Bibliography

The Basics:

In 1972, after attending Harvard Medical School and training in the Surgery Department of the Massachusetts General Hospital under R. Clement Darling, MD, Robert Linton, MD, and Gerald W. Austen , MD, Dr. Jeffrey K. Raines received a PhD in Engineering from MIT (1). His thesis title was Diagnosis and Analysis of Arteriosclerosis in the Lower Limbs from the Arterial Pressure Pulse (2). This work outlined the construction and testing of a new medical device called the Pulse Volume Recorder (PVR). This device was built and distributed by Life Sciences, Inc. and became a central device in the diagnosis of peripheral vascular disease and in the development of Vascular Diagnostic Laboratories around the world. Also in 1972, the device was formally introduced via a presentation at the Society for Vascular Surgery and publication in the Journal of Surgery (3). To this day, with the initial design intact, this device remains the second most common physiologic Vascular Laboratory test ordered for arterial disease worldwide.

Soteria Medical, LLC is an FDA registered medical device developer and marketer incorporated in Florida during the first quarter of 2012. The FDA Registration Number is 3009723714; details are given at www.FDA.gov. The devices which form the foundation of the company are state-of-the-art noninvasive cardiovascular systems. The firm's main focus is primary and secondary prevention of coronary artery disease (CAD), the single leading cause of death in the United States and most countries of the developed world. Since incorporation, the firm has completed development of a successful corporate infrastructure, product-line, secure intellectual property, regulatory requirements, manufacturing and business strategies which include market identification and penetration. The current step along the firm's critical path is a launch of the Soteria Cardiac Platform.

Dr. Raines has a long and extensive background in medicine and science. He started his career as an NIH Fellow at the Harvard Medical School and Massachusetts Institute of Technology. He was the Founding Director of the Vascular Laboratory, Department of Surgery, Massachusetts General Hospital. During that period which began in 1972 he designed the Pulse Volume Recorder (PVR) which became a central medical device in the diagnosis of peripheral vascular disease and in the development of Vascular Diagnostic Laboratories around the world. Later in his career, Dr. Raines was a pioneer in the development of B-Mode Ultrasound. More recently he has developed an automated and internally calibrated system that can be used in the clinical setting to obtain accurate arterial compliance measurements to assess atherosclerosis. This Service is called the Soterogram and is featured by Soteria Medical, LLC. 









                                                         





The Basis:

It was well known, that the upper extremity arteries and even the carotid arteries did not refiect disease in the coronary arteries due to differences in distribution of elastin, collagen, and smooth muscle between these beds. The major technical challenge was to devise an accurate method to measure local arterial volume (i.e. /::,,. volume - the numerator in the definition of compliance) . Dr. Raines realized this required an automated and internally calibrated system controlled by a small chip (i.e. microprocessor) within the system. A device was developed and built that could be used in the clinical setting to obtain accurate arterial compliance measurements in the lower extremity (thigh and calf levels). This device is now called the Soterogram. Over the next few years Dr. Raines was awarded 8 United States Patents for this work; a complete patent listing is given in his resume (1). An independent analysis of this new technology was performed in July 2010 by Patent Attorney David R. Schaffer, Esq. of the Miles and Stockbridge patent firm (Tyson' s Corner, VA) .

The Patent Attorneys managing the firms Intellectual Property are Jennie S. Malloy, Esq. and Jason Lacosse, Esq. of the firm Malloy and Malloy (Coral Gables, FL) .

Working from the tenet that early atherosclerosis increases the thickness of the arterial wall (occurring well in advance of blood flow alterations detected by other measures), Dr. Raines was given funding to seriously extend the design of his Pulse Volume Recorder to accurately and noninvasively measure arterial compliance in the lower extremity.



