Disease Updates and the Role of Genetics
Heart disease is still the number one cause of death in the United States, causing nearly one million heart attacks and more than half a million deaths each year. Prevention is, of course, critical — maintaining a healthy lifestyle through diet and exercise, and not smoking. But many other factors contribute to whether or not someone will develop heart disease, including hypertension, high cholesterol and genetics.
A group of Eisenhower Medical Center physicians recently sat down to discuss new data on hypertension, new anticoagulation medications for the treatment of high cholesterol, and the current and future role of genetics in cardiology. The participants were Eisenhower Cardiologists Leon Feldman, MD, Andrew Rubin, MD and Damon Kelsay, MD. Cardiologist Philip Shaver, MD moderated the discussion.
Our population is aging. It is estimated that 70 percent of health care will be directed to geriatric needs in the future. Between 1980 and 2009, the United States population age 65 and older increased from 25.6 million to 39.6 million. By 2040, it is estimated that we’ll have 75 million adults over the age of 65. Based on research, 60 percent of the population will have hypertension by age 60. By age 70, 65 percent of men and 75 percent of women have hypertension. Even those with normal blood pressure readings at age 55 have a 90 percent chance of becoming hypertensive during their lifetime. Dr. Rubin, based on what we’ve learned in recent years, how do you manage your patients?
Dr. Shaver: You’re talking about the Hypertension in the Very Elderly Trial (HYVET)?
Dr. Rubin: The most recent literature states that we may not need to treat the elderly differently, but our 2011 guidelines suggest that a reasonable blood pressure reading for an elderly person may be less than 150 rather than less than 140.
Dr. Shaver: The only data we really have on patients over 80 is the HYVET study. HYVET is interesting because the medications they used in that study were a diuretic and an ACE inhibitor. The study was done in several countries, however, not in the United States — the blood pressure goal was about 150. Dr. Feldman, do you have any different thoughts on this?
Dr. Feldman: I agree that we have been struggling to define what an ideal blood pressure is for an aging population. It is possible that seniors who have had high blood pressure for many years, may not benefit from following the same strict guidelines that have been applied to younger patients with cardiac risk factors such as diabetes. Overly aggressive blood pressure treatment may lead to falling and its complications like bone fractures or bleeding. I think we have to temper what we do with blood pressure control, realizing that there are consequences to multiple medical therapies. I want to emphasize that blood pressure control is much more than a single measurement during an office visit. Physicians use an average pressure over a longer time span.
Dr. Shaver: It’s interesting that the American Heart Association years ago told us how to take blood pressures. If we do it by the book, the patient should have been relaxed for five minutes, sitting with their feet firmly on the ground, their back supported and their arm resting on a table at heart level. I wonder how many people really take their blood pressure that way. Dr. Kelsay, if you have a patient who comes in, and you get a blood pressure reading of 160/80, and they say, “You know, doc, it’s you, it’s not me.” How much do you rely on home blood pressures or ambulatory (24-hour monitoring) blood pressure?
Dr. Kelsay: I do a lot of home blood pressure monitoring with proper instruction to the patients on how to take blood pressure at home. I think that’s key. I also ask patients to bring in their blood pressure monitoring device to check it against ours. And I make sure that we recheck their blood pressure after we know they’ve been resting and relaxing in the office. If I have to keep them an extra 30 minutes to relax, I routinely do that.
Dr. Feldman: I have to bring up one other point about this. The studies that have looked at the benefit of blood pressure control long-term used periodic readings, perhaps weeks or months between measurements. Sometimes I see patients who will measure their blood pressures two, three or four times daily with their lists in hand. To try to analyze what this means for their long-term care is difficult. Studies just don’t address that kind of frequency for blood pressure readings.
Dr. Feldman: I think we should educate patients in terms of high blood pressure as one cardiovascular risk factor, as part of the whole program. We want to control blood pressure, but we also want to address weight, nutrition, diabetes, activity, and tobacco use.
You can address all these factors to a certain degree by nonmedical therapy. By exercising regularly, losing weight, cutting back on salt and minimizing alcohol, then maybe the patient can avoid taking multiple medications.
Dr. Shaver: How responsive are your patients to lifestyle changes, Dr. Kelsay?
Dr. Kelsay: One of the compelling pieces of data comes from the Diabetes Prevention Program which shows that patients who do 150 minutes of exercise a week — 30 minutes, five days a week — have about a 50 percent cardiovascular risk reduction when coupled with seven percent weight loss based on their initial program enrollment weight. Regular exercise is a huge benefit which will motivate some people when they realize the amount of cardiovascular risk reduction benefit they can receive. But with our older population, exercise can sometimes be difficult because of orthopedic issues. It’s important to find exercises they can do, given their orthopedic limitations. So, I really do push exercise. There’s also about a 58 percent risk reduction from being prediabetic to having full-blown diabetes with 150 minutes of exercise a week and adhering to a healthy diet and weight loss program. It is also correlated with seven percent weight reduction in the total program, so it’s an exercise and weight loss program that achieves this substantial cardiovascular risk reduction.
