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CLINICAL REVIEW: Ian A Scott Evaluating cardiovascular risk assessment for asymptomatic people BMJ 2009; 338: a2844 [Full text]

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Pulse Mass Index as first cardiovascular risk approach

Enrique J. Sánchez-Delgado   (11 January 2009)

NICE and QRISK

Philip M Ranson   (14 January 2009)

Re: NICE and QRISK

Ian A Scott   (15 January 2009)

Cardiovascular risk assessment: vitamin D levels are important

Peter J Lewis   (20 January 2009)

Fatty Acid Abnormalities are the major risk factor

Eduardo Siguel   (21 January 2009)

Re: Fatty Acid Abnormalities are the major risk factor

Leslie O Simpson   (22 January 2009)

Fatty Acid Abnormalities are the major risk factor: clarification 1

Eduardo Siguel   (22 January 2009)

Joint British Societies Cardiovascular Risk Charts

Rupert A Payne, David J. Webb, Simon R.J. Maxwell   (14 May 2009)

Joint British Societies Cardiovascular Risk Charts

Paul N. Durrington   (22 October 2009)

Pulse Mass Index as first cardiovascular risk approach 11 January 2009
Enrique J. Sánchez-Delgado, Internal Medicine-Clinical Pharmacology. Director of Medical Education Hospital Metropolitano Vivan Pellas, Managua, Nicaragua Send response to journal: Re: Pulse Mass Index as first cardiovascular risk approach	Pulse Mass Index as first cardiovascular risk approach In his review on evaluating cardiovascular risk assessment for asymptomatic people (BMJ 5 Jan 2009), Ian Scott analyses the Framingham Risk Score and the QRISK2. Both the QRISK2, as the report from Aage Tverdal et. al. on heart rate and mortality from cardiovascular causes (European Heart Journal, November 2, 2008), are in agreement that a high HR (or other risk factors that increase the RHR) is associated with an unfavourable pattern of risk factors and may be a marker for sympathetic nervous system activity. All the major CV risk factors – cholesterol, triglycerides, blood pressure, body mass index, family history of CV disease, smoking, and sedentary lifestyle – increased significantly across increasing quartiles of HR. These findings are in fully agreement with our findings on the Pulse Mass Index, published in The Lancet, March 13, 1999, which we recently presented, actualized, in the World Congress of Internal Medicine, in Buenos Aires, Argentina, September 19, 2008. The Pulse Mass Index (Resting Heart Rate multiplied by the Body Mass Index and divided by 1730), has a very high (95%) correlation with the Framingham Risk Score. A Pulse Mass Index over 1.3 indicates with a high probability a high cardiovascular risk and the need of a more complete evaluation (eg. exercise EKG or Coronary CT or calcium score) and management of the CV risk factors in these patients. Since our first report we explained that we correlated the Pulse with the BMI, because the HR reflects the oxidative metabolic rate and activity of the sympathetic nervous system, such as under stress, obesity or hyperinsulinemia and that these findings probably indicate the relation between hyperinsulinemia, stimulation of the sympathetic nervous system, and oxidative metabolism that is seen in obese patients and which improves when they exercise regularly or lose weight. The Pulse Mass Index is also the most simple and economical first clinical approach to the risk evaluation in a large population, and more so in the developing countries, where around 80% of all cardiovascular deaths occur. Prof. Enrique Sánchez Delgado, MD Internal Medicine-Clinical Pharmacology Director of Medical Education Hospital Metropolitano Vivan Pellas, Managua, Nicaragua esanchez@metropolitano.com.ni Competing interests: None declared
NICE and QRISK 14 January 2009
Philip M Ranson, Associate Director - External Communications MidCity Place 71 High Holborn London WC1V 6NA Send response to journal: Re: NICE and QRISK	Ian A Scott is incorrect when he states that NICE recently endorsed QRISK as the preferred risk prediction tool for UK citizens. In its clinical guideline Lipid modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (NICE clinical guideline no.67 (2008)) NICE recommends that a modified version of the Framingham 1991 10-year risk equations should be used to assess CVD risk. Competing interests: None declared
Re: NICE and QRISK 15 January 2009
