A Free-Ranging Roundtable Discussion on Hypertension
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Journal of Human Hypertension (2005) 19, 259–266 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh COMMENTARY A free-ranging roundtable discussion on hypertension JB Standridge, JE Sealey, JH Laragh, MC Houston, H Gavras, RJ Johnson, JD Blumenfeld, M Brown, BM Egan, JI Meltzer, T Shimosawa and T Fujita Family Medicine, University of Tennessee College of Medicine, Chattanooga, TN, USA Journal of Human Hypertension (2005) 19, 259–266. doi:10.1038/sj.jhh.1001811 Published online 17 February 2005 Tokyo, Japan. The following is not verbatim but instead represents a summary of key points made over a 3-h dinner discussion. John Laragh, MD, is Professor of Medicine in Cardiothoracic Surgery and Director of the Cardio- vascular Center at New York Presbyterian Hospital, Weill Medical College, Cornell University. He served for 22 years concurrently as chief of the division of cardiology. Both scientist and clinician, Dr Laragh has published nearly 1000 scientific articles that describe his discoveries and insights. In 1986, he founded the American Society of Hypertension, becoming its first president and founded the American Journal of Hypertension serving as its editor in chief. Dr Laragh: Why don’t we go around the table and let everyone say some things about the work they are During the Nineteenth Annual Scientific Meeting of doing and the particular aspects of hypertension the American Society of Hypertension in New York, they are interested in at this time. We have a very NY, on May 20, 2004, a gathering of international wide ranging group of hypertension experts as- hypertension experts was convened to discuss far- sembled here tonight, and I think that everyone reaching aspects of researching and managing will be excited to learn what areas are of interest to hypertension. Dr John Laragh of Cornell University, each of our participants. Why don’t we start with New York, NY, USA; presided. Additional partici- Jean Sealey? pants were, in order of participation, Jean E Sealey, DSc, New York, NY, USA; Mark C Houston, MD, Jean E Sealey, DSc, is Research Professor Emeritus of Nashville, TN, USA; Haralambos Gavras, MD, Medicine in Physiology & Biophysics, Weill Medical Boston, MA, USA; Richard J Johnson MD, Gaines- College of Cornell University. ville, FL, USA; Jon D Blumenfeld, MD, New York, NY, USA; Morris Brown, MD, Cambridge, England; Dr Sealey: My primary professional interest is to John B Standridge, MD, Chattanooga, TN, USA; explain to medical practitioners how and why the Brent M Egan, MD, Charleston, SC, USA; Jay I plasma renin test is an invaluable tool for the Meltzer, MD, New York, NY, USA; Tatsuo Shimosa- diagnosis and treatment of their hypertensive wa, MD, PhD, Tokyo, Japan; Hans R Brunner, MD, patients—because it discriminates the patient Lausanne, Switzerland; and Toshiro Fujita, MD, whose hypertension is caused by excessive volume expansion (renin suppressed) from one whose hypertension is caused by excess renin (renin not Correspondence: Dr JB Standridge, Family Medicine, University of suppressed). Tennessee College of Medicine, 1100 E. 3rd Street, Chattanooga, TN 37403, USA. In an untreated hypertensive patient, a suppressed E-mail: [email protected] plasma renin test reveals that this patient’s hyperten- Published online 17 February 2005 sion is caused by excessive sodium retention and ASH hypertension roundtable JB Standridge et al 260 volume expansion (PRA less than 0.65 ng/ml/h; the National Vital Statistics Registry and the Direct Renin less than 5 mU/ml). We call this a ‘V’ concurrent rise in ESRD based on the USRDS annual patient. In contrast a plasma renin test that is not data reports from 1980 to 1998. Annual increases in suppressed (PRA greater than 0.65 ng/ml/h; Direct diuretic expenditure and distribution are associated Renin greater than 5 mU/ml) reveals that the hyper- with increases in ESRD incidence rate growth 2 tension is caused by too much renin for the level of years later. Decreases in diuretic distribution are blood pressure. We call this an ‘R’ patient. The renin associated with reductions in ESRD incidence test identifies V and R patients each of whom growth 2 years later. The predominant diuretics responds differently to V or R antihypertensive used were HCTZ and furosemide. drugs. The blood pressure of V patients responds A statistically significant (P ¼ 0.03) direct linear best to V drugs—diuretics, aldosterone receptor association between changes in diuretic distribution antagonists and calcium channel blockers. The and subsequent changes in the growth rate of ESRD blood pressure of R patients responds best to exists. The beneficial effects of diuretics related to antirenin system R drugs—ACE inhibitors, angio- CHF, CVA and, to a lesser extent, CHD may tensin receptor blockers and b-blockers. Moreover, a simultaneously be either permissive of nephrotoxi- primary R drug is only a placebo in a V patient while city or directly nephrotoxic. a primary V