockers and other cardiac drugs which buy time for our heart to develop collateral circulation.
Formation of collateral vesels is one of the expected outcomes of a procedure called EECP EKG-Gated Extracorporal Counter Pulsation. My previous article on EECP discussed this.
Autonomic Nervous System- Parasympathetic vs Sympathetic
Dr. Cowan tells us something we already know. The heart is very sensitive to our emotional state. Our language is filled with idioms and phases relating to the heart, such as “She broke my heart”.. People have been known to succumb from heart attack on the basis of a sudden severe emotional shock, fear, grief etc. This is called the Broken Heart Syndrome as described by Dr. Wittstein in the Cleveland Clinic Journal of Medicine(2007).
Our physiology colleagues have studied the nervous innervation to the heart. Luckily for us, the heart beat is automatic, controlled by the autonomic nervous system consisting of the sympathetic branch which speeds up the heart rate, and the parasympathetic branch (from the Vagus Nerve) which slows down the heart rate.
Studies of the autonomic nervous system using heart rate variability monitors show that patients with reduced parasympathetic activity have higher risk for heart attack, and that heart attack victims have reduced parasympathetic activity.
Dr. Sroka, an expert on the autonomic nervous system, reports that heart attack victims will show a peculiar sudden drop-off of parasympathetic activity just prior to their heart attack. In addition, this reduction in parasympathetic activity can be prevented by Ouabain, an endogenous cardiac steroid which restores parasympathetic activity by enhancing release of its principal neurotransmitter ACH (Acetlycholine) .
Read the .pdf of Dr Sroka’s article on Myocardial Ischemia in which he proposes that ischemic events can be triggered by the autonomic nervous system. This could certainly explain the reported cases of heart attacks with completely normal coronary arteries: Sroka_Myocardial_Ischemia_ANS
Beta Blockers, Calcium Chanel Blockers, Nitrates, Aspirin and other blood thinners are typically used for medical treatment of the stable angina patient. Above left chemcial structure of Ouabain, Notice steroidal ring component. courtesy of Wikimedia commons.
Enter the Cardiac Glycoside- Ouabain
Dr, Thomas Cowen again differs from mainstream cardiology in his drug of choice for medical treatment of the stable angina patient. Dr. Cowan reports great success with an old botanical drug called Ouabain, also called Strophanthus (Strodival), obtained from an African plant, and still in use by cardiologists in Germany obtainable from local German pharmacies. Dr Cowan reports that in his office practice this medication has been successful in preventing heart attacks.
The Endogenous Cardiac Glycosides
In 1991 researchers discovered that Ouabain from the Strophanthus plant is identical to our own endogenous cardiac glycosides made by the adrenal gland. Digoxin (Digitalis from the Foxglove plant) is another one of the endogenous cardiac glycosides. Above image shows chemical structure of endogenous cardiac steroids courtesy of Schoner 2007.
Benefits in Cardiac Ischemia, Angina, and Infarction
Both animal (Vatner) and human studies (Sharma) show striking benefits to the myocardium during ischemic events by using an ouabain preparation called Strodival/Strophanthum.(5-18). Indeed, Ouabain has been dubbed “the insulin of the heart”: Click Here to read pdf article: Ouabain_the_insulin_of_the_heart.
More on Ouabain/Strophanthun clinical experience from Dr Debusman, a German cardiologist.
More on Ouabain by Dr. Sroka.
Conclusion: The story is familiar. A natural plant botanical substance, Ouabain, sharing its identity with an endogenous hormone produced by the adrenal gland, exhibits striking health benefits for angina, ischemia, and myocardial infarction prevention. Yet this natural drug is largely ignored by mainstream cardiology because it cannot be patented, and therefore lacking in large controlled studies.
.Articles with Related Interest:
Preventing Heart Disease Parts one, two, three and four
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
Links and References:
Endogenous Cardiac Glycosidess
What Causes Heart Attacks by Dr. Thomas Cowan
The conventional view of the cause of heart disease is that the central events occur in the coronary arteries. Dr. Cowan rebuts this theory, laying out the case that heart disease is actually better understood from the perspective of events happening in the myocardium, and describing the precise and well-documented events that do lead to heart attacks.
Also see: http://www.westonaprice.org/modern-diseases/what-causes-heart-attacks/
What Causes Heart Attacks Posted on June 8, 2010 by Thomas Cowan, M.D. In my practice, I generally use oral strophanthin in the form of the preparation known as Strodival for all my angina and MI patients, and I have uniformly recorded a decrease in angina episodes, improved exercise tolerance and, thus far, no MIs. When combined with a nourishing traditional diet, cod liver oil, high vitamin butter oil, CoQ10 (which helps strengthen the heart muscle) and Standard Process heart nutrients (Cardioplus, two capsules three times per day, and Cataplex E2, two tablets three times per day),
Cardiac Infarction g-Strophanthin ( Ouabain ) – the Endogenous Hormone. Dr. rer.nat.Rainer Moser Diploma chemist
Rolf-Jurgen Petry January 25, 2009
Strophanthin / ouabain is free available in German pharmacies as a homeopathic medicine (“Strophactiv” from the company “magnetactiv”). D4 = 1:10.000, there is enough substance in it to generate a substantial effect, additionally to the homeopathic effect.
Allopathic / substantial ouabain (“Strodival”) is available only with a prescription from a physician. You can get it at the pharmacy of the Airport of Munich, likely also at other German airports or international pharmacies.
Strodival mr = enteric-coated capsules with 3 mg each for prophylaxis. Strodival = capsules to bite (adsorption with the tongue and mouth) with 3 mg each for acute situations.
Strodival spezial with 6 mg is not available any more.
The pharmacy “Schloss-Apotheke” in Koblenz / Germany makes a ouabain solution, and also ouabain pharmaceutical phials for intravenous injection, likely they sell it abroad with a prescription. Tel. 0049-261-18439
More information about ouabain on http://ouabain.twoday.net
Best wishes, Rolf-Jurgen Petry (author of a book about ouabain with 1665 references and a preface from Prof. Hans Schaefer (Heidelberg), who was a world-famous physiolgist for decades (available only in German language yet, is there an edition who wants to translate it into English ?)
September 12, 2009
International Reseller of Strodival:
Masters Pharmaceuticals Ltd
Unit 380, Centennial Avenue
Centennial Park, Elstree
Hertfordshire WD6 3TJ
Tel: 0208 327 0900
Fax: 0208 327 0901
US TOLL FREE Tel: 1-800-969-1152 FAX: 1-800-969-1153
Dr Debusmann What is Strophanthin?
Dr. Wieland Debusmann who had a heart attack himself at the young age of 42, is the expert on ouabain. On his detailed website – www.strophantus.de – all aspects of ouabain are dealt with in English. Rolf-Jürgen Petry has written a very good book “Strophanthin” (89). His website – www.strophanthin.org – is also instructive and available in English.
