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Theme I: genetic animal models in hypertension: where do things stand and where are they going?
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AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
A S H XIV ABSTRACTS
T h u r s d a y , M a y 20, B r o a d w a y B a l l r o o m N o r t h , 1:30 P M T h e m e II: H y p e r t e n s i o n , D r u g s , C a n c e r a n d Clinical Issues CALCIUM CHANNEL BLOCKERS AND CANCER. P. Hamet*, Research Centre, Centre hospitalier de rUniversite de Montreal (CHUM), Montreal, Quebec, Canada Almost two years ago, the Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension published its opinion on the effects of calcium antagonists on the risks of cancer and other conditions. This group opinion however did not put at the rest the debate in the literature and among the medical public. This (~unresolvedissue)) can be traced back through the evolution of antihypertensive therapy, as many agents have been related in retrospective studies with the increased cancer incidence (J Hypertens 15:105-115, 1996; Hypertension 28(3):321-324, 1996). There are, unfortunately, no significant prospective studies concerning cancer and incidence and hypertension, which could exclude or include the relationship. However, there are several epidemiological data that suggest some, although modest, risk factors for hypertension itself. Hopefully, definite data will come from the large prospective trials comparing multiple classes of antihypertensive medication. Retrospective studies, which have suggested that calcium antagonists are a risk factor for cancer development, have also evoked potential of their biological mechanism. Usually, it is the inhibition of the apoptotic process, an essential event for cellular turnover. Although chronic data are not available at the present time, the published experimental evidence actually opposes this view, as it appears that calcium antagonists promote an early window ot apoptosis, tollowed by a decrease of DNA synthesis in cardiovascular target organs, actually similarly to converting-enzyme inhibitors and angiotensin II antagonists (Hypertension 29[part 2]:340-349, 1997). Therefore, a possibility remains that the apparent risk factor of calcium antagonists is a consequence of indication bias, certainly if hypertension would be in itself a risk factor for cancer development. Both questions, i.e., the potential that hypertension constitutes a risk factor for cancer development itself and/or long term safety of antihypertensive agents as modulators of proliferative disorder will however require our continuous attention until the issue is solved. Key Words: cancer, calcium channel blockers, hypertension
T h u r s d a y , M a y 20, A s t o r B a l l r o o m , 5:00 P M T h e m e I: G e n e t i c A n i m a l M o d e l s i n
Hypertension: Where D o T h i n g s Stand and Where Are They Going?
T h u r s d a y , M a y 20, B r o a d w a y B a l l r o o m N o r t h , 5:00 P M T h e m e II: N e w D r u g s
Pulse Pressure StanleyS. Franklin,M.D., Universityof California,lrvine The significance of diastolic (DBP), Systolic (DBP) and pulse pressure (PP) as hypertensive cardiovascular risk factors has been controversial. There are problems with the present guidelines, in that SBP and DBP only represent two inflection points on the propagated pulse wave that is measured at the brachial artery. The heart is exposed to the central aortic pressure--not to the brachial artery pressure. Moreover, both peripheral vascular resistance and large artery stiffness contribute to hypertensive cardiovascular risk. In the young, both SBP and DBP are good surrogate measurements of resistance. In middle-aged and elderly, elevated SBP is a better surrogate measurement of resistance than DBP, but SBP underestimates large artery stiffness. PP, the difference between peak SBP and end DBP, is the single best blood pressure surrogate for large artery stiffhess. Epidemiological studies over the past decade point to SBP and DBP as the best cardiovascular risk markers for young subjects, whereas PP takes over as the more powerful risk marker for middle-aged and elderly subjects. These findings support the concept that cardiovascular events are more related to the pulsatile stress of large artery stiffness during systole than the steady-state stress of small vessel resistance during diastole. Therefore, at similar elevations of SBP, middle-aged and older subjects with isolated systolic hypertension are at greater risk for cardiovascular events than those with combined systolic/diastolic hypertension. Key Words: blood pressure, pulse pressure, hypertension, aging, epidemiology T h u r s d a y , M a y 20, A s t o r B a l l r o o m , 5:00 P M T h e m e I: G e n e t i c A n i m a l M o d e l s i n Hypertension: Where D o T h i n g s Stand and Where Are They Going?
Genetics of Experimental Hypertension: Future challenges and applications
GENETICS OF EXPERIMENTAL HYPERTENSION: CURRENT STATUS Anna F Dominiczak MD, Department of Medicine and Therapeutics, University of Glasgow, Scotland.