drug in an R patient raises plasma renin Published hypertension trials and surveys, such levels even higher and may even worsen the as EWPHE, HEP, STOP, NHANES III survey, Syst- hypertension. EUR, SHEP, INSIGHT and ALLHAT, have indepen- However, more than that, the renin test leads to dently demonstrated this. Possible mechanisms for a logical approach for the treatment of patients renal injury with chronic diuretic therapy include already taking antihypertensive drugs who are glomerulosclerosis with glomerular capillary hyper- seemingly unresponsive. There are only two reasons tension, mesangial matrix expansion, mesangial for resistance to antihypertensive drugs: (i) exces- hypercellularity, dyslipidaemia, hyperglycaemia, sive volume expansion: that patient’s plasma renin hyperuricaemia and increased intrarenal oxidative is suppressed—patient needs more volume deple- stress. tion and doesn’t need R drugs. (ii) Excessive salt Diuretic therapy stimulates growth-promoting, depletion: renin very high (46.5 ng/ml/h)—this profibrotic or proinflammatory mediators such as patient’s lively renin secretion has over-reacted to homocysteine, PAI-1, PDGF, LDL-cholesterol, aldos- diuretics, raising renin even higher and in so doing terone, endothelin and angiotensin II levels, TGF-b, preventing blood pressure from falling. Such pa- TNF-a and COX-2. tients need to cut back on the diuretics and use only Calcium channel blockers (CCBs), ACE inhibitors R drugs instead. (ACEIs) and angiotensin receptor blockers (ARBs) By understanding of how the renin system works, have shown renal protective effects and slowing and by measuring plasma renin levels, deciding on of the development of glomerulosclerosis while the best antihypertensive treatment strategy is as achieving the same magnitude of blood pressure easy as falling off a log! reduction seen with HCTZ therapy. NHANES III survey noted an increased prevalence Dr Laragh: This is certainly an apropos summary of elevated creatinine in patients receiving diuretics of the work Jean and I, and many others, have been for hypertension compared to those receiving any engaged in for the last 50 years. We have published other antihypertensive medication category. over 900 articles on the topic of renin and In addition, exposure to thiazide diuretics has hypertension and believe that this approach is been epidemiologically linked to an increased risk mechanistically correct. The holy grail would be to for the development of renal cell carcinoma, and in control the majority of individuals with elevated patients with congestive heart failure, the mortality blood pressure with one drug, based on whether is higher in those receiving chronic diuretic therapy they are a V or an R patient. than in patients not receiving long-term diuretic Well, let’s move on around the table. Next to Jean therapy. Since diuretic acquisition cost is relatively is seated Dr Mark Houston, who has done some inexpensive, superficial analysis might suggest that fascinating work associating chronic diuretic use diuretic therapy is more ‘cost-effective’ than alter- and the increasing prevalence of chronic renal native therapies. However, the economy of low failure in the US. Mark? acquisition cost is negated by concomitant expenses of treating the iatrogenic chronic complications Mark C Houston, MD, SCH, FACP, is Clinical (new onset diabetes, dyslipidaemia, gout, hypoka- Professor of Medicine, Vanderbilt University Medi- laemia, renal carcinoma, ESRD). cal School, and Director, Hypertension Institute, St Thomas Hospital, Nashville, TN, USA. Dr Laragh: Thank you, Mark. This is very impor- tant work indeed, and we need to get the word out to Dr Houston: A highly significant inverse relation- practitioners who, under the influence of govern- ship exists between the decline in age-adjusted ment-sponsored guidelines, are still in the ‘diuretics cardiovascular disease mortality in the US based on first’ camp. Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 261 Now we come to my long-time friend and work is being carried out in this area other than colleague, Dr Harry Gavras. Harry is the current myocardial perfusion imaging. president of the American Society of Hypertension. It helps to predict hypertension if we understand His lovely wife, Irene, who is a physician, scientist, the genomics. A lot of work has been performed and scholar, joins us as well. Harry, what are you with some early enthusiasm, but these things take thinking these days? time. With regard to the diagnosis of monogenic disorders, we have four or five genes that increase Irene Gavras, MD, is a Professor of Medicine at blood pressure—prototypes to see how these geno- Boston University School of Medicine and attending types misbehave in some rare families—but these physician at Boston Medical Center. Haralambos results have not yet shed light on the causes of Gavras, MD, is a Professor of Medicine at Boston essential hypertension, which results from interac- University School of Medicine, Chief of Hyperten- tion of genes with environment.