Strophanthin was, by chance, discovered in Africa in 1859. In England processed, in France analysed and in Germany first used with great health-effective-qualities, by Prof. Albert Fraenkel (v. interesting piece in wikipedia) intravenously. Fraenkels boss was Prof. Ludolf von Krehl. Both founded important clinics in Heidelberg and Badenweiler and well-known medical prizes are named after them.
When in 1924 Prof. Ernst Edens (3), Ordinarius of Medicin University Clinic Düsseldorf presented to his intern colleagues his outstanding experiences with Strophanthin as a cure for Angina pectoris and Heart attacks he earned, curiously, not just euphoria but also scepticism and rejection.
Prof Ernst Edens (3) said, “not using Strophanthin is a medical mistake”. Until about 1975 Strophanthin was used intravenously with success in nearly all hospitals and university clinics in Germany and is until today, known for its good effect by all older doctors. Also, older experienced nurses have confirmed to me the great reputation of Strophanthin. Also the oral preparate (orally and not intravenously) developed since 1947, displays convincing results. Even though today it is nearly the best and side-effect free heart remedy, the opinion of the medical academics is:
a. it doesn’t work
b. it is highly poisonous
c. there are better remedies today
In response to a:
98 % of all doctors that have used or continued to use it, have observed an extremely high effectiveness, the other 2 % remain within limits, positive. None of the doctors asked were negative about its effectiveness. (Questionnaire from 3650 doctors, 1984) (4).
A placebo controlled, double blind study observed a highly significant effectiveness of orally taken Strophanthin. All Angina pectoris patients experienced an improved EKG and well-feeling, the most a marked improvement in condition (5).
Prof. Dormann used Strophanthin capsules for 12 years in a large Berlin hospital: 99 % of patients with Angina pectoris took a stomach acid resistant capsule and were complaint free after 2 weeks (82 % after 1 week), all previous remedies were omitted (6).
Ouabain the wasted opportunity
strophanthin Knut Sroka, MD
Fighting Heart Disease through Information, Research and Education. Carlos E. T. B. Monteiro is an independent researcher and scientist from Brazil having an experience of about 43 years in dealing with medical matters.
In 1972 he turned to be a disciple and follower in the scientific plan from Dr. Quintiliano H. de Mesquita, who has developed the myogenic theory of myocardial infarction and other pioneer contributions to medical literature (QHM Memorial). Carlos Monteiro has accompanied Dr. Mesquita as a special collaborator until his death in 2000.
In 1999 he participated in the foundation of Infarct Combat Project and elected president by the board of directors with the support from Dr. Mesquita who was one of the members.
Carlos Monteiro still defending Dr. Mesquita’s medical and scientific ideas, through Infarct Combat Project. Recently he has developed a new hypothesis to explain atherosclerosis that was named acidity theory of atherosclerosis. The blog new evidences about his Acidity Theory you can find here http://www.infarctcombat.org/MyogenicTheory.html
Roberts, William C. “Coronary arteries in fatal acute myocardial infarction.” Circulation 45.1 (1972): 215-230.
Am J Cardiol. 1998 Oct 1;82(7):839-44.Intracoronary aspiration thrombectomy for acute myocardial infarction. Murakami T1, Mizuno S, Takahashi Y, Ohsato K, Moriuchi I, Arai Y, Mifune J, Shimizu M, Ohnaka M.Department of Cardiology, Fukui Cardiovascular Center, Shimbo, Japan.
Am J Cardiol. 1998 Oct 1;82(7):896-7.
Coronary thrombosis during acute myocardial infarction: Roberts was right! O’Neill WW.Pathologic studies have varied with clinical belief regarding the role of acute thrombotic occlusion as the inciting event during myocardial infarction. Aspiration thrombectomy, by employing a new catheter, has been performed during myocardial infarction and confirms the pathologic findings that intracoronary thrombus is absent in a substantial number of patients with acute myocardial infarction.
Thomas Cowan Web Site on Heart Disease
Knut Sroka MD
Fig. 1: Defect in the “PNS” expressed by an almost “rigid pulse rate” PNS= Parasympathetic Nervous System
This simple illustration provides surprising information. The upper curve is that of a healthy person, the lower that of a person with coronary heart disease. The upper curve shows a typically normal wave-like pattern during 6 deep breaths. The lower curve shows an almost ”rigid pulse” (33). The above graph is a very good example of the defective PNS function in a heart patient.
Based on my own research and on a dozen international studies, the relationship between PNS reduction and heart seizure is presented in my comprehensive article “On the genesis of myocardial ischemia” (17). According to these studies, about ¾ of all heart seizures are triggered in this way.
Uninhibited SNS impulses on the heart, when the PNS brake is blocked, present a constellation, which results in heart seizure and heart attack (17).
A bloodless (“ischemic”) area then develops. Please note that such a bloodless area does not arise as a result of circulation problems due to blocked coronary arteries. This bloodless area is the result of an acute overexpansion of parts of the heart muscle, ultimately the result of a defect in PNS heart control.
Chronic stable angina: In 2003, a very good publication from the Mayo Clinic (1), USA, which I have already quoted on the subject of “bypass surgery” (Section 1) stated the following:
Balloon and stents are suitable for reducing complaints, i.e. for relieving symptoms.
Balloons and stents do not prevent heart attacks and do not prolong life.
Stents prevent the development of renewed stenoses at the same location in the vessel, but do not reduce the frequency of heart attacks or deaths.
Ouabain increases the heart’s performance, without increasing the oxygen consumption (77). And very important: when the heart metabolism is whipped up by adrenaline, then ouabain reduces the oxygen consumption of the heart (78). In such a situation, as is the case during a heart seizure, ouabain has an oxygen-saving effect.
German pharmacologist of the time, H. Gremels, had, as early as the 1930’s, clearly shown that ouabain drastically increases the effects of the PNS on the heart within a few minutes (up to a maximum of 1000 times greater). The effect of the SNS is reduced; and even the smallest doses of ouabain have the full effect (78).
Dr. Wieland Debusmann, who had a heart attack himself at the young age of 42, is an expert on ouabain. On his detailed website – www.strophantus.de –
((((((((((((((((((( ++++++++++++++ !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
17) ouabain_the_insulin_of_the_heart full pdf
PERSPECTIVE CUNICAL PRACTICE – Ouabain – the insulin of the heart. lnt J Clin Pract, November 2010, 64, 12, 1591-1594
This effect was the basis for the chance discovery of ouabain in 1859 by be English botanist Kirk. He bad discovered the fast onset of action of ouabain on the heart by using a
toothbrusb contaminated witb Strophanthus seeds.
The rapid onset of effect of oral ouabain was used in medical practice for a ‘Strophanthin-quick-test’: patients with suspected heart disease were given two tablets of 3 mg that they had to chew and distribute in the mouth. In the case of heart disease, a relief of complaints was observed within 5-10 min. This test was used routinely in German physicians’ offices well as into the 1970s.
by Medapharrna (Meda Pharrna GmbH & Co. KG, Bad Hornburg v.d.H., Gerrnany).