Ian A Scott, Director of Internal Medicine Princess Alexandra Hospital, Brisbane, Australia Send response to journal: Re: Re: NICE and QRISK	I stand corrected in regards to NICE endorsement of QRISK, and I thank Michael Power for his clarification. My error resulted from retrieving a press release issued on 16/2/08(accessed at: www.ehiprimarycare.com/News/3478/qrisk_could_cut_heart_disease) which I did not check further as I assumed it was correct. The key statements in this news release were: 'The National Institute for Clinical Excellence (NICE) has recommended that the QRisk formula for identifying those most at risk of developing cardiovascular disease (CVD) replace the current guidance in England and Wales....NICE has now recommended that the formula is adopted across medical practice in England and Wales - replacing the current standard guidance for predicting CVD, the Framingham risk score.......NICE evaluated QRisk for inclusion in its forthcoming national guidance on lipid modification therapy, and in a consultation document issued this month, said: “Emerging evidence suggests that QRisk gives a better estimation of risk in the general population of England and Wales than the Framingham equations.' I am now informed that while NICE did originally recommend QRISK, they changed their minds, and in their interim final decision published in Sept 2008 they stated that clinicians should use the "1991 Framingham equation", and more research should be urgently done into QRISK. This is on the NICE website, but it is not easy to find. NICE's search engine will not locate it, and Google takes you to an archive page which looks like a current page. The latest guideline can be found at: http://www.nice.org.uk/Guidance/CG67/NiceGuidance/pdf/English Putting the issue of NICE endorsement to one side, the evidence as stated in my article does suggest that QRISK performs better than Framingham and with time and more validation studies will probably become the risk calculator of choice. Competing interests: None declared
Cardiovascular risk assessment: vitamin D levels are important 20 January 2009
Peter J Lewis, Integrative physician 15 South Steyne, Manly, NSW 2095, Australia Send response to journal: Re: Cardiovascular risk assessment: vitamin D levels are important	Ian Scott, in his review of cardiovascular risk assessment in asymptomatic people (1), seems to have overlooked the growing body of evidence that vitamin D deficiency is an important, common and easily treatable cardiovascular risk factor. Nearly 20 years ago, Scragg and colleagues investigated the relationship between the plasma level of 25-hydroxy-vitamin D (25(OH)D) and myocardial infarction (MI) in community-based case-control study (2). They found myocardial infarction to be inversely associated with plasma 25 -hydroxy-vitamin D levels. MI patients had significantly lower mean 25(OH)D levels than controls; the relative risk of MI for subjects with 25(OH)D levels equal or above the median was 0.43 compared to subjects below the median. Watson and colleagues found serum 1,25-dihydroxy-vitamin D (1,25(OH)2D) levels to be inversely correlated with coronary calcification (3). An association between vitamin D deficiency and subsequent cardiovascular events was found among the 1,739 Framingham Offspring Study participants without prior cardiovascular disease (4). After a mean follow -up period of 5.4 years, a graded increase in cardiovascular risk was found across categories of 25(OH)D; the risk of cardiovascular event was 53-80% higher in those people with low vitamin D levels. Giovannucci and colleagues assessed prospectively whether plasma 25(OH)D levels are associated with risk of coronary heart disease (5). A nested case-control study was conducted in 18,225 men in the Health Professionals Follow-up Study; the men were aged 40-75 years and free of diagnosed cardiovascular disease at blood collection. During 10 years of follow-up, 454 men developed non-fatal myocardial infarction or fatal coronary artery disease. Low levels of 25(OH)D were associated with higher risk of MI in a graded manner; after adjustment for matched variables, the relative risk for men deficient in 25(OH)D was 2.43 compared with those considered to be sufficient in 25(OH)D. A prospective cohort study of 3,258 consecutive male and female patients scheduled for coronary angiography found low 25(OH)D and 1,25(OH)2D to be independently associated with all-cause