NJ Samani, Department of Cardiology, University of Leicester, Leicester, UK
The last decade has brought new molecular genetic tools which allowed us to map several quantitative trait loci (QTLs) responsible for blood pressure regulation and other cardiovascular, cerebro- vascular, renal and metabolic phenotypes in rodent models of hypertension Further confirmation and refinement of individual QTLs have been achieved using traditional and "speed" congenic strategies, the latter being based on marker-assisted breeding protocols. Moreover, several groups have translated the information obtained in experimental studies to facilitate the quest for genetic determinants of human essential hypertension. Of these strategies, the most important appears to be the method of homology mapping which uses the available information on syntenic groups of genes and markers between rat, mouse and human and facilitates a direct translation of the QTLs from rat to man. It is now timely to use all these new genomic and phenotypic resources to move towards the positional cloning of susceptibility and severity genes in cardiovascular disease models.
In the last decade, the chromosomal locations of the major genes influencing blood pressure in the main genetic models of hypertension have been mapped. At the same time, elegant studies have identified important genetic contributions to other cardiovascular phenotypes such as stroke sensitivity and response to specific antihypertensive drugs. Although, the work illustrates the successful application of molecular techniques to the dissection of complex genetic traits, much further needs to be done. Specifically, the nature of the causative genes themselves still remain largely elusive. This is because mapping using co-segregation analysis is too imprecise to implicate a specific gene. This has greatly impeded the transfer of the data to man. Currently, individual loci are being isolated in congenic strains to facilitate physical mapping of causative genes. However, such positional cloning remains a major challenge. Further, since the phenotypes of interest are largely quantitative, ultimate proof that a particular mutation is responsible will require the development of new techniques for in vivo gene modification applicable to the rat. Identification of major genetic determinants of hypertension and related phenotypes, and elucidation of the mechanisms involved remain important goals, and the experimental models will continue to be valuable in achieving these. However, major hurdles remain to be overcome before the data can be applied with accuracy to man.
Key Words:
Candidate genes, genome wide scans, congenic strategies, positional cloning, homology mapping.
Key Words:
Genetics, Hypertension, Molecular Biology, Experimental models
AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
A S H XIV ABSTRACTS
T h u r s d a y , M a y 20, B r o a d w a y B a l l r o o m N o r t h , 1:30 P M T h e m e II: H y p e r t e n s i o n , D r u g s , C a n c e r a n d Clinical Issues CALCIUM CHANNEL BLOCKERS AND CANCER. P. Hamet*, Research Centre, Centre hospitalier de rUniversite de Montreal (CHUM), Montreal, Quebec, Canada Almost two years ago, the Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension published its opinion on the effects of calcium antagonists on the risks of cancer and other conditions. This group opinion however did not put at the rest the debate in the literature and among the medical public. This (~unresolvedissue)) can be traced back through the evolution of antihypertensive therapy, as many agents have been related in retrospective studies with the increased cancer incidence (J Hypertens 15:105-115, 1996; Hypertension 28(3):321-324, 1996). There are, unfortunately, no significant prospective studies concerning cancer and incidence and hypertension, which could exclude or include the relationship. However, there are several epidemiological data that suggest some, although modest, risk factors for hypertension itself. Hopefully, definite data will come from the large prospective trials comparing multiple classes of antihypertensive medication. Retrospective studies, which have suggested that calcium antagonists are a risk factor for cancer development, have also evoked potential of their biological mechanism. Usually, it is the inhibition of the apoptotic process, an essential event for cellular turnover. Although chronic data are not available at the present time, the published experimental evidence actually opposes this view, as it appears that calcium antagonists promote an early window ot apoptosis, tollowed by a decrease of DNA synthesis in cardiovascular target organs, actually similarly to converting-enzyme inhibitors and angiotensin II antagonists (Hypertension 29[part 2]:340-349, 1997). Therefore, a possibility remains that the apparent risk factor of calcium antagonists is a consequence of indication bias, certainly if hypertension would be in itself a risk factor for cancer development. Both questions, i.e., the potential that hypertension constitutes a risk factor for cancer development itself and/or long term safety of antihypertensive agents as modulators of proliferative disorder will however require our continuous attention until the issue is solved. Key Words: cancer, calcium channel blockers, hypertension
T h u r s d a y , M a y 20, A s t o r B a l l r o o m , 5:00 P M T h e m e I: G e n e t i c A n i m a l M o d e l s i n
Hypertension: Where D o T h i n g s Stand and Where Are They Going?