The Challenge:

In 1989, Stephen E. Epstein, MD was the Chief of Cardiology at the National Heart, Lung, and Blood Institute. Dr. Epstein and his colleagues in the New England Journal of Medicine discussed continuing sudden cardiac death without warning and possible mechanisms and implication for screening asymptomatic populations (4). On the strength of considerable material, Dr. Epstein made two very important observations: (i) "Among patients who experience an acute myocardial infarction, who had previously undergone catheterization, the infarction-related vessel at the initial catheterization was narrowed less than 503 in between 50 to 70 percent of patients." and (ii) "From this analysis, it appears that attempts to detect ischemia by screening asymptomatic subjects in the hope of preventing sudden coronary death will be largely futile, and that the only currently viable approach to this problem is the use of preventive measures designed to diminish the risk that coronary atherosclerosis will develop" .

To be very focused Dr. Epstein made two very acute conclusions. First, the degree of coronary artery disease that produces myocardial infarction in up to 703 of individuals did not reduce blood flow to the heart muscle. Second, if physicians insist on looking for and using tests that only measure ischemia (i.e. reduction in blood flow to the heart muscle), that this form of testing will fail.

Confirmation of Dr. Epstein' s conclusions came a few years later secondary to excellent experiments carried out and published by Aarcelo Di Carli, MD in Circulation from UCLA School of Medicine (5). In this work, Dr.Di Carli and associates clearly demonstrated that myocardial blood flow was not reduced until at least 60% of the arterial cross-sectional area had been obstructed by atherosclerotic disease.

If one combines the Epstein and DiCarli works, the result is the conclusion that another factor is at play in myocardial infarction other than high-grade coronary artery obstruction and myocardial ischemia.



The Understanding:

 Since the development and distribution of the Pulse Volume Recorder (PVR) in 1972, Dr. Raines continued working on improvements that would expand the use of the PVR to other areas. Most of this work in this period involved peripheral vascular disease and not coronary artery disease and may be found in his attached resume (1). Also, during this period it became clear to many cardiovascular specialists, including Dr. Raines, that atherosclerosis was a process that involved: (i) smooth muscle cell migration from media of the arterial wall, (ii) associated thickening of the intima, (iii) complex disease of the arterial wall (i.e. lipid pools, thrombus, necrosis, fibrous caps, calcification, and plaque rupture), and (iv) disruption of the endothelial surface (interface between the wall and fiowing blood). The following plates show a normal arterial cross-section on the right with a thin wall and intima and smooth endothelial surface. The diseased artery on the left shows the thickened wall, thickened intima, and irregular endothelial surface. This is a clear picture of early atherosclerosis.










Jay N. Cohn, MD, a highly respected cardiologist from the University of Minnesota published a paper in the American Journal of Hypertension titled Arterial Compliance to Stratify Cardiovascular Risk: More Precision in Therapeutic Decision Making (6) . Dr. Cohn in the abstract of this publication opened with the following statement : "The focus of attention in preventing and treating cardiovascular (CV) disease is shifting toward the arterial wall. Evidence has been accumulating for several years that protecting the endothelium is key to reducing CV risk. Endothelial dysfunction results in reduced compliance, or increased arterial stiffness ..." In this paper Dr. Cohn goes on to discuss arterial wall disease, hemodynamics (i.e. blood fiow), and the relationship of arterial compliance (.6. volume I .6. pressure) in several disease states (i.e. diabetes) .


The Publications:

 A significant infrastructure had developed around this work and included, in addition to Dr. Raines (University of Miami) a number prominent cardiovascular investigators : (i) W . Virgil Brown, MD - Emory University, (ii) David Herrington, MD - Bowman Gray School of Medicine, (iii) Lori Mosca, MD, PhD - Columbia University, and (iv) JHC Reiber, MD, PhD - University of Leiden and University of Groningen, The Netherlands. The FDA was also closely involved in this work. This Team was funded to perform two major clinical studies.

The first study was called the Precision Study, carried out in the 6 academic medical centers listed above. This study involved 418 subjects , equally divided between males and females between 20 and 80 years of age. These subjects all had documented low cardiovascular risk. This was defined as absence of smoking, hypertension, diabetes, elevated blood lipids, obesity, and cardiovascular pharmacy. In addition to a detailed examination, each subject underwent two Soterograms. This data has become the reference population for the Soterogram.