Strodival mr® (3 mg) from MEDA, Bad Homburg/Germany
The dosage is declared as 1 – 4 x 3 – 6 mg daily; principally success and demand should regulate the dosage. There is no real danger of overdosage as often seen with digitalis preparations.
American Journal of Cardiology
Volume 16, Issue 6 , Pages 859-880, December 1965
Acute coronary occlusion as a cause of myocardial infarct and sudden coronary heart death
Giorgio Baroldi, M.D.
The incidence of acute occlusion was investigated in 208 hospitalized patients dying from acute or recent coagulative necrosis of the myocardium, in 116 cases of sudden, unexpected “coronary” heart death, and in 125 cases of sudden but not unexpected “coronary” heart death. The approximate ages of both the vascular and myocardial lesions and the prior sclerotic reduction of the lumen of the acute or recently occluded vessels were studied and correlated with the corresponding enlargement of the collateral arterial circulation.
From the high incidence of acute or recent coagulation necrosis and/or sudden heart death without acute occlusion (53, 53, and 54% in the three groups studied), the low incidence of a “coeval” relation between the acute or recent occlusion and the stage of the myocardial damage (23, 22, and 19%, respectively), the high incidence of sclerotic reduction of the lumen in excess of 65 per cent in the acutely or recently occluded vessels (82, 91, and 96%, respectively), and the marked enlargement of the collateral circulation found in this study, it appears that in the so-called myocardial infarct or the sudden “coronary” heart death in the human being, most of the cases develop independently of an acute occlusion and that it is incorrect to apply the term “myocardial infarct” to the lesions. It is also our belief that the acute or recent thrombosis occurring in most of the instances should not be considered as the cause of the acute or recent myocardial coagulative necrosis or sudden death or both, but rather as the result of particular hemodynamic conditions existing in and around the involved vessel.
21) full pdf
Coronary Thrombosis and Fatal Myocardial Ischemia
WILLIAM C. ROBERTS Circulation. 1974;49:1-3
In conclusion, there is substantial evidence that acute thrombus formation does not precipitate acute fatal IHD. The major problem is diffuse
generalized coronary atherosclerosis with severe (>75%) luminal narrowing (at least 2 of the 3 major coronary arteries).
22) Silver, MALCOLM D., GIORGIo Baroldi, and F. A. B. I. O. Mariani. ” The relationship between acute occlusive coronary thrombi and myocardial infarction studied in 100 consecutive patients.”
Circulation 61.2 (1980): 219-227.
These data support the concept that an occlusive coronary thrombus has no
primary role in the pathogenesis of a myocardial infarct.
These data support the concept that an occlusive coronary thrombus has no
primary role in the pathogenesis of a myocardial infarct.
SUMMARY A prospective study was done on 100 hearts from patients who had clinically proved myocardial
infarction with histologic confirmation. The following variables were considered and related statistically: age, set and duration of patient survival; heart weight; type, form, length and degree of preexisting stenosis in the coronary system; the location and type of coronary occlusion; the location, type and size of an infarct and the other forms of irreversible myocardial damage found. Fifty-five percent of the hearts had no occlusive thrombus in the coronary artery supplying the infarcted myocardium. In 45 cases in which thrombi were found, all but one were in a supplying coronary artery. The occurrence of thrombi was associated with an increased size of infarct, most frequently with transmural infarcts (55%) and less often with those involving the inner two thirds of the wall (30%) or with subendocardial infarcts (27%). Most infarcts developed in patients with 70% stenosis in the coronary artery system, although the size of an infarct was independent of the number, degree, length and distribution of severe stenoses found in the system. A supplying artery usually showed a stenosis of > 70% along its course or, if it contained an acute occlusive thrombus, the thrombus was at a stenosis caused by an atheromatous plaque. These data support the concept that an occlusive coronary thrombus has no primary role in the pathogenesis of a myocardial infarct.
Endocrinology. 1994 Aug;135(2):794-7.
Ouabain is secreted by bovine adrenocortical cells.
Laredo J1, Hamilton BP, Hamlyn JM. 1Department of Physiology, University of Maryland, Baltimore 21201.
Ouabain is a specific inhibitor of the sodium pump. This steroid has been found in the mammalian circulation in significant amounts and may be of adrenal origin. Secretion of ouabain from adrenal cells has been little studied and the purpose of the present work was to determine the adrenal distribution of ouabain, aldosterone and cortisol, and to characterize the effects of ACTH and angiotensin II on the secretion of these steroids in primary cultures of bovine adrenocortical cells. In fresh bovine adrenals, the cortical to medullary ratios for aldosterone, cortisol and ouabain were 14, 4.25 and 2.5, respectively. All three steroids were detected in elevated amounts in the conditioned medium of primary cultures of adrenocortical cells. Reverse phase HPLC of the secreted ouabain immunoreactivity showed it was isopolar with commercial ouabain. In the presence of 10 nM ACTH or angiotensin II, the secretion of all three steroids increased significantly with similar time courses. The stimulated secretion of ouabain exceeded the intracellular content of this steroid in either control or activated cells by 3-5 fold. The amount of angiotensin II stimulated ouabain secretion was greater from cells incubated in larger volumes. These results show that ouabain is enriched in the bovine adrenal cortex, and is secreted by primary cultures of these cells. The secretion of ouabain is increased by ACTH and angiotensin II, is due to either de novo synthesis or transformation of an intracellular precursor that is not overtly immunoreactive, and is feedback regulated by either ouabain itself or a cosecreted factor. These cells may be useful to study stimulus-secretion coupling and the biosynthetic pathway of ouabain.
Endocrinology. 1996 Feb;137(2):533-9.
Ouabain production by cultured adrenal cells.
Doris PA1, Hayward-Lester A, Bourne D, Stocco DM.
The adrenal cortex releases a sodium pump inhibitor. The present studies tested whether this material was endogenous and identical to ouabain by 1) studying the production of ouabain in long term cultures of adrenocortical cells, 2) seeking evidence that ouabain might be taken up from exogenous sources by adrenocortical cells, 3) examining the release of adrenocortical cells loaded with exogenous ouabain, 4) attempting to stimulate ouabain steroidogenesis in cultured adrenocortical cells, and 5) performing further chemical analysis on ouabain immunoreactivity released by cultured adrenocortical cells. Our results indicate that ouabain immunoreactivity is present in conditioned medium from both murine Y-1 adrenocortical cultures and primary bovine adrenocortical cell (BAC) cultures. We also found that BACs bind and internalize [3H]ouabain. Bound [3H]ouabain is released from BACs by both receptor dissociation and cytoplasmic release of internalized [3H]ouabain. Only one isoform of membrane sodium, potassium-adenosine triphosphatase, alpha 1, was expressed in the adrenal. Authentic ouabain was not metabolized during membrane binding or while present intracellularly. Stimulation of steroidogenesis in Y-1 and BAC with 22R-hydroxycholesterol and 25-hydroxycholesterol was performed and confirmed increased steroidogenesis; however, there was no effect on ouabain immunoreactivity content or release. Comparison of the ouabain binding density in cultured BAC, hepatoma cells, and 3T3 fibroblasts indicated that adrenocortical cells have a high ouabain-binding capacity. HPLC studies of the ouabain immunoreactivity released by bovine adrenocortical cells indicated that essentially no authentic ouabain was secreted. The present studies confirm that both BAC and Y-1 cultures release a ouabain-like material that differs in structure from authentic plant ouabain and is not a product of cholesterol side-chain cleavage.
