Available online at www.sciencedirect.com
ScienceDirect Journal of Electrocardiology 47 (2014) 593 – 594 www.jecgonline.com
Editorial
A New Gold Rush? The Future in ECG Research☆ To be invited to provide a perspective on “the ventricular hypertrophies”, based mostly on having lived through most of the significant work on this problem, is quite a challenge. It is true that I began reading electrocardiograms (ECGs) when my teaching hospital, Grady Hospital in Atlanta, had a single Cambridge string galvanometer recording device, producing a photographic record requiring a darkroom and developing tanks. I was mentored by Robert Grant, who had no laboratory, no staff, and no research budget. His equipment was his fertile brain, able to visualize events spatially and relate this to clinical events and patients, and, from this, synthesize a whole conceptual strategy for interpretation of the ECG. (Grant was also a sculptor.) Yes, many of his generalizations have needed tweaking over the years, but the validity of the basic framework still holds together remarkably well. The pity is that Grant's technique of recognizing an unusual ECG, going to the bedside, talking with and examining the patient, learning about the family history, and trying to fit the whole thing into his basic scheme; is seldom used. My other mentor, Eugene Stead, often compared medical research to “mining gold”. Some investigators have the unique ability to find gold when others have searched and failed to find it, but often, in the real world, someone accidentally “stubs their toe” on a big nugget, resulting in a new discovery. Others follow, profiting from his good luck, mining the area for great profit. Still others learn how to be more skillful in seeking the hidden ore, using science and technology to both find it and refine it. We are clearly in this phase at the present time in ECG research. In this symposium, we see the results of some of this research. The use of controlled clinical trials, with computerized data bases, as a technique for comparing a patient with him or herself some years earlier, and/or controlling for many conditions in between, is being used effectively in determining the risk of certain ECG findings. These techniques are also being effectively used in comparing the effects of one medication to others in reversing ECG changes related to hypertension, and other forms of right or left ventricular overload. Basic animal studies are being used to examine the effects of hypertension and hypertrophy on the action potential in various layers of the myocardium, perhaps leading to the understanding and future use of the ventricular gradient as a ☆
Funding and conflicts: This manuscript received no funding support. The author is aware of no conflicts of interest in the preparation of this manuscript. http://dx.doi.org/10.1016/j.jelectrocard.2014.06.008 0022-0736/© 2014 Elsevier Inc. All rights reserved.
clinical prognostic tool. There are many other examples. Look for them! Instead of looking back, I would like to look ahead. I claim no special skill in sniffing out territory laden with gold nuggets, but would like to speculate on areas in which I would buy land and try my mining skills. The first is in genetics and heart disease. We already have some notable nugget finds. Mayosi [1] utilized genome-wide linkage analysis in families with ECG and Echo-defined LVH, and found that both have genetic signals, but not for the same chromosomal sites. These findings imply that while both the ECG and Echo based indicators are genetically derived, they are independent of each other. It is also of interest that the ECG defined “LVH” has stronger linkages than the Echo defined LVH. The time is ripe for greater utilization of these techniques. Families interested in their family tree now have access to less precise but still powerful methods for defining genetic linkages through commercial providers of genetic genealogy tools. Y chromosome analyses have been available for more than a decade, followed by maternal microsomal and now autosomal chromosomal methods. I am amazed at the ability of family groups to establish kinships over multiple generations, and to identify the precise family tree branch and chromosomal location of the connections. Families with a family history of sudden death, or cardiomyopathy, or premature coronary disease have both the interest and ability to work with interested medical investigators to explore the chromosomal locations and other linkages of hereditable cardiac problems, including ECG patterns and their evolution. The observation that certain drugs seem to induce reversal in the ECG manifestations of left ventricular hypertrophy, while others do not, seems to point us to another nugget laden territory worth exploring. Drugs blocking the renin angiotensin system (RAS) (ACE inhibitors and angiotensin II blockers) [2,3] seem to have a greater ability to reverse ECG findings, beyond the reduction of blood pressure. The RAS system has a well established role in inflammation, endothelial dysfunction, and plaque formation. Could this be part of the linkage between ECG findings seen with hypertensive left ventricular hypertrophy and increased mass? Could ECG-LVH be related to endothelial dysfunction rather than myocardial mass? These linkages usually have genetic and lifestyle components as well, and will probably be difficult to unravel, but well worth the effort! Animal studies could be extremely useful in hypothesis creation and testing prior to testing in human populations.
594
Editorial
Another area in which nuggets have already been found is in the creation and use of planned data bases, designed for maximum utility in analyzing information over time. The MESA data base is one example which is already in full use, and one of its outcomes is included in this symposium [4]. This data base is chosen as an example, because it includes the use of digitized data, recorded with technical standards higher than those generally used for ECG records. The standards generally used for ECG recording in hospitals and physician offices make it difficult or impossible to utilize them in comparisons over time. The frequency response of the galvanometer must be higher than the clinical standard, leads must be simultaneously recorded, and the record must be in digital form and available for automated analyses. The shocking revelation in the above manuscript [4] that electrode placement alone can cause an amplitude variation in the 15–20% range, is enough to require that this source of error must be minimized by careful training of recording personnel. The MESA data base, once again, points the way. It is designed to be used by multiple users, utilizing a breadth of subjects, diversity of data, and an invitation to any investigator with a clear hypothesis to use the data, subject to approval by a panel of experts. The care in recording and storing data makes it relatively easy to use advanced signal processing methods. Once established, these data bases must be fully utilized to justify the high cost of gathering, storage, and use of this complex information. At the present time, many cardiovascular studies are being carried out in clinical settings in which other parameters, such as Echo or MRI, are being measured. It is important that ECG records be recorded alongside these records of other diagnostic modalities, and that these ECGs be digitally recorded with high technical quality and with multiple simultaneous leads. These technical standards will make possible the cross correlation of
information from multiple sources. As with population based data sets, these interdisciplinary and intermethodologic clinical data sets should be shared, among investigators, institutions, across national boundaries, etc. They are so difficult to obtain and expensive to maintain, they should be viewed as national and international resources, and made available to all qualified investigators. I would like to return to a point made at the beginning of this editorial. The patient and the clinician attempting to guide this patient to a favorable outcome are the beneficiaries of our efforts. If we could break the code, the ECG could be the Rosetta stone, enabling us to better understand and predict the future. As always, this requires hard work, careful thought and planning, and a lot of luck, but the odds have never been better for another gold rush! E. Harvey Estes, MD Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA References [1] Mayosi BM, Avery PJ, Farrall M, Keavney B, Watkins H. Genome-wide linkage analysis of electrocardiographic and echocardiographic left ventricular hypertrophy in families with hypertension. Eur Heart J 2008;29:525–30. [2] Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction – A LIFE review. J Electrocardiol 2014;45:630–5 [in this issue]. [3] Verdecchia P, Gentile G, Angeli F, Reboldi G. Evidence for cardiovascular, cerebrovascular, and renal protective effects of reninangiotensin system blockers. Ther Adv Cardiovasc Dis 2012;6:81–9. [4] Rautaharju PM, Soliman EZ. Electrocardiographic left ventricular hypertrophy and the risk of adverse cardiovascular events: a critical appraisal. J Electrocardiol 2014;45:649–54 [in this issue].
ScienceDirect Journal of Electrocardiology 47 (2014) 593 – 594 www.jecgonline.com
Editorial
A New Gold Rush? The Future in ECG Research☆ To be invited to provide a perspective on “the ventricular hypertrophies”, based mostly on having lived through most of the significant work on this problem, is quite a challenge. It is true that I began reading electrocardiograms (ECGs) when my teaching hospital, Grady Hospital in Atlanta, had a single Cambridge string galvanometer recording device, producing a photographic record requiring a darkroom and developing tanks. I was mentored by Robert Grant, who had no laboratory, no staff, and no research budget. His equipment was his fertile brain, able to visualize events spatially and relate this to clinical events and patients, and, from this, synthesize a whole conceptual strategy for interpretation of the ECG. (Grant was also a sculptor.) Yes, many of his generalizations have needed tweaking over the years, but the validity of the basic framework still holds together remarkably well. The pity is that Grant's technique of recognizing an unusual ECG, going to the bedside, talking with and examining the patient, learning about the family history, and trying to fit the whole thing into his basic scheme; is seldom used. My other mentor, Eugene Stead, often compared medical research to “mining gold”. Some investigators have the unique ability to find gold when others have searched and failed to find it, but often, in the real world, someone accidentally “stubs their toe” on a big nugget, resulting in a new discovery. Others follow, profiting from his good luck, mining the area for great profit. Still others learn how to be more skillful in seeking the hidden ore, using science and technology to both find it and refine it. We are clearly in this phase at the present time in ECG research. In this symposium, we see the results of some of this research. The use of controlled clinical trials, with computerized data bases, as a technique for comparing a patient with him or herself some years earlier, and/or controlling for many conditions in between, is being used effectively in determining the risk of certain ECG findings. These techniques are also being effectively used in comparing the effects of one medication to others in reversing ECG changes related to hypertension, and other forms of right or left ventricular overload. Basic animal studies are being used to examine the effects of hypertension and hypertrophy on the action potential in various layers of the myocardium, perhaps leading to the understanding and future use of the ventricular gradient as a ☆
Funding and conflicts: This manuscript received no funding support. The author is aware of no conflicts of interest in the preparation of this manuscript. http://dx.doi.org/10.1016/j.jelectrocard.2014.06.008 0022-0736/© 2014 Elsevier Inc. All rights reserved.