The second study was the Accuracy Study and was carried out in the 4 US-based medical centers listed above. This study involved 343 subjects, equally divided between males and females between 35 and 79 years of age with four levels of cardiovascular risk: low risk, moderate risk, equivalent coronary artery disease, and documented coronary artery disease.

Each subject underwent four Soterograms, thoracic and abdominal aortic Magnetic Resonance Imaging (MRI) to define cardiovascular atherosclerosis, clinical laboratory, and stress ECG/ Echocardiogram . This data was used to define atherosclerotic burden as a function of Soterogram findings.

On completion of the Precision and Accuracy Studies, the Team began publishing results.It is important to note that all the listed investigators have remained at their respective Institutions, remain active in the technology, and work together. Dr. Stephen Epstein previously the Director of the Cardiology Branch of the NIH and now Cardiologist at the Medstar Medical Center in Washington, DC has agreed to serve as Chairman of the Soteria Medical, LLC Medical Advisory Board.

The initial publications from the referenced studies focused on comparing Compliance Data asortained from the Soterogram with known cardiovascular risk factors. These publications included:

(i) Standard cardiovascular risk factors (8), (ii) Coronary artery disease as determined by cardiac catheterization (9), (iii) Atherosclerotic Burden (10), (iv) Framingham coronary artery risk assessment (11), (v) Aortic wall thickness and conventional risk factors (12), and (vi) our flagship publication in Circulation comparing Compliance with most known risk factors on a strict statistical basis (13).

The second tier of publications involved comparing Compliance measurements in specific clinical settings. One study selected high-risk cardiovascular patients and treated them aggressively with Simvastatin which is a lipid-lowering statin agent (14). Another study determined the accuracy and operational mechanics of the Soteria ABlgram with conventional Ankle/ Arm Index methods and the SP-10 Standard established by the FDA (1 5). In another study, Compliance was used to predict cardiovascular exercise tolerance in individuals without known coronary artery disease (16). Finally, in this series Compliance measurement levels were compared to triglyceride-rich lipoproteins in healthy men and women (17).

The final paper to date is a very interesting application of Compliance measurements and the Soteria Cardiac Platform. The study was conducted by psychiatrists at the Emory School of Medicine. For a number of years it has been suspected that psychiatric diagnosis and/or second generation antipsychotics may contribute to coronary artery disease and stroke. In this study psychotic patients

and/or underwent Compliance measurements with interesting results which may open an unexpected avenue of application for this technology (18). This research has recently been accelerated.


The Summary:

Atherosclerosis is the leading cause of death for both genders in the developed world leading to massive morbidity and mortality. The financial costs secondary to myocardial infarction, cerebrovascular accident, and peripheral vascular occlusion are staggering. Despite extensive efforts to reduce this statistic , approximately 503 of all deaths secondary to coronary artery disease still occur suddenly without previous symptoms or opportunity for treatment.It has become clear that early atherosclerotic changes in the arterial wall are the root cause in many cases of sudden coronary artery occlusion and death. This same situation is also true in the cerebrovascular system leading to cerebrovascular accident, disability, and death. Early atherosclerotic changes do not disturb the ability of the diseased artery to carry normal levels of blood flow to the intended muscle mass and/or organ. Therefore, all tests that measure blood flow parameters (i.e. hemodynamics) will be blinded to this disease and therefore its risk.


​Traditional Bibliography:

1. Raines J. Curriculum Vitae I Resume. July 2012. 

2. Raines J. Diagnosis and analysis of arteriosclerosis in the lower limbs from the arterial pressure pulse. PhD Thesis - Massachusetts Institute of Technology, September 1972. 

3. Darling RC, Raines J, Brener BJ, Austen WG. Quantitative segmental Pulse Volume Recorder: A clinical tool. Surgery, 72:874-887, 1972. 