Gen Pharmacol. 1998 Oct;31(4):499-501.
Is ouabain produced by the adrenal gland?
Foster RH1, Prat H, Rothman I.
1. Ouabain or a related stereoisomer, termed endogenous ouabain, has been identified in adrenal cortex tissue and culture medium from adrenocortical cells. 2. Angiotensin II and adrenocorticotropin, the main activators of aldosterone secretion from adrenal glomerulosa cells appear to increase the production of this compound. 3. The purpose of this review is to briefly discuss recent available experimental evidence suggesting that endogenous ouabain is secreted by the zona glomerulosa of the adrenal gland.
Necropsy Studies in Myocardial Infarction with Minimal or No Coronary Luminal Reduction Due to Atherosclerosis R. S. ELIOT, M.D.; G. BAROLDI, M.D.; A. LEONE, M.D.+ Author Affiliations From the University of Nebraska, Division of Cardiology, Department of Medicine, the Institute of Morbid Anatomy, School of Medicine, University of Milan and CNR Institute Fisiologic Clinica, Medical School, University of Pisa, Italy.
A postmortem study was conducted on the hearts of 10 patients who died with a typical clinical picture of acute myocardial infarction within 25 days of onset of symptoms. The coronary arterial systems of the patients revealed minimal or no luminal reduction due to coronary atherosclerosis or other cause. These cases contribute to the understanding of the pathogenesis of acute myocardial infarction in that they document the presence of typical acute myocardial infarction in the absence of chronic or acute coronary arterial obstruction. They further suggest that the hearts of those dying of typical myocardial infarction show minimal or no coronary disease in approximately 7% when studied as described.
Circulation. 1977 Apr;55(4):578-80.
The nature and clinical features of myocardial infarction with normal coronary arteriogram.
Rosenblatt A, Selzer A.
Six new cases of acute myocardial infarction with normal coronary arteriogram are presented and supplemented by 19 collected cases (group I). These are compared with 16 cases of myocardial infarction caused by occlusive coronary artery disease in a comparable population (group ii). The following significant differences between the two groups are established: patients in group I were younger (27.5 years vs 33.7 years, P less than 0.005); at least one risk factor was present in all patients in group II, but in only 40% of group I (P less than 0.0001). effort angina preceded the attack in ten patients of group II, but in none of group I (P less than 0.0001). The attack was unheralded in 24 of the 25 patients in group I, but was preceded by prodromes in 11 of 16 in group II (P less than 0.0001). Attacks of pain following myocardial infarction occurred in five patients of group 2 and II of group II) (P less than 0.001). Results are discussed in the light of the nature of myocardial infarction in group I. No support is found for the coronary spasm theory. The most likely mechanism for development of myocardial infarction in group I is thought to be a thromboembolic “accident.” This accident is not necessarily related to atherosclerotic coronary disease and is presumed to be benign in nature.
Am J Cardiol. 1981 Jul;48(1):28-32.
Myocardial infarction with normal coronary arteries: a prospective clinical-angiographic study.
Betriu A, Pare JC, Sanz GA, Casals F, Magriña J, Castañer A, Navarro-Lopez F.
The association of myocardial infarction with normal coronary arteries was analyzed prospectively. A series of 259 consecutive men aged 60 years or less underwent selective coronary angiography 30 days after a definite infarct. Coronary arterial lesions were documented in 251 patients, normal coronary arteries in the remaining 8. The latter patients had a significantly lower (p less than 0.001) mean age than the former; no patient older than 50 years had patent coronary arteries, whereas 5 of the 11 patients under age 35 had normal arteries. The prevalence of risk factors was similar in both groups of patients. Although there were no group differences in infarct size or location, patients with normal coronary arteries had a higher ejection fraction (p less than 0.01) and a lower left ventricular end-diastolic pressure (p less than 0.05). A previous history of angina or infarction and the occurrence of new coronary events were confined to patients with coronary arterial lesions. The clinical course of patients presenting with normal angiograms was uneventful. Transient coronary occlusion, the most likely mechanism of infarction in this group of patients, could not be ascribed to either spasm or platelet hyperactivity.
Tex Heart Inst J. 1985 Mar;12(1):1-7.
Acute myocardial infarction with “normal” coronary arteries: clinical and angiographic profiles, with ergonovine testing. Salem BI1, Haikal M, Zambrano A, Bollis A, Gowda S.
Author information 1Cardiac Catheterization Laboratory, 224 South Wood Mill Road, Suite 710, Chesterfield, Missouri 63017, USA.
Abstract Among 528 patients consecutively undergoing selective coronary angiography after acute myocardial infarction, ten cases (1.9%) with angiographically normal coronary arteries were identified. Eight of these ten patients were 45 years of age or younger and comprised 11% of those studied in this age group, with higher prevalence in females (five of 18 [28%]) versus males, (three of 57 [5%]). Common features besides the young age of patients included predominance of female sex, smoking as a risk factor, and the lack of preinfarction symptoms. An ergonovine test was carried out in seven of these patients, and all tested patients failed to show any evidence of focal coronary spasm. Three patients had recanalization of the infarct-related vessel by intracoronary streptokinase. The lack of a history of variant angina in nine patients, the negative response to ergonovine provocation in seven, and documented thrombolysis after intracoronary streptokinase in three seem to indicate that a thrombotic process is a leading factor in myocardial infarction in such cases. Angiographic studies of this young subset of patients would enhance their identification and might reveal the pathophysiologic mechanisms involved with potentially significant clinical implications. Long-term follow-up of such cases will be needed to determine their ultimate prognosis.
Eur Heart J. 2001 Aug;22(16):1459-65.
Clinical characteristics, aetiological factors and long-term prognosis of myocardial infarction with an absolutely normal coronary angiogram; a 3-year follow-up study of 91 patients.
Da Costa A1, Isaaz K, Faure E, Mourot S, Cerisier A, Lamaud M.
The purpose of this study was to evaluate the clinical outcome of a large cohort of patients who suffered an acute myocardial infarction with absolutely normal epicardial coronary arteries at the post-myocardial infarction coronary angiogram. The aetiological and prognostic factors in this population were also analysed.
BACKGROUND:Few data exist concerning the outcome, and aetiological and prognostic factors, of patients with myocardial infarction and angiographically absolutely normal coronary arteries.
