Abstract
This month, The Journal of Clinical Hypertension features a hypertension icon from outside of the United States. Professor Alberto Zanchetti of Milan, Italy has been one of the most prominent researchers and teachers in the field of hypertension in Europe for the past 40 years. Those of us who have attended the European or International Society of Hypertension meetings have marveled at his energy, breadth of knowledge, and his ability to translate science into clinical practice. He has been in the forefront of new drug research for many years and has chaired or participated in almost all of the guideline committees in Europe that have set policy and established hypertension treatment recommendations. My own memories of Alberto conjure images of a man who truly had influence, not only in medicine, but in the outside world as well. Professor Zanchetti delayed a TWA flight from Milan to New York when I was late in arriving at the airport. He convinced La Scala to present an unscheduled opera for attendees at the European Society of Hypertension in Milan. That gives a picture of the man who gets things done. For these gracious acts, and for his enormous positive influence on generations of physicians not only in Europe, but also around the world, we salute him as one of the icons in hypertension.
DR. MOSER: Alberto, you and I go back a long way, to the time when you were first involved in the International Society of Hypertension (ISH) and the European Hypertension Society meetings in Milan. You have had a distinguished career in hypertension from the very beginning of modern therapy. Tell me a little bit about how you got started. Was it something you were interested in at the beginning of your career or were you primarily interested in physiology or pharmacology?
DR. ZANCHETTI: I started in physiology and was most interested in the neural control of blood pressure (BP). When I joined Professor Bartorelli's group, which was active in the hypertension area, I became interested in studying the neural mechanisms of hypertension.
DR. MOSER: Bartorelli was one of the leading hypertension experts in Italy and Europe. What years were those?
DR. ZANCHETTI: The late 1950s. These were times when little could be done except diagnosing hypertension, so we spent most of our time on pathophysiology concerns.
DR. MOSER: Were they still doing sympathectomies in Italy at that time? DR. ZANCHETTI: No, not very much.
DR. MOSER: But data from these radical procedures established the rationale for medication that blocked the sympathetic nervous system. So, you originally worked with hexamethonium.
DR. ZANCHETTI: Yes, and then with mecamylamine and other ganglion blockers. This approach was consistent with our interest in sympathetic control of BP. We treated severely ill patients and management was difficult. Patients had severe hypertension when lying down and severe hypotension when standing up. But survival was increased. Some of these patients would have died within a year or two. It was a very difficult clinical situation, that one can hardly understand now, when so many efficacious and well‐tolerated antihypertensive agents are available. I am proud that I am one of the few who have worked with practically all the various classes of agents that have made antihypertensive therapy so successful. Together with this continuing activity in the therapeutic area, I became more and more involved in studying the pathophysiology of hypertension. We did a lot of studies on baroreflexes in hypertension and studied the interaction between neural and renal factors in the control of BP. Most of these studies were done in the 60s, 70s, and 80s. When I gave the international lecture in 1977 at the American Heart Association, it was mostly on neural regulation of renin release and my Volhard Award lecture at the ISH meeting in 1986 was on interactions between neural and renal mechanisms in hypertension.
DR. MOSER: Perhaps we have gotten somewhat complacent in recent years because we have medications that seem to affect everything—the sympathetic system, sodium excretion, and the renin‐angiotensin system. But, we still have problems controlling many patients. For example, despite the availability of effective treatment, there is some difficulty in treating the elderly. When you decrease someone's systolic BP from 180 to 160 or so, they sometimes feel bad. Is that a baroreceptor problem? Should we wait a while and then increase dosages? How long does it take for “resetting,” and how long do we wait?
DR. ZANCHETTI: I think you need some time to get a new setting of the baroreceptors. This is why preaching that decreasing BP should be somewhat gradual is acceptable. But I also think that some data like the recent Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) study suggest that in particularly complicated patients, BP lowering should be less gradual. The VALUE study showed that better control in the first 3 months might help to reduce cardiovascular events.
DR. MOSER: Some of our colleagues are now saying that we should reduce BP very quickly in the elderly. I'm not sure what quickly means. Do we do this over 2 weeks or over a month or two? Can we really say how long it takes to reset baroreceptors? You're the expert, what do you think?
DR. ZANCHETTI: I think that baroreceptor resetting may take some time and, in elderly people with atherosclerosis, it is not as easy to influence baroreceptors as it is in the young. However, we should probably not wait too long. What should be avoided is a very quick decrease in BP in a matter of minutes or hours. I personally dislike the use of medications such as sublingual nitroglycerine or nifedipine in emergency rooms to reduce the pressure in a short time. We probably should aim at reducing BP within 2 to 3 weeks.
DR. MOSER: Your studies on baroreceptors certainly gave you a clinical feeling about what you can and cannot do.
DR. ZANCHETTI: Yes, it was an interesting area of research, and we also studied the action of different drugs and different clinical situations. The basic knowledge in physiology and pharmacology helps to guide therapy.
DR. MOSER: What other areas of hypertension did you investigate?
DR. ZANCHETTI: We did a lot on the diagnostic and therapeutic aspects of hypertension and tried to translate knowledge into practice. What we did initially, together with Giuseppe Mancia, was a lot of continuous BP measuring, initially by the intra‐arterial methodology. This was probably a first when Giuseppe and I demonstrated the existence of a white‐coat effect. In the 1980s, we showed that whenever a doctor entered the room, an increase in BP was noted; this was higher than BPs recorded during the day's activities when a doctor wasn't present. BP went up a little less with the nurse than the doctor.
DR. MOSER: You and Giuseppe certainly did a great deal of work in this area. How do you feel about the white‐coat syndrome? Should we do ambulatory monitoring on everybody, or should the casual pressures still be the BP that you use to determine risk and prognosis?