Dr. Shaver: Salt intake is probably more important in our elderly patients than younger patients. One recommended amount of daily sodium is 1,500 milligrams but that’s very difficult to do. Getting down to 2,300 milligrams of salt per day will actually drop a patient’s systolic pressure — on average, eight points in elderly patients and only about four points in younger patients. So limiting salt intake to 2,300 milligrams or less is a very effective therapy. That may be one reason diuretics seem to be more effective in the elderly.
Dr. Kelsay: This also brings to mind the idea of the stiff artery hypothesis — which means relatively mild fluid balance fluctuations and intravascular volume causing significant pressure changes in an inelastic (stiff) artery. It no doubt has a significant effect on blood pressure. It is also a reason why the elderly are so prone to getting dehydration-related hypotension and that needs to be warned against. They need to avoid dehydration, which really accentuates the effects of the antihypertensives, resulting in hypotension (low blood pressure), dizziness, and an increase in falls.
Dr. Shaver: Let’s talk about cholesterol. Cardiovascular disease is the leading cause of death in the industrialized world and the prevention of cardiovascular disease seems undeniably linked to lowering the bad, or LDL, cholesterol. Does anyone disagree that statins are effective? Dr. Kelsay, what prevents your patients from taking statins?
Dr. Kelsay: Real or perceived intolerance.
Dr. Shaver: What kind of intolerance?
Dr. Kelsay: Often myopathic (muscular)-related — muscle aches and pains, things of that nature. It is surprising how many things can potentially be attributed to statins that quite possibly have very little to do with them.
Dr. Shaver: There’s actually a genetic basis for myopathicrelated reactions to statins. A couple of years ago, The New England Journal of Medicine reported on a genotype that is predisposed to that, but the big three complaints with statins are: 1. Do they cause cancer? 2. Do they cause cognitive impairment? 3. Do they cause diabetes? According to the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), it appears that there can be an increase in the incidence of diabetes.
Dr. Kelsay: I think the side effects of statins are overwhelmed by the benefits. I don’t think it’s a balanced trade-off. It’s clearly very beneficial to use statins, especially in an older population. Personally, I would not be dissuaded from using statins.
Dr. Rubin: The struggle comes from the primary prevention patient who has no overwhelming risk factors for vascular disease, yet comes in with elevated LDL or elevated total cholesterol, or low HDL (the good cholesterol). In that population of patients, you get the most resistance in trying to convince someone to start a statin early for its long-term protective effects. Even though it’s a low, low incidence of side effects, there are side effects to statin drugs. Also, people come in with their own particular philosophies about taking medication and whether there are other, more natural ways of protecting their long-term health.
Dr. Shaver: What do you do if you have someone who is experiencing muscle pain and no long wishes to take their medication, but you feel strongly that they should be on a statin as a secondary prevention?
Dr. Rubin: Just because they have muscle pains from one statin agent, assuming the pain is a result of the statin agent, doesn’t mean they’re going to necessarily develop the same side effect from a different statin agent. Frequently I’ll give them a different statin agent at a very low dosage and if tolerated, gradually raise the dosage and frequency. I’ll see what their response is in terms of muscle complaints, as well as LDL response, and increase the dosage over time, if allowed. So, I’ll try a different statin agent before I give up on statins.
Dr Feldman: I think we have been convinced as cardiologists, as well as in the general medical community, of the power of statin medications, both to lower LDL and to improve outcomes. This may occur by complex mechanisms beyond simply lowering cholesterol. When patients try multiple statin medications and find that they are not tolerable, we then move to different classes of agents. Obviously dietary intervention is important, but there are non-statin medications that can be effective, safe and well tolerated.
Dr. Shaver: Let’s move on to anticoagulants. The blood thinner warfarin has been the dominant anticoagulant for 58 years. In the last year, we’ve been introduced to a drug called dabigatran or Pradaxa®, and subsequently rivaroxaban or Xarelto®, and there’s one pending FDA approval called apixaban. So how does this change your practice, Dr. Rubin?
Dr. Rubin: Warfarin has been used for more than 50 years and has always been problematic because it has a narrow therapeutic window — meaning that there is a fine line between efficacy and toxicity. Drug interactions and food interactions can also be cumbersome on the patient. The most difficult aspect for the patient is the monitoring and getting to an office to take the blood test. Those issues have been the problems with warfarin.