METHODS:Ninety-one patients (34 females/57 males; mean age 50+/-13 years, range 24–78 years) admitted with an acute myocardial infarction had absolutely normal coronary arteries at the angiogram performed 6.2+/-4 days (range 1–15 days) after the myocardial infarction, defined by smooth contours and no focal reduction (NC). Of the 91 NC patients, 71 were evaluated prospectively, alongside a systematic search of all aetiological factors reported in the literature. The NC patients were matched for age, sex, and the same period of myocardial infarction onset with a group of 91 patients with coronary artery stenosis (>50% diameter stenosis) at the angiogram performed 7.3+/-4 days (range 1–15 days) after the myocardial infarction (SC).
RESULTS:The percent of smokers was similar between the two groups; higher prevalence rates of coronary heart disease family history, obesity, hypertension, hypercholesterolaemia and diabetes mellitus were found in SC (P=0.043 to 0.0001). In NC, coronary spasm was found in 15.5%, congenital coagulation disorders in 12.8%, collagen tissue disorders in 2.2%, embolization in 2.2%, and oral contraceptive use in 1.1%. Left ventricular ejection fraction at hospital discharge was higher in NC (60%+/-13%) than in SC (55%+/-13%, P=0.04). The mean follow-up was 35 months (range 1–100 months). Kaplan-Meier event-free survival, with the combined end-point defined as death, reinfarction, heart failure and stroke was 75% in NC vs 50% in SC (P<0.0001). Survival rate was 94.5% in NC compared to 92% in SC (ns). Univariate predictors of events in NC were left ventricular ejection fraction (P=0.03), age (P=0.02), diabetes (P=0.01), and smoking (P=0.03). Using Cox multivariate analysis, independent predictors of long-term outcome in NC patients were left ventricular ejection fraction (P=0.003) and diabetes (P=0.004).
CONCLUSION:Aetiological factors, predominantly coronary spasm and inherited coagulation disorder, can be detected in only one third of the patients with myocardial infarction and absolutely normal coronary angiograms despite a systematic search in a prospective population. Mortality rates are similar but morbidity is lower in myocardial infarction patients with absolutely normal coronary angiography compared with those with coronary artery stenosis. The only two independent factors predictive of poor outcome in myocardial infarction patients with normal coronary arteries are left ventricular function and diabetes.
Z Kardiol. 1979 Aug;68(8):534-40.
[Coronary reserve, left ventricular function, and coronary risk factors in patients with myocardial infarction, but normal coronary arteries (author’s transl)].
[Article in German] Opherk D, Mäurer W, Mehmel HC, Müller JH, Zebe H, Kübler W.
Abstract In 5 patients with angiographically normal coronary arteries and previous myocardial infarction (left ventricular a- or dyscinesia), measurement of coronary reserve revealed normal values. On average, patients with myocardial infarction and normal coronary arteries were younger than patients with angiographically proven obstructive coronary lesions (p less than 0,001), and did not exhibit a rise in coronary risk factors. These results suggest that in some cases myocardial infarction is due to acute, completely reversible occlusion or severe stenosis of larger coronary arteries without morphological or functional defects of coronary arteries detectable later on.
Z Kardiol. 2000 Jan;89(1):36-42.
[Acute myocardial infarction in patients with angiographically normal coronary arteries: clinical features and medium term follow-up].
[Article in German] Meierhenrich R1, Carlsson J, Brockmeier J, Miketic S, Sorges E, Tebbe U.
Author information 1Universitätsklinik für Anästhesiologie, Klinikum der Universität Ulm, Steinhövelstr. 9, D-89075 Ulm.
Circulation. 1986 Sep;74(3):469-76.
Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study.
Cohen M, Rentrop KP.
We have shown improvement in collateral filling immediately after sudden controlled coronary occlusion in human subjects undergoing elective coronary angioplasty. It has been suggested but not proved that collateral circulation can limit myocardial ischemia. We prospectively studied 23 patients with isolated left anterior descending (n = 14) or right coronary (n = 9) disease and normal left ventriculograms during elective coronary angioplasty. A second arterial catheter was used for injection of the contralateral artery to assess collateral filling before balloon placement and during coronary occlusion by balloon inflation. Left ventriculography was performed during another inflation. Grading of collateral filling was as follows: 0 = none, 1 = filling of side branches only, 2 = partial filling of the epicardial segment, 3 = complete filling of the epicardial segment. Indexes of myocardial ischemia included percent of the left ventricular perimeter showing new hypocontractility and the sum of ST segment elevation measured on a simultaneous 12-lead electrocardiogram recorded during each inflation. Collateral filling during balloon occlusion and indexes of ischemia were assessed at 30 to 40 sec into inflation. Aortic pressure and heart rate did not correlate with the percent hypocontractile perimeter nor the sum of ST segment elevation. There was a significant correlation between the grade of collateral filling during inflation and both percent hypocontractile perimeter (r = -.85) and the sum of ST segment elevation (r = -.87). Anginal pain occurred in all patients with grade 0 or 1 collateral filling but in only 36% of patients with grade 2 or 3 collaterals. In conclusion, collateral circulation limits myocardial ischemia as assessed by the extent of new ventricular asynergy and electrocardiographic changes during coronary occlusion in patients.
free full text
BMC Med. 2013 Jun 4;11:143. doi: 10.1186/1741-7015-11-143.
The collateral circulation of the heart.
Meier P1, Schirmer SH, Lansky AJ, Timmis A, Pitt B, Seiler C.
The coronary arteries have been regarded as end arteries for decades. However, there are functionally relevant anastomotic vessels, known as collateral arteries, which interconnect epicardial coronary arteries. These vessels provide an alternative source of blood supply to the myocardium in cases of occlusive coronary artery disease. The relevance of these collateral arteries is a matter of ongoing debate, but increasing evidence indicates a relevant protective role in patients with coronary artery disease. The collateral circulation can be assessed by different methods; the gold standard involves intracoronary pressure measurements. While the first clinical trials to therapeutically induce growth of collateral arteries have been unavailing, recent pilot studies using external counterpulsation or growth factors such as granulocyte colony stimulating factor (G-CSF) have shown promising results.
Heart. 2010 Feb;96(3):202-7. doi: 10.1136/hrt.2009.184507. Epub 2009 Nov 5.
Coronary collateral growth by external counterpulsation: a randomised controlled trial.
Gloekler S1, Meier P, de Marchi SF, Rutz T, Traupe T, Rimoldi SF, Wustmann K, Steck H, Cook S, Vogel R, Togni M, Seiler C.
The efficacy of external counterpulsation (ECP) on coronary collateral growth has not been investigated in a randomised controlled study. Objective To test the hypothesis that ECP augments collateral function during a 1 min coronary balloon occlusion.
PATIENTS AND METHODS:
Twenty patients with chronic stable coronary artery disease were studied. Before and after 30 h of randomly allocated ECP (20 90 min sessions over 4 weeks at 300 mm Hg inflation pressure) or sham ECP (same setting at 80 mm Hg inflation pressure), the invasive collateral flow index (CFI, no unit) was obtained in 34 vessels without coronary intervention. CFI was determined by the ratio of mean distal coronary occlusive pressure to mean aortic pressure with central venous pressure subtracted from both. Additionally, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography, and brachial artery flow-mediated dilatation was obtained.