4. Epstein SE, Quyyumi AA Bonow RO. Sudden cardiac death without warning: Possible mechanisms and implications for screening asymptomatic populations. New England Journal of Medicine, 321:320 -324, 1989. 

5. Di Carli M, Czernin J, Hoh CK, Brunken RC, Huang S, Phelps M, Schelbert HR. Relation among stenosis severity, myocardial blood ftow, and flow reserve in patients with coronary artery disease. Circulation, 91:1944-1951, 1995. 

6. Cohn JN. Arterial Compliance to stratify cardiovascular risk: More precision in therapeutic decision making. American Journal of Hypertension, 14:2585-2635, 2001. 

7. David R. Shaffer, Esq. Search and opinion concerning the Soteria Cardiac Platform (Soterogram) [previously the Atherocor Atherogram System]. Miles and Stockbridge Patent Attorneys. 2010. 

8. Willens HJ, Davis W, Herrington DM, Wade K, Kesler K, Mallon S, Brown WV, Reiber JHC, and Raines J: Relationship of peripheral arterial compliance and standard cardiovascular risk factors. Journal of Vascular and Endovascular Surgery, 37:197-206, 2003. 

9. Herrington DM, Kesler K, Reiber JHC, Davis W, Brown WV, Helms R, Mallon S, and Raines J. Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease. American Heart Journal, 146(4):662-667, 2003. 

10. Raines J, Willens H, Noicely K, Wallace D, Herrington DM, Hundley G, Mosca L, Davis W, and Brown WV . Peripheral arterial compliance and atherosclerotic burden. Proceedings of the 3rd International Congress on Heart Disease, 2003.

 
11. Davis W, Brown WV, Herrington DM, Mosca L Wallace D, Willlens H, Raines J. Correlation of peripheral arterial compliance and Framingham coronary heart disease risk evaluation. Presentation, Abstract, and Paper, American College of Cardiology, 2003. 

12. Rerkpattenapipat P, Hundley W, Brown WV, Raines J, Mosca L, Davis W, Wallace D, Herrington D. Obesity is associated with aortic wall thickness independent of conventional risk factors. American Heart Association, Abstract, 03-SS-4094, 2003. 

13. Herrington DM, Brown WV, Mosca L, Davis W, Eggleston B, Hundley WG, Raines J. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation, 1 10:432-437, 2004. 


14. Saliashvili c;;, Davis W, Harris M, Le NA Brown WV. Simvastatin improved arterial compliance in high risk patients. Vascular and Endovascular Surgery, 38(6); 519-123, 2004. 


15. Raines J, Farrar J, Noicely K, Pena J, Davis W, Wallace D: Ankle/Brachial Index in the primary care setting. Journal of Vascular and Endovascular Surgery, 38(2):131-136, 2004. 


16. Willens H, Chirinos J, Brown WV. Davis W. Herrington DM. Mosca L. Homma S, Moussa M, Walker G, Raines J. Usefulness of arterial compliance in the thigh in predicting exercise capacity in individuals without coronary heart disease. American Journal of Cardiology, 96(2) :306-\310, 2005. 


17. Le NA Brown WV, Davis W, Herrington DM, Mosca L, Homma S, Eggleston B, Willens H, Raines J. Comparison of the relation of triglyceride-rich lipoproteins and muscular artery compliance in healthy women versus healthy men. American Journal of Cardiology, 95(9):1049-54, 2005. 

18. Koola MM, Brown WV, Qualls C, Cuthbert B, Hollis JP, Kelly DL, Le NA Raines J, Duncan EJ. Reduced arterial compliance in patients with psychiatric diagnose. Schizophrenia Research, 137:251-253, 2012. 

19. VOCAL Technologies, Ltd. Blind Signal Separation. www .vocal.com/blind-signal-separation/, 2012.

The Soteria Medical platform

Dr. Jeffrey K. Raines ​

CEO & President, Soteria Medical, LLC 

Emeritus Professor Surgery 

Harvard Medical School & University of Miami