and cardiovascular mortality (6). Multivariate-adjusted hazard ratios (HR) for those in the lower two 25(OH)D quartiles were higher for all-cause mortality (HR 2.08 and 1.53 respectively), and for cardiovascular mortality (HR 2.22 and 1.82 respectively) compared with those in the highest quartile. Similar results were obtained for patients in the lowest 1,25(OH)2D quartile. In a cross-sectional study involving an analysis of data from a cross -sectional sample of 16,603 men and women, subjects with cardiovascular disease were found to have a greater frequency of vitamin D deficiency than those without (7). The authors concluded, ‘These results indicate a strong and independent relationship of 25(OH)D deficiency and cardiovascular disease in a large sample representative of the US adult population’. Vitamin D receptors are found in vascular smooth muscle, endothelium and cardiomyocytes. There are number of potential mechanisms whereby vitamin D deficiency may adversely affect cardiovascular health (8). These include: • Up-regulation of the rennin-angiotensin-aldosterone system, leading to hypertension, and hypertrophy of the left ventricle and vascular smooth muscle • Secondary hyperparathyroidism • Increased insulin resistance • Increased systemic inflammation (as documented by elevated levels of C-reactive protein and interleukin-10) • Calcification of heart valves, myocardium and coronary arteries A meta-analysis of 18 randomised controlled trials (comprising 57,000 individuals) found that a vitamin D intake of >500 IU/day reduced all- cause mortality, in part by decreasing cardiovascular deaths (9). Vitamin D deficiency is an under-recognised, but important cardiovascular risk factor which should be tested for; many experts in the field now suggest that optimal 25(OH)D levels are at least 100 nmol/L (40 ng/ml). Treatment with appropriate vitamin D supplementation - as a general rule, every 1,000 IU of vitamin D3 ingested daily will raise the 25(OH)D level by about 10 nmol/L (4 ng/ml) over 3 months - is simple, safe and inexpensive. References 1. Scott IA. Evaluating cardiovascular risk assessment for asymptomatic people. BMJ 2009;164-168 2. Scragg R et al. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol 1990;19(3):559-63 3. Watson KE et al. Active Serum Vitamin D Levels Are Inversely Correlated With Coronary Calcification. Circulation 1997;96:1755-1760 4. Wang TJ et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-511 5. Giovannucci E et al. 25-Hydroxyvitamin D and Risk of Myocardial Infarction in Men: A Prospective Study. Arch Int Med 2008;168(11):1174- 1180 6. Dobnig H et al. Independent Association of Low Serum 25- Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Intern Med 2008;168(12):1340-1349 7. Kendrick J et al. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 2008; Nov 11 [Epub ahead of print] 8. Lee JH et al. Vitamin D Deficiency: An Important, Common, and Easily Treatable Cardiovascular Risk Factor. J Am Coll Cardiol 2008; 52:1949-1956 9. Autier P, Gandini S. Vitamin D supplementation and total mortality; a meta-analysis of randomised controlled trials. Arch Int Med 2007; 167:1730-7 Competing interests: None declared
Fatty Acid Abnormalities are the major risk factor 21 January 2009
Eduardo Siguel, Physician, lipid research Essential fats, LLC, Gaithersburg, MD, USA, 20898 Send response to journal: Re: Fatty Acid Abnormalities are the major risk factor	This is a highly simplified discussion Cardiovascular risk assessment for asymptomatic people ought to identify the individuals who have the greatest risk even though they have no symptoms. A sound approach requires an appropriate theoretical model of cardiovascular disease, what causes cardiovascular disease. I proposed that the most common cause of acquired, progressive cardiovascular disease is an abnormality of fatty acid metabolism. According to my theory, optimal heart (and cardiovascular system) function requires optimal cell function. Optimal cell function requires optimal membrane function. I proposed that a major factor in suboptimal membrane function are suboptimal levels of essential fats (mostly deficiencies, but can also be imbalances). According to my concepts, abnormal levels of the essential fats make membranes less flexible (fluid). Their conformation (shape changes) properties are less desirable. To compensate, the body makes more cholesterol and more MUFA (monounsaturated fatty acids). Thus, I proposed that elevated total cholesterol is not a disease or an abnormality, but a compensatory mechanism used by the body to maintain membrane fluidity close to desirable levels. Like other regulatory systems, the body may overcompensate and overproduce cholesterol. Regardless, higher cholesterol levels can cause other complications. Abnormal essential fat levels (and suboptimal membrane function) are also the primary factor in hypertension (among other reasons, because membranes, cells and vessels lose elasticity), hormone function (receptors are less fluid and adaptable), and others. Excessive intake of saturated fatty acids (SFAs) creates a condition I labeled as relative essential fatty acid deficiency. With so much SFA, the body cannot optimally use its levels of essential fats (the junk mail syndrome, too much junk mail, important mail is lost). Some of the consequences are that lowering total cholesterol or eating more MUFAs is not the best treatment (contrary to prevailing views). My theory is complex and can be read, in part, in my published papers, book and web site www.essentialfats.com. To support my theory I invented accurate means to measure fatty acids and measured fatty acids in over 1,000 individuals, including samples from one of the Framingham Heart Disease study. Based on my communications with Framingham researchers, who gave me the blood samples, I was the first researcher to measure fatty acid profiles in Framingham subjects. Together with other samples I analyzed, I found that adult americans have huge deficiencies of essential fats, particularly of omega-3s, and too many trans fatty acids. Clinical studies have shown that correcting low levels of essential fats (e.g., eating more w3s) lowers the risk of cardiovascular disease. This is what studies of Mediterranean and other diets accomplish. Subjects eat diets with a relatively high % of calories from essential fats. Losing weight, in many subjects, also increases their relative percent of essential fats (because subjects, depending on weight loss means, tend to lose more SFAs and MUFAs than essential fats). The authors did not report fatty acid profiles. I propose that abnormalities of essential fats are the most significant risk factor for asymptomatic heart disease. As a sideline, Dr. Sinclair, a British researcher, wrote about some of these subjects as early as 1962 (but, unfortunately, few read him now). He was too far ahead for his time. The technology to measure fatty acids accurately did not exist until the 1980s. There are too many fatty acids in human blood. The methods used before 1980 did not allow their accurate measurement. In the 1980s gas chromatography was improved by a factor of 10 to 100 with the use of 100m capillary columns. I found that a mixture of fats in blood that separated into about 20 peaks with technology prior to 1980 separated into more than 300 peaks with better technology. The 300 peaks were too many for the existing integrators and computers. It took the development of modern PCs and newer software to be able to accurately integrate or calculate the quantity of each fatty acid. Until then, clinicians and researchers believed that adults ate too much fat and plenty of essential fatty acids. Thus the recommendations for low fat diets. See my articles and web site for a history on these matters. References Hugh Sinclair. Essential Fatty Acids. Br Med J. 1962 August 4; 2(5300): 337. Siguel E, Maclure, M. Relative Activity of Unsaturated Fatty Acid Metabolic Pathways in Humans. Metabolism, 1987; 36: 664-69. Siguel, E. Method and Apparatus for Diagnosis of Fatty Acid or Lipid Abnormalities. U.S. Patent No. 5075101, Issue date 12/24/91. Siguel E, Lerman, RH. Altered Fatty Acid Metabolism in Patients With Angiographically Documented Coronary Artery Disease. Metabolism 1994; 43:982-93. Siguel E. Essential and Trans Fatty Acid Metabolism in Health and Disease. Nutrition Issue. Comprehensive Therapy, 1994; 20(9):500-10 (Review). Siguel, E. A New Relationship between Total/HDL Cholesterol and Polyunsaturated Fatty Acids. Lipids, 1996; 31:S51-6. Edward Siguel, MD, PhD. www. Essentialfats.com (see statement on potential financial conflicts). Author has patent on fatty acid profiles, reported above. Competing interests: Patent for fatty acids Research on fatty acids