RESULTS: CFI changed from 0.125 (0.073; interquartile range) at baseline to 0.174 (0.104) at follow-up in the ECP group (p=0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (p=0.14). Baseline to follow-up change of coronary collateral conductance was from 0.365 (0.268) to 0.568 (0.585) ml/min/100 mm Hg in the ECP group (p=0.072), and from 0.229 (0.212) to 0.305 (0.422) ml/min/100 mm Hg in the sham ECP group (p=0.45). There was a correlation between the flow-mediated dilatation change from baseline to follow-up and the corresponding CFI change (r=0.584, p=0.027).
CONCLUSIONS: ECP appears to be effective in promoting coronary collateral growth. The extent of collateral function improvement is related to the amount of improvement in the systemic endothelial function.
Am J Physiol. 1987 Nov;253(5 Pt 2):H1279-88.
Development of coronary collateral circulation in left circumflex Ameroid-occluded swine myocardium. Roth DM1, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor CM.
Coronary collateral development was examined in 34 pigs after gradual occlusion of the left circumflex coronary artery (LCX) with an Ameroid constrictor. Collateral development was assessed by measurements of myocardial blood flow and regional myocardial function at rest and during exercise over a 16-wk period after placement of the constrictor. Coronary collateral development was adequate to prevent severe infarction and restore blood flow to the collateral-dependent LCX region within 3-7 wk. Infarction averaged 5.0 +/- 1.3% of the LCX region. Blood flows at rest were 1.05 +/- 0.14 and 1.13 +/- 0.15 ml.min-1.g-1 in the subendocardium of the collateral and control regions, respectively, 7 wk postoperatively. Concurrently, collateral vessel development supported normal myocardial function at rest as determined by systolic wall thickening in the LCX region. However, collateral development was limited, since blood flows during moderate and severe exercise were reduced in the LCX region compared with control and left anterior descending and right coronary regions. Blood flow ratios (collateral/control flow) during severe exercise 3 wk postoperatively were 0.23 +/- 0.03 and 0.57 +/- 0.05 in the subendocardium and subepicardium and were constant throughout the 16-wk period throughout the study. Myocardial function of the collateral region also was reduced during exercise and a 30-min recovery period. We suggest that this limited coronary collateral circulation, which develops in response to gradual coronary occlusion in swine, serves as a model for the human collateral circulation for the study of protocols to alter growth and development of coronary collateral vessels.
Atherosclerosis. 2001 Apr;155(2):499-508.
Coronary atherosclerosis in unheralded sudden coronary death under age 50: histo-pathologic comparison with ‘healthy’ subjects dying out of hospital. Schmermund A1, Schwartz RS, Adamzik M, Sangiorgi G, Pfeifer EA, Rumberger JA, Burke AP, Farb A, Virmani R.
sudden coronary death (SCD) in older individuals is generally associated with extensive coronary atherosclerosis, although it may be the first manifestation of ischaemic heart disease. In younger age-groups, SCD may occur in the presence of less severe disease. We sought to (1) examine the extent of coronary atherosclerosis in young victims of SCD compared with age- and sex-matched controls, (2) analyse the composition of atherosclerotic plaques in these patients, (3) identify the predominant mechanism of SCD, and (4) evaluate the possibility of detecting this mechanism on the basis of morphologic plaque features, in particular presence and amount of lipid accumulation and calcific deposits.
METHODS AND RESULTS:
coronary arteries were obtained at autopsy from 28 victims of SCD under age 50 with no prior clinical manifestation of ischaemic heart disease (IHD) and no myocardial scar formation and from 16 age- and sex-matched subjects dying of noncardiac causes out of hospital. Sections of all available major coronary arteries were cut in 5-mm intervals to yield a total of 1357 histologic sections, which were analysed using digitised planimetry. Victims of SCD had significantly more major coronary arteries per subject with luminal area narrowing > or = 75% than controls (on average, 2.1 vs. 0.2). Plaque area per histologic section was 5.1 +/- 2.1 mm(2) in SCD cases and 2.0 +/- 0.9 mm(2) in controls (P < 0.001). The major constituent of all plaques was fibrous tissue. Lipid core area per section was 0.49 +/- 0.59 mm(2) in SCD cases and 0.004 +/- 0.01 mm(2) in controls (P < 0.001), and calcified plaque area was 0.18 +/- 0.19 mm(2) in SCD cases and 0.02 +/- 0.05 mm(2) in controls (P < 0.001), both defining significant differences between SCD cases and controls. Arterial thrombosis, most often with underlying plaque rupture was the mechanism of SCD in > 80% of the cases. Considering histologic sections with > or = 50 and with > or = 75% area stenosis, plaque rupture was independently predicted by lipid core area. Calcific deposits were a frequent feature of plaque rupture but were only associated with it in univariate analysis.
the extent and severity of coronary atherosclerosis in young victims of SCD as the first manifestation of IHD was substantially greater than in age-and sex-matched controls and comparable with that previously reported in SCD cases with a broader age range. Lipid core and calcified plaque areas provided for excellent separation between the two groups, which may have implications for identifying persons at increased risk for SCD by non invasive visualisation and assessment of the coronary arteries.
Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose–response meta-regression
Stefanie Hillebrand1,*, Karin B. Gast1,2, Renée de Mutsert1, Cees A. Swenne3, J. Wouter Jukema3, Saskia Middeldorp4, Frits R. Rosendaal1 and Olaf M. Dekkers1,5
+ Author Affiliations 1Department of Clinical Epidemiology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Aims Heart rate variability (HRV) is associated with cardiovascular disease (CVD) in individuals with known CVD. It is less clear whether HRV is associated with a first cardiovascular event. Therefore, we performed a meta-analysis to study the association between HRV and incident cardiovascular events in populations without known CVD.
Methods and results We performed a meta-analysis and dose–response meta-regression of studies assessing the association between HRV and CVD. We searched Pubmed, Embase, Web of Science, Cochrane library, ScienceDirect, and CINAHL up to December 2011 for eligible studies. We selected studies that used the standard deviation of the normalized N–N interval (SDNN), low-frequency (LF) or high-frequency (HF) spectral component as a measure of HRV. Primary outcomes were (non)fatal cardiovascular events. Eight studies with a total number of 21 988 participants were included. The pooled relative risk (RR) comparing the lowest level to the highest level of SDNN was 1.35 (95% CI 1.10, 1.67). The pooled RRs for LF and HF were 1.45 (95% CI 1.12, 1.87) and 1.32 (95% CI 0.96, 1.81), respectively. In a meta-regression, the predicted RR of incident CVD of the 10th and 90th HRV (SDNN) percentiles compared with the 50th percentile were 1.50 (95% CI 1.22, 1.83) and 0.67 (95% CI 0.41, 1.09).
Conclusion In conclusion, low HRV is associated with a 32–45% increased risk of a first cardiovascular event in populations without known CVD. An increase in SDNN of 1% results in an ∼1% lower risk of fatal or non-fatal CVD.