How my practice has changed with the new anticoagulants is that if I have a patient who has had difficulty with warfarin, or is looking for something new, I’ll offer them one of the new anticoagulants. I haven’t switched all my patients — the new anticoagulants are only indicated for a subpopulation of patients who are on warfarin. It’s not indicated for patients with valve replacement, but it is indicated for atrial fibrillation not associated with significant valve disease. So for patients who are new and require anticoagulant for atrial fibrillation in the absence of significant valve disease, we’ll have a discussion about whether they want to take warfarin. The benefits are that it’s less expensive and has been used for more than 50 years. Or, the patient can try one of the newer anticoagulants which are much easier to take in terms of not needing to get your blood tested, less potential for interactions and most importantly to me, less risk of bleeding in the brain.
All blood thinners are going to cause bleeding. In some populations, newer anticoagulants may cause an increase in bleeding, especially in the elderly. But the lack of the intracerebral (brain) bleeding in these anticoagulants is the big plus. The fact that there is no reversal agent and that they’re new are problems for some people. But warfarin doesn’t really have a true immediate reversal agent as well. For my patients who are new to an anticoagulant for atrial fibrillation, I discuss the positives and negatives of the new anticoagulants. I don’t change those who are on warfarin unless there’s been a problem or they voice a willingness to change.
Dr. Shaver: I’d like to talk about genetics and coronary artery disease, and genetics in general. There are, in fact, 33 genes that have been found to be pertinent in predicting coronary artery disease. The one that is most commonly described, the 9p21 gene, is the one I most often hear quoted at meetings and interestingly, correlates with coronary calcification, but not acute infarctions (heart attacks). And so, I see this as a great opportunity. We know that 23 genes of the 33 known genes are unrelated to high blood pressure and high cholesterol which are the major risk factors for coronary artery disease. To me, that gets into the group of patients who have stopped smoking, who have control of their blood pressure and cholesterol, but remain at risk. Our best therapies at this time reduce the risk of heart attacks by 40 percent. The 60 percent of those still at risk is where the 23 genes are going to be important — for example, showing risk separate from our known risk factors. That is where the research is going to take us.
Eventually, we will base certain medication prescriptions on whether or not someone metabolizes medications quickly, based on their genetics. Genetics is fascinating research and will eventually bear great fruit.
There are more applications for genetics in electrophysiology. It is now applicable in hypertrophic cardiomyopathy for detecting family members who may not express the phenotype but who are at high risk. There are abnormalities in the electrocardiogram which predict sudden death that are genetically determined, like the Long QT syndrome (a heart rhythm disorder that can potentially cause fast, chaotic heartbeats). Testing young relatives of these patients may detect those at high risk.
Dr. Feldman: I think the field of electrophysiology has been at the forefront of analyzing the genetics of ion channels for this small but important group of diseases that can lead to life-threatening heart rhythm abnormalities. The presentation of these diseases can be dramatic, with fainting or even death. The research is critically important both for the affected patients and their families, which may be similarly at risk.
The classic example is the Long QT syndrome where abnormal genes lead to impaired potassium movement within cells. This puts the patient at high risk for dangerous arrhythmias.
Ten years ago, genetic testing was limited to being a research tool at a university hospital. Now, when I evaluate a patient (or family member of a patient) who suffered a cardiac arrest, a genetic panel can be ordered with relative ease. It has been a tremendous advance.
Dr. Rubin: Genetic research is locally conducted on Eisenhower’s campus at the nonprofit Genetic Research Institute of the Desert, which was established in 2003 by the late Dr. Lawrence A. Cone. Over the years it has provided a number of publications, posters and abstracts internationally, beginning with research about why certain patients with AIDS responded to certain drugs while other patients had a different response. They’ve also studied breast cancer response to therapy, multiple sclerosis and more recently, prostate cancer and melanoma. This research is great for the desert because it’s a basic science and real research. It has also been a great opportunity for high school students and local college students to learn the basics of research and genetics.
Dr. Shaver: The Cleveland Clinic Medical Journal had a review article on genetic counselors, and who needs their expertise. This is an interesting specialty. These counselors are trained at a master’s degree level and must take a certifying exam. According to the article, there are now 4,000 genetic counselors in this country.
Dr. Rubin: There is such potential for genetics in medicine. But even though we know a lot about genetics, there is so much more we don’t yet know. I think genetics is a great field for students who are going to college who have an interest in science. We will learn much more in the coming years of how to integrate genetics into patient care.
Dr. Kelsay: The most recent College of Cardiology Self-Assessment Program has a section on genetics which says that the primary emphasis for genetic research and testing is that we use it for identifying those family members with high-risk disease processes (for example, hypertrophic cardiomyopathy and Long QT syndrome). But there hasn’t been any strong push for studying the genetic links of coronary artery disease in individuals, because the disease process is complex (multifactural). There are so many different factors, and to my knowledge, the cost [of genetic testing] hasn’t come down to the point where it’s as routine as having a blood chemistry panel done.