DR. ZANCHETTI: I am convinced that clinic or office BP is a fairly good guide for deciding about treatment in most patients. There are a number of patients where ambulatory BP monitoring is very useful, however. It is certainly useful in research, particularly if you want to make a close correlation between BP reduction and target organ involvement, but is not always necessary in the usual clinical practice. Office pressures can still be used to determine medications and dosages, and self‐measurement of BP at home has become a helpful complement for the physician's decisions.
DR. MOSER: What about all of the other important things you've done through the years. You have also been a premier educator in Italy and Europe. You highlighted clinical hypertension and the importance of treating hypertension in Europe and influenced many physicians. You deserve a lot of credit.
DR. ZANCHETTI: I was involved first with the ISH, of which I was President in 1978‐80, and together with Professor Bartorelli organized two of the early meetings in the 1970s. I also organized another ISH meeting in Milan in 1981. From that time on, we held European meetings every 2 years in Milan. This eventually gave rise to the European Society of Hypertension, and I was president of that society, as well.
DR. MOSER: I remember participating in the Milan meetings. You were a wonderful host on all occasions, including the time you arranged a special concert at La Scala for meeting attendees. Since 1995, you have been Editor in Chief of a superb hypertension journal, The Journal of Hypertension. Are you going to continue that for a while?
DR. ZANCHETTI: My present appointment expires in 2006, so it depends on the Society as to whether or not they want to change or continue.
DR. MOSER: Alberto, you have viewed the past. Where do you think we should be going in the future? Do you think we need more studies, more drugs, and a better approach to treatment? How would you increase the number of patients under control?
DR. ZANCHETTI: The major issue in treatment now is that while we have good recommendations for treating BP that are based on solid science, we still have not managed to control a great many patients. Recommendations from both sides of the ocean are to go below 140 mm Hg systolic, or even lower if possible, and in some complicated patients, to attempt goals even below 130 mm Hg. But even in the United States where doctors are somewhat more aggressive, only a certain percentage of hypertensive patients are achieving goal. We are not doing a great job. So this is the main issue for the future. Probably we insist too much in saying that goal is not being achieved because of lack of compliance on the part of the patient. We also blame the doctor for not following the guidelines strictly, and so on, but we neglect the fact that in many patients it is really difficult to lower systolic BP to below 140, especially in the elderly. Look at the clinical trials where specific protocols are followed. Even in the most recent trials, only about 60% of the patients achieved goal levels of below 140/90 mm Hg. It still is difficult to achieve goal pressures, particularly in complicated patients. So probably, we need either more effective drugs or finding or using better combinations to control patients. We should also remember that, for example, in the Hypertension Detection and Follow‐up Program and other trials, for the same BP control, morbidity and mortality remained higher in people in whom treatment was started when hypertension‐related complications had already occurred. Probably we need to start treatment earlier, before even moderate organ damage occurs. Although we can delay and sometimes reverse these changes even if treatment is delayed, we may not be able to completely reverse them.
DR. MOSER: You remember when the US guidelines were recommending that we should treat diastolic BPs of 90 instead of waiting until they reach 105 mm Hg or 110 mm Hg; some of the European countries were saying that this was too aggressive.
DR. ZANCHETTI: I think the 2003 European guidelines that I contributed to as chairman of the Writing Committee put a lot of emphasis on detection of early cardiovascular damage. This is probably important in deciding on treatment, particularly to use as a goal for reversal during hypertension treatment. Patient adherence is important, and physician adherence is extremely important, too. But, most important is the concept that we should start treatment earlier to prevent vascular damage, some of which may not be detected in a routine exam. We should insist that doctors comply with guidelines and stress patient compliance with doctors' recommendations. Experts and specialists should do more to educate the public because doctors may only spend a few minutes with each patient. This is another strong limitation to improving outcome. In spite of all that, even if all these things are corrected, I think we probably need earlier initiation of treatment for benefits of prevention.
DR. MOSER: European experts have moved more and more to the concept that the BP number rather than any particular drug makes the difference. It doesn't matter what medication you use except, perhaps, in diabetic nephropathy. In the United States, some investigators still believe that specific medications make a difference in determining outcome. For example, diuretics are recognized as initial therapy in most cases and other specific drugs with comorbidities like heart failure, nephropathy, etc. How do you stand on this? Do you think that it is the BP and not specific medications that make a difference?
DR. ZANCHETTI: I think that the lowering of BP is the most important mechanism. Whenever you lower BP, you get benefits. It is also likely that there are differences between different agents, but these are subtle differences that can hardly translate into morbidity or mortality differences during trials lasting 4 or 5 years. Differences may more easily be assessed by studying hypertension‐related organ damage instead, as different actions on left ventricular hypertrophy, carotid atherosclerosis, or microalbuminuria may translate into survival differences over a very long term. Furthermore, we should consider that all patients do not respond to the same drugs. We should find out the drug or drug combination that is most effective in lowering BP in each particular patient.
DR. MOSER: So combination therapy is here to stay?
DR. ZANCHETTI: I think that, in many cases, we should start hypertension therapy with combination therapy. You remember as well as I the Veterans Administration (VA) study that first showed the benefits of lowering BP. It used triple‐drug therapy, a combination that Ciba‐Geigy was marketing—reserpine, hydralazine, and hydrochlorothiazide—and it was very effective. Finally, we should look more and more at BP as a component of cardiovascular risk and more and more at treatment of all risk factors. Probably most important is lowering BP together with lowering serum lipids and smoking cessation. DR. MOSER: With this in mind, the American Society on Hypertension is looking into a new definition of hypertension as a metabolic disease. Thank you, Alberto. Your contributions to research and medical education have been significant. We all wish you good luck in the future.