Am J Epidemiol. 1997 Apr 15;145(8):696-706.
Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study.
Liao D1, Cai J, Rosamond WD, Barnes RW, Hutchinson RG, Whitsel EA, Rautaharju P, Heiss G.
Cardiac autonomic activity, as assessed by heart rate variability, has been found to be associated with postmyocardial infarction mortality, sudden death, and all-cause mortality. However, the association of heart rate variability and the incidence of coronary heart disease (CHD) is not well described. The authors report on the association of baseline cardiac autonomic activity (1987-1989) with incident CHD after 3 years (1990-1992) of follow-up of the Atherosclerosis Risk in Communities Study cohort selected from four study centers in the United States by using a case-cohort design. The authors examined 137 incident cases of CHD and a stratified random sample of 2,252 examinees free of CHD at baseline. Baseline, supine, resting beat-to-beat heart rate data were collected. High- (0.16-0.35 Hz) and low- (0.025-0.15 Hz) frequency spectral powers and high-/low-frequency power ratio, estimated from spectral analysis, and standard deviation of all normal R-R intervals, calculated from time domain analysis, were used as the conventional indices of cardiac parasympathetic, sympatho-parasympathetic, and their balance, respectively. Incident CHD was defined as hospitalized myocardial infarction, fatal CHD, or cardiac revascularization procedures during 3 years of follow-up. The age, race, gender, and other CHD risk factor-adjusted relative risks (and 95% confidence intervals) of incident CHD comparing the lowest quartile with the upper three quartiles of high-frequency power, low-frequency power, high-/low-frequency power ratio, and standard deviation of R-R intervals were 1.72 (95% confidence interval (CI) 1.17-2.51), 1.09 (95% CI 0.72-1.64), 1.25 (95% CI 0.84-1.86), and 1.39 (95% CI 0.94-2.04), respectively. The findings from this population-based, prospective study suggest that altered cardiac autonomic activity, especially lower parasympathetic activity, is associated with the risk of developing CHD.
Br Heart J. Sep 1989; 62(3): 165–170.
Cardiac parasympathetic activity during the early hours of acute myocardial infarction.
D McAreavey, J M Neilson, D J Ewing, and D C Russell
Cardiac parasympathetic activity was assessed in 21 patients during the first 24 hours of acute myocardial infarction by measuring abrupt beat by beat changes in RR interval, which are expressed as “RR counts”. Eleven patients had inferior wall infarction and 10 had anterior wall myocardial infarction. The whole recording period was analysed in 11 patients (five inferior and six anterior), and intermittent hourly periods were analysed in all 21 subjects. Mean RR counts were significantly lower in patients with anterior than inferior infarction, and below the normal range. Although mean heart rates were faster in the group with anterior infarction, there was a dissociation between RR counts and mean heart rate that was consistent with RR interval variability being an independent measure of parasympathetic activity. This study indicates that cardiac parasympathetic activity during acute myocardial infarction can be simply and reliably assessed from continuous electrocardiographic recordings, and it showed significantly lower cardiac parasympathetic activity in patients with anterior infarction.
Heart. 2013 Aug;99(15):1100-5. doi: 10.1136/heartjnl-2013-304006. Epub 2013 May 28.
Clinical parameters associated with collateral development in patients with chronic total coronary occlusion.
van der Hoeven NW1, Teunissen PF, Werner GS, Delewi R, Schirmer SH, Traupe T, van der Laan AM, Tijssen JG, Piek JJ, Seiler C, van Royen N.
Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis.
DESIGN: Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI).
PATIENTS: Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed.
INTERVENTIONS: Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure.
RESULTS: The mean CFI was 0.39 ± 0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011).
CONCLUSIONS: In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.
Eur J Clin Invest. 2010 May;40(5):465-76. doi: 10.1111/j.1365-2362.2010.
The human coronary collateral circulation.
Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischaemia. Well-developed coronary collateral arteries in patients with coronary artery disease (CAD) mitigate myocardial infarcts and improve survival.
METHODS AND RESULTS: Collateral arteries preventing myocardial ischaemia during brief vascular occlusion are present in 1/3 of patients with CAD. Among individuals without relevant coronary stenoses, there are preformed collateral arteries preventing myocardial ischaemia in 20-25%. Collateral flow sufficient to prevent myocardial ischaemia during coronary occlusion amounts to double dagger25% of the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction and the inverse of collateral supply. Coronary collateral flow can be assessed only during vascular occlusion of the collateral-receiving artery. The gold standard for coronary collateral assessment is the measurement of intracoronary occlusive pressure- or velocity-derived collateral flow index expressing collateral as a fraction of flow during vessel patency. Approximately one of five patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients.
CONCLUSIONS: Promotion of collateral growth should aim at inducing the development of large conductive collateral arteries (i.e. arteriogenesis) and not so much the sprouting of capillary like vessels (i.e. angiogenesis). Large conductive collateral arteries appear to be effectively promoted via the activation of monocytes/macrophages by means of granulocyte-colony stimulating factor or of augmenting coronary flow velocity.
Br Heart J. Feb 1987; 57(2): 139–143.
Importance of angina for development of collateral circulation.
M Fujita, S Sasayama, A Ohno, H Nakajima, and H Asanoi
The extent of collateral circulation in 46 patients who had intracoronary thrombolysis within six hours of the onset of acute myocardial infarction was evaluated. Patients who had had a previous myocardial infarction (4 cases) or who had spontaneously recanalized infarct related coronary arteries (5 cases) were excluded from the analysis. Collateral development was graded during coronary cineangiography according to the extent of opacification of the collateral and epicardial arteries distal to the site of occlusion (collateral index 0 to 3). Angina was considered to be present before myocardial infarction if it had occurred more than one week before acute myocardial infarction. Collateral channels were visible in only two of 19 patients without angina before infarction and nine of the 18 patients with angina before infarction. The prevalence of angina and the collateral index were not significantly influenced by the extent of coronary vessel disease. It is concluded that myocardial ischaemia is important in promoting collateral development in man as well as in laboratory animals.
J Cardiol. 2006 Mar;47(3):115-21.
[Effect of collateral circulation on myocardial protection in patients with acute myocardial infarction: comparison of technetium-99m-tetrofosmin myocardial single photon emission computed tomography and coronary angiography].
[Article in Japanese] Yoshida M1, Kondo M, Abe Y, Kubota T, Matsuoka R, Araki M, Tanio H, Doyama K.
Evaluation of myocardial blood flow from collateral vessels into the infarct area has been estimated by coronary angiography. In patients with acute myocardial infarction with Thrombolysis in Myocardial Infarction (TIMI) 0 flow, myocardial tracer uptake on single photon emission computed tomography (SPECT) images can predict the collateral blood flow in the infarct area if technetium (Tc)-99m-tetrofosmin was administered before recanalization. The present study investigated whether collateral blood flow evaluated by myocardial scintigraphy is a good predictor of myocardial salvage in patients with acute myocardial infarction.