T h u r s d a y , M a y 20, B r o a d w a y B a l l r o o m N o r t h , 5:00 P M T h e m e II: N e w D r u g s
Pulse Pressure StanleyS. Franklin,M.D., Universityof California,lrvine The significance of diastolic (DBP), Systolic (DBP) and pulse pressure (PP) as hypertensive cardiovascular risk factors has been controversial. There are problems with the present guidelines, in that SBP and DBP only represent two inflection points on the propagated pulse wave that is measured at the brachial artery. The heart is exposed to the central aortic pressure--not to the brachial artery pressure. Moreover, both peripheral vascular resistance and large artery stiffness contribute to hypertensive cardiovascular risk. In the young, both SBP and DBP are good surrogate measurements of resistance. In middle-aged and elderly, elevated SBP is a better surrogate measurement of resistance than DBP, but SBP underestimates large artery stiffness. PP, the difference between peak SBP and end DBP, is the single best blood pressure surrogate for large artery stiffhess. Epidemiological studies over the past decade point to SBP and DBP as the best cardiovascular risk markers for young subjects, whereas PP takes over as the more powerful risk marker for middle-aged and elderly subjects. These findings support the concept that cardiovascular events are more related to the pulsatile stress of large artery stiffness during systole than the steady-state stress of small vessel resistance during diastole. Therefore, at similar elevations of SBP, middle-aged and older subjects with isolated systolic hypertension are at greater risk for cardiovascular events than those with combined systolic/diastolic hypertension. Key Words: blood pressure, pulse pressure, hypertension, aging, epidemiology T h u r s d a y , M a y 20, A s t o r B a l l r o o m , 5:00 P M T h e m e I: G e n e t i c A n i m a l M o d e l s i n Hypertension: Where D o T h i n g s Stand and Where Are They Going?
Genetics of Experimental Hypertension: Future challenges and applications
GENETICS OF EXPERIMENTAL HYPERTENSION: CURRENT STATUS Anna F Dominiczak MD, Department of Medicine and Therapeutics, University of Glasgow, Scotland.
NJ Samani, Department of Cardiology, University of Leicester, Leicester, UK
The last decade has brought new molecular genetic tools which allowed us to map several quantitative trait loci (QTLs) responsible for blood pressure regulation and other cardiovascular, cerebro- vascular, renal and metabolic phenotypes in rodent models of hypertension Further confirmation and refinement of individual QTLs have been achieved using traditional and "speed" congenic strategies, the latter being based on marker-assisted breeding protocols. Moreover, several groups have translated the information obtained in experimental studies to facilitate the quest for genetic determinants of human essential hypertension. Of these strategies, the most important appears to be the method of homology mapping which uses the available information on syntenic groups of genes and markers between rat, mouse and human and facilitates a direct translation of the QTLs from rat to man. It is now timely to use all these new genomic and phenotypic resources to move towards the positional cloning of susceptibility and severity genes in cardiovascular disease models.
In the last decade, the chromosomal locations of the major genes influencing blood pressure in the main genetic models of hypertension have been mapped. At the same time, elegant studies have identified important genetic contributions to other cardiovascular phenotypes such as stroke sensitivity and response to specific antihypertensive drugs. Although, the work illustrates the successful application of molecular techniques to the dissection of complex genetic traits, much further needs to be done. Specifically, the nature of the causative genes themselves still remain largely elusive. This is because mapping using co-segregation analysis is too imprecise to implicate a specific gene. This has greatly impeded the transfer of the data to man. Currently, individual loci are being isolated in congenic strains to facilitate physical mapping of causative genes. However, such positional cloning remains a major challenge. Further, since the phenotypes of interest are largely quantitative, ultimate proof that a particular mutation is responsible will require the development of new techniques for in vivo gene modification applicable to the rat. Identification of major genetic determinants of hypertension and related phenotypes, and elucidation of the mechanisms involved remain important goals, and the experimental models will continue to be valuable in achieving these. However, major hurdles remain to be overcome before the data can be applied with accuracy to man.
Key Words:
Candidate genes, genome wide scans, congenic strategies, positional cloning, homology mapping.
Key Words:
Genetics, Hypertension, Molecular Biology, Experimental models