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The cause of mortality in patients with familial hypercholesterolaemia is actually complex
- Sergio Stagnaro (28 April 2001)
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Evidence that a high cholesterol does not cause atherosclerosis
- Uffe Ravnskov (30 April 2001)
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The rise and fall of heart disease
- Jörgen Vesti-Nielsen (30 April 2001)
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Familial Hypercholesterolaemia and Premature Coronary Heart Disease - The EARS Findings
- Denis St J O'Reilly (11 May 2001)
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Neuropathy from statins
- Elias Ragi (12 November 2001)
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Sergio Stagnaro, Specialist in Blood, Metabolic and Gastrointestinal Diseases Riva Trigoso (Genoa) Italy
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Sirs, The Authors underline a very interesting fact, we all have to consider with greatest attention: mortality due, for instance, to coronary artery disorders in population involved by familial hypercholesterolaemia is really more complex than generally admitted."Post hoc, ergo propter hoc"is not fortunately acceptable. We all must suggest a possible explanation in order to enlighten the complex pathophysology of coronary artery disease and prevent possibly its complication. To put my opinion must succinctly, I would tell you that in earlier papers I described a biophysical-semeiotic method, reliable as well as useful in bed-side diagnosis of ischaemic heart disease, even clinically silent and/or initial (1, 2) (See: http://digilander.iol.it/semeioticabiofisica). Biophysical Semeiotic allows the doctor to recognize early and promptly coronary ischaemic disorders, even if symptomless. In fact, the clinical phenomenology occurs after years or, more precisely, decades since the first vascular functional modifications (endothelial dysfunction, alteration of arterio-venous anastomosis, including endoarterial bloking devises) and structural lesions of heart macro- and micro-vessels (intimal thikening, smooth muscle cells proliferation, etc). Beside biophysical-semeiotic signs that are easy to recognize, a lot more technical parameters are described in my bibliography, which certainly facilitates the bed-side diagnosis of coronary disorders – silent, initial, not intense – that possibly are not detected by means of electrocardiography and independently by cholesterolaemia and other parameters that are well-known and generally recognised (prinicipal) risk factors. Of interest, from the above-mentioned research, initiated 55 years ago, an "arteriosclerotic constitution" can be recognised. Yours, Stagnaro Sergio MD
1.Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109 (1997) 2.Stagnaro-Neri M., Stagnaro S., Deterministic chaotic biological system: the microcirculatory bed. Theoretical and practical aspects. Gazz. Med. It. – Arch. Sc. Med. 153, 99 (1994) |
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Uffe Ravnskov Magle Stora Kyrkogata 9, S-22350, Lund
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The findings by Sijbrands et al1 that unselected individuals from a pedigree with familial hypercholesterolemia had a normal life span and a standard mortality close to one is further evidence that the LDL- hypothesis, the foundation of the cholesterol campaign, is wrong. Patients with familial hypercholesterolaemia usually have a total serum cholesterol around ten or even higher. Extrapolating from the data of the MR.FIT screenees2 a cholesterol value of that level is associated with a risk of coronary death that is at least ten times higher than in individuals with a low to normal cholesterol. The low standard mortality seen in the Dutch pedigree of individuals with familial hypercholesterolaemia is therefore best explained by a protective effect of a high cholesterol in this condition, for instance against infections, as suggested by the authors. This explanation is in accord with the idea that atherosclerosis has an infectious origin, but also with the fact that in many studies a high cholesterol in old people was associated with a low risk of coronary and total mortality. Why then is a high cholesterol a risk factor for coronary heart disease in individuals without familial hypercholesterolaemia? And why does coronary heart disease occur at a very young age in some individuals affected with this disease? In the first group the high cholesterol may be secondary to other, more important factors, such as lack of exercise, mental stress, smoking, and overweight, all of which are known to be associated with an elevated cholesterol.3 In the second, the deposition of cholesterol in the artery walls may, by genetic or environmental reasons,1 be more pronounced in some pedigrees. That a high cholesterol is a secondary phenomenon and not the very cause of atherosclerosis is in accord with other observations. For instance, there is no correlation between the serum cholesterol concentration and the degree of atherosclerosis seen at autopsy;3 there is no association between spontaneous or induced variations in the serum cholesterol concentration and atherosclerosis growth at angiography;3 a lowering of cholesterol by diet or non-statin drugs does not affect coronary or total mortality;3 and the protective effect of the statins is independent on the degree of cholesterol lowering, indicating that the statins exert their effect by other ways than by a lowering of the cholesterol concentration.3 It is time for a paradigm shift in atherosclerosis research. Uffe Ravnskov 1. Sijbrands EJG, Westendorp J, Defesche JC, de Meier PHEM, Smelt AHM, Kastelein JP. Mortality over two centuries in large pedigree with familial hyper cholesterolaemia: family tree mortality study. BMJ 2001;322:1019-1023 ( 28 April ). 2. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? JAMA 1986;256:2823-8. 3. Ravnskov U. The Cholesterol Myths. New Trends Publishing, Washington D.C. 2000. |