clinical prognostic tool. There are many other examples. Look for them! Instead of looking back, I would like to look ahead. I claim no special skill in sniffing out territory laden with gold nuggets, but would like to speculate on areas in which I would buy land and try my mining skills. The first is in genetics and heart disease. We already have some notable nugget finds. Mayosi [1] utilized genome-wide linkage analysis in families with ECG and Echo-defined LVH, and found that both have genetic signals, but not for the same chromosomal sites. These findings imply that while both the ECG and Echo based indicators are genetically derived, they are independent of each other. It is also of interest that the ECG defined “LVH” has stronger linkages than the Echo defined LVH. The time is ripe for greater utilization of these techniques. Families interested in their family tree now have access to less precise but still powerful methods for defining genetic linkages through commercial providers of genetic genealogy tools. Y chromosome analyses have been available for more than a decade, followed by maternal microsomal and now autosomal chromosomal methods. I am amazed at the ability of family groups to establish kinships over multiple generations, and to identify the precise family tree branch and chromosomal location of the connections. Families with a family history of sudden death, or cardiomyopathy, or premature coronary disease have both the interest and ability to work with interested medical investigators to explore the chromosomal locations and other linkages of hereditable cardiac problems, including ECG patterns and their evolution. The observation that certain drugs seem to induce reversal in the ECG manifestations of left ventricular hypertrophy, while others do not, seems to point us to another nugget laden territory worth exploring. Drugs blocking the renin angiotensin system (RAS) (ACE inhibitors and angiotensin II blockers) [2,3] seem to have a greater ability to reverse ECG findings, beyond the reduction of blood pressure. The RAS system has a well established role in inflammation, endothelial dysfunction, and plaque formation. Could this be part of the linkage between ECG findings seen with hypertensive left ventricular hypertrophy and increased mass? Could ECG-LVH be related to endothelial dysfunction rather than myocardial mass? These linkages usually have genetic and lifestyle components as well, and will probably be difficult to unravel, but well worth the effort! Animal studies could be extremely useful in hypothesis creation and testing prior to testing in human populations.
594
Editorial
Another area in which nuggets have already been found is in the creation and use of planned data bases, designed for maximum utility in analyzing information over time. The MESA data base is one example which is already in full use, and one of its outcomes is included in this symposium [4]. This data base is chosen as an example, because it includes the use of digitized data, recorded with technical standards higher than those generally used for ECG records. The standards generally used for ECG recording in hospitals and physician offices make it difficult or impossible to utilize them in comparisons over time. The frequency response of the galvanometer must be higher than the clinical standard, leads must be simultaneously recorded, and the record must be in digital form and available for automated analyses. The shocking revelation in the above manuscript [4] that electrode placement alone can cause an amplitude variation in the 15–20% range, is enough to require that this source of error must be minimized by careful training of recording personnel. The MESA data base, once again, points the way. It is designed to be used by multiple users, utilizing a breadth of subjects, diversity of data, and an invitation to any investigator with a clear hypothesis to use the data, subject to approval by a panel of experts. The care in recording and storing data makes it relatively easy to use advanced signal processing methods. Once established, these data bases must be fully utilized to justify the high cost of gathering, storage, and use of this complex information. At the present time, many cardiovascular studies are being carried out in clinical settings in which other parameters, such as Echo or MRI, are being measured. It is important that ECG records be recorded alongside these records of other diagnostic modalities, and that these ECGs be digitally recorded with high technical quality and with multiple simultaneous leads. These technical standards will make possible the cross correlation of
information from multiple sources. As with population based data sets, these interdisciplinary and intermethodologic clinical data sets should be shared, among investigators, institutions, across national boundaries, etc. They are so difficult to obtain and expensive to maintain, they should be viewed as national and international resources, and made available to all qualified investigators. I would like to return to a point made at the beginning of this editorial. The patient and the clinician attempting to guide this patient to a favorable outcome are the beneficiaries of our efforts. If we could break the code, the ECG could be the Rosetta stone, enabling us to better understand and predict the future. As always, this requires hard work, careful thought and planning, and a lot of luck, but the odds have never been better for another gold rush! E. Harvey Estes, MD Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA References [1] Mayosi BM, Avery PJ, Farrall M, Keavney B, Watkins H. Genome-wide linkage analysis of electrocardiographic and echocardiographic left ventricular hypertrophy in families with hypertension. Eur Heart J 2008;29:525–30. [2] Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction – A LIFE review. J Electrocardiol 2014;45:630–5 [in this issue]. [3] Verdecchia P, Gentile G, Angeli F, Reboldi G. Evidence for cardiovascular, cerebrovascular, and renal protective effects of reninangiotensin system blockers. Ther Adv Cardiovasc Dis 2012;6:81–9. [4] Rautaharju PM, Soliman EZ. Electrocardiographic left ventricular hypertrophy and the risk of adverse cardiovascular events: a critical appraisal. J Electrocardiol 2014;45:649–54 [in this issue].