METHODS:The study group consisted of 30 patients (mean age 65 +/- 14 years, 23 males, 7 females) with first acute myocardial infarction and coronary angiography evidence of total occlusion (TIMI 0) within 12 hr after the onset. All patients had one vessel disease related to infarction and TIMI 3 flow after percutaneous coronary intervention (PCI). Tc-99m-tetrofosmin was injected intravenously before the PCI. The regional severity score index (RSSI) was obtained from SPECT using the 17 segment method with the four-point scoring system. Myocardial viability was evaluated by the RSSI obtained from thallium-glucose-insulin infusion SPECT after 1 week and regional wall motion score index obtained from echocardiography during the chronic phase.
RESULTS:The patients were divided into two groups according to the angiographic collateral finding. There were no differences in RSSI on thallium-glucose-insulin SPECT and regional wall motion score between the good collateral group (n = 8) and poor collateral group (n = 22). Myocardial Tc-99m-tetrofosmin RSSI was similar in these groups. On the other hand, the patients were divided according to Tc-99m-tetrofosmin scintigraphic evaluation before PCI. RSSI on thallium-glucose-insulin SPECT was significantly greater (0.7 +/- 0.5 vs 1.5 +/- 0.4, p < 0.01) and regional wall motion score was significantly less (1.46 +/- 0.50 vs 2.08 +/- 0.78, p < 0.05) in the lower Tc-99m-tetrofosmin RSSI (< 1.9) group (n = 22) compared with the higher RSSI (> or = 1.9) group (n = 8). In addition, a significant correlation was obtained between Tc-99 m-tetrofosmin RSSI and regional wall motion score index (r = 0.53, p < 0.01).
CONCLUSIONS:The collateral flow evaluated by scintigraphy was significantly correlated with myocardial viability.
Circulation. 1976 Mar;53(3 Suppl):I57-62.
Influence of collateral flow on the ischemic tolerance of the heart following acute and subacute coronary occlusion.
Schaper W, Pasyk S.
Acute occlusion of the circumflex branch of the left coronary artery was produced in chronically instrumented conscious dogs. Tracer microspheres were used to measure during an established time period, the distribution of collateral flow within the infarcting myocardium. For up to 2 hours after coronary occlusion the amount and distribution of the collateral flow remained unchanged. Two to 4 hours after coronary occlusion the subendocardial flow fell to almost zero and the subepicardial flow rose. Between 6 and 48 hours subepicardial and total collateral flow rose markedly. A no-reflow phenomenon is responsible for the decline of collateral flow in the subendocardium. Evidence for this hypothesis was provided by releasing the artery 1,2, 4 and 6 hours after occlusion. The amount of subendocardium that could not be reperfused was small after 1 hour and large after 6 hours of occlusion. When the total collateral flow was very low, the subepicardium was not able to be reperfused and a transmural myocardial infarction developed. We conclude that the time delay between onset of ischemia and the appearance of a no-reflow phenomenon depends upon the amount of collateral flow. The occurrence of a no-reflow phenomenon in the subendocardium increases the amount of flow to the subepicardium which increases its chances of survival. Beyond the sixth hour after occlusion the total amount of collateral flow increases which is interpreted as a reduction of collateral resistance by passive caliber changes of the collateral vessels. DNA-synthesis that signal active caliber changes through cellular proliferation were always detected 24 hours after complete occlusion of a coronary artery regardless whether the time between onset of stenosis until complete occlusion was varied between 36 hours and 5 days. When the time to complete occlusion was 4 days, myocardial infarction was prevented due to growth-transformation of pre-existing collaterals. Four phases of collateral reactions in acute coronary occlusion were observed: redistribution of available collateral flow in favor of the subepicardium (t = 1 to 4 hours after occlusion), 2) increase of total collateral flow due to passive “stretch” of collateral vessels (t = 4 to 24 hours after occlusion), 3) radial growth of collateral vessels due to active cellular proliferation, (t = 24 hours to 5 days) 4) cellular proliferation to ensure a normal wall thickness in growth’transformed collaterals (t = 5 days to 20 days after coronary occlusion). In subacute coronary occlusion the first phase does, of course, not apply.
Endogenous and exogenous cardiac glycosides: their roles in hypertension,
salt metabolism, and cell growth
Wilhelm Schoner and Georgios Scheiner-Bobis
Institute of Biochemistry and Endocrinology, Justus Liebig University Giessen, Giessen, Germany
Semin Nephrol. 2005 Sep;25(5):343-51.
Endogenous cardiac glycosides: hormones using the sodium pump as signal transducer.
Schoner W1, Scheiner-Bobis G.
The search for an endogenous digitalis has led to the identification of the cardenolides ouabain and digoxin and the bufadienolide marinobufagenin in mammalian tissues and biological fluids. Ouabain’s release from adrenal glands is under the control of epinephrine and angiotensin II; hence, its blood concentration changes rapidly on physical exercise. It also is controlled by brain areas sensing cerebrospinal Na+ concentration and apparently the body’s K+ content because urinary K+ loss leads to an increase in its plasma concentration as well. Long-term treatment of rats with ouabain results in arterial hypertension, and 50% of Caucasians with low-renin hypertension have increased plasma concentrations of this cardenolide. Levels of digoxin, which is synthesized from acetate in adrenal glands, increase slightly in blood on prolonged exercise. It counteracts the hypertensinogenic action of ouabain in rats, as does the ouabain antagonist PST 2238. The plasma concentration of the bufadienolide marinobufagenin is increased after cardiac infarction. It may show natriuretic properties because it inhibits the alpha1 isoform of Na+/K+-adenosine triphosphatase (ATPase), the main sodium pump isoform of the kidney, much better than other sodium pump isoforms. These effects of endogenous cardiac glycosides are observed at concentrations that do not inhibit the sodium pump. Apparently, Na+/K+-ATPase is used by these steroids as a signal transducer to activate tissue proliferation, heart contractility, arterial hypertension, and natriuresis via various intracellular signaling pathways.
Am J Cardiovasc Drugs. 2007;7(3):173-89.
Endogenous and exogenous cardiac glycosides and their mechanisms of action.
Schoner W1, Scheiner-Bobis G.
Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body’s K(+) content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca(2+) influx via the Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-kappaB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy. In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive alpha(1) isoform of Na(+)/K(+)-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.
Ouabain Study in Dog Lab – Benefits for Ischemic Myocardium
CIRCULATION VOL 58, No 4, OCTOBER 1978
STEPHEN F. VATNER, M.D. AND HANK BAIG, M.S.E.E.
Comparison of the Effects of Ouabain and Isoproterenol on Ischemic Myocardium of Conscious Dogs.
Ouabain appeared to alleviate the ischemic condition
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
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Elisa Bernstein August 5, 2014 at 3:00 AM
Fascinating! I knew there had to be a missing link between heart attacks & stress, and of course it’s the adrenals. I think that when they talk about “kidney jing” determining longevity in Chinese medicine, they mean the adrenals, because they sit on top of the kidneys. Thanks for this amazingly researched article.
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