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Jörgen Vesti-Nielsen, Consultant Physician Dept. og medicine, Blekingesjukhuset, Karlshamn Sweden
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The Rise and Fall of Heart Disease The mortality from this study follows exactly the dramatic rise and fall of heart disease in the previous century. (1) It is of course clear that ‘cholesterol’ is unable to explain the epidemic pattern, since the rise was unparalleled by increases in fat consumption necessary to affect it. ( the increases would have to be truly enormous). Besides, to think that Cholesterol, an essential substance in our lives, suddenly, in the previous century should have become toxic, is nonsense. Such a hypothesis that the rise in heart disease should have been caused by increased fat consumption is crucified on the cross of biology. Our blood cholesterol is well protected by feedback mechanisms. Only truly momentous changes would affect it as every physician can observe every day in his own patients. And the fall in heart disease goes on just as it has for the last 35 years completely, it seems, unaware of the ‘scientifically proven’ fact that cholesterol is a killer.(2) Jörgen Vesti-Nielsen 1 R. E. Stallones, 'The Rise and Fall of Ischaemic heart Disease', Scientific American, 1980, vol. 243, pp. 43-9) 2 Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA Project populations, the Lancet 1999; 353: 1547-57. |
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Denis St J O'Reilly, Consultant Royal Infirmary , Glasgow .
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EDITOR - The study by Sijbrands and colleagues is a valuable contribution to our understanding of the natural history and clinical significance of Familial Hypercholesterolaemia (FH).1 Studies on FH are susceptible biase as the families are almost invariably identified when members present with coronary heart disease (CHD). The findings of the First and Second European Atherosclerosis Research Studies (EARS I and II) indicate that FH is not a significant factor in premature CHD. The EARS studies were established to investigate the importance and interaction of genetic and environmental factors in the development of atherosclerosis.2 In the EARS studies, University students between the ages of 18 and 26 years, whose fathers had proven CHD before the age of 55 years, were recruited from the local indigenous population attending 18 Universities throughout Europe. Age and sex-matched controls were recruited from the same populations for each case. Applying the Simon Broome Foundation criteria for the diagnosis of possible FH, ie a cholesterol >7.5 mmol/l,3 only 2 of 1089 students with a proven family history of paternal premature CHD and 4 of 1727 controls had FH. Thus, the prevalence of FH in both groups was not significantly different at approximately 1 in 500, which is the estimated prevalence of the condition in the general population. While it has been proven beyond reasonable doubt that hyperlipidaemia is a major risk factor for atherosclerosis and that reducing plasma lipid concentrations by lifestyle or drug treatment will delay or even reverse the development of atherosclerosis, the evidence that heterozygote FH is, of itself, a cause of atherosclerosis is unsatisfactory. Denis St.J O'Reilly, Laurence Tiret
ON BEHALF OF THE EARS GROUP CONFLICT OF INTEREST - NONE. 1 Sijbrands EJG, Westendorp RGJ, Defesche JC, de Meier PHEM, Smelt AHM, Kastelein JPJ. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. Br Med J 2001; 7293: 1019-22. 2 The EARS Group. The European Atherosclerosis Research Study (EARS): Design and Objectives. Int J Epidemiol 1994; 23(3): 465-71. 3 Scientific Steering Committee of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Br Med J 1991; 303: 873-6. |
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Elias Ragi, Consultant Clinical Neurophysiologist Royal Devon and Exeter Hospital, Exeter, EX2 5DW
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Sir, As I continue to discover neuropathy from anticholesterol statins, may I follow up on my letter of 5 May. In your Journal's issue of 16 December 2000, Kastelein exalts the merits of lowering blood cholesterol with statins. In 6 January issue, Muldoon et al exonerate statins from "significant" non-illness mortality and thus implicitly amplify the benefits from statins. In the past year, I have discovered - and reported to the Medicines Control Agency - 16 cases of progressive generalised axonal neuropathy, most likley to have been caused by statins. Patients were 52 to 80 years old, mean 62, mostly males (4:1). Statins inculpated, and number, are: simvastatin - 5; pravastatin - 4; atorvastatin - 4; cerivastatin - 3. Most patients presented with rather progressive weakness or loss of co-ordination in the lower limbs. Neuropathy - and its association with statins - was discovered by nerve conduction studies. In some cases, it is the patient who first suspected the association. Weakness occured within two months of instituting, or increasing dosage, of the statin. The neuropathy is severe and in several cases leading to muscle denervation. Neuropathy may reverse if the stain is stopped. Yet neuropathy was not suspected and the patient asked to continue on the statin. I declare having no competing interests. Yours faithfully Dr Elias Ragi
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