Re: Fatty Acid Abnormalities are the major risk factor 22 January 2009
Leslie O Simpson, retired experimental pathologist Dunedin, New Zealand 9077 Send response to journal: Re: Re: Fatty Acid Abnormalities are the major risk factor	Although it is clear that Dr.Siguel's measurement of fatty acids deserves clinical acceptance, it is surprising that he appears to be unaware of the importance of fatty acids in blood flow. The omega-3 in sardine oil has been shown to increase the fluidity of erythrocyte membrane lipids which is accompanied by a reduction in blood viscosity. Four grams daily of evening primrose oil have been shown to provide sufficient gammalinolenic acid to produce a significant increase in the blood levels of prostaglandin E1. Prostaglandin E1 has been shown to increase the fluidity of red cell membrane lipids which improved blood filterability. When plasma cholesterol levels are raised, there is a comparable increase in the cholesterol content of the erythrocyte membrane and this is associated with a reduction in red cell deformability. When plasma levels of cholesterol are reduced, comparable changes occur in the red cell membrane and normal levels of deformability are restored. In contrast to Dr.Siguel's suggestion that the fatty acid levels contribute to cardiovascular disease, there is a significant literature which shows that reduced red cell deformability and increased blood viscosity play a major part in such disorders. Therefore it would be of interest to learn how the levels of fatty acids, as determined by Dr.Siguel's tests, related to blood viscosity and red cell deformability. Competing interests: None declared
Fatty Acid Abnormalities are the major risk factor: clarification 1 22 January 2009
Eduardo Siguel, Physician, lipid research Gaithersburg, MD, 20898, USA Send response to journal: Re: Fatty Acid Abnormalities are the major risk factor: clarification 1	Based on reader’s comments, I clarify I did not mean to imply that “fatty acid levels contribute to cardiovascular disease” but rather that suboptimal distributions of fatty acid levels contribute to cardiovascular disease. In practice, one common suboptimal distribution is low levels of omega-3 fatty acids. Less common are low levels of omega-6 fatty acids. Suboptimal levels of essential fats have undesirable effects on blood flow. As a general rule, low levels of essential fats decrease membrane fluidity. This means decrease red cell deformability, increased blood viscosity. Suboptimal (usually low) levels of omega-3s contribute to undesirable platelet function (usually inappropriate or undesirable coagulability or platelet aggregation), shorter red cell survival (probably caused in part by reduced deformability that increases probability of cell destruction). There are many other issues involved. I see no inconsistencies with the statements by Leslie O Simpson. Competing interests: Fatty acid patent
Joint British Societies Cardiovascular Risk Charts 14 May 2009
Rupert A Payne, Lecturer in Clinical Pharmacology University of Edinburgh, Queen's Medical Research Inst., 47 Little France Cres, Edinburgh EH16 4TJ, David J. Webb, Simon R.J. Maxwell Send response to journal: Re: Joint British Societies Cardiovascular Risk Charts	Scott discusses the assessment of cardiovascular risk in asymptomatic individuals[1]. The Joint British Societies’ (JBS) charts employ a “traffic-lights” system to emphasise different cardiovascular risk categories, and provide a useful means of conveying this information to patients. They were published in 2005 in conjunction with the JBS2 guidelines[2], and are reproduced biannually in the BNF. We recently observed that the green (<10% risk) area was missing from the charts for non-diabetic male smokers aged 50-59 years, and to a minor degree in the charts for similarly aged male smokers, and older non- diabetic male non-smokers. The charts were inaccurately reproduced in this form for over 3 years. We estimate that 16% of the 2.5 million non-smoking 50-59 year-old UK men would be wrongly categorised into the higher (10- 20%) risk category[3]. This had the potential to cause patients unnecessary concern. Lifestyle advice may also have differed between low and moderate risk patients. Furthermore, lower (10%) drug treatment thresholds are a future possibility given the increasing evidence for treating lower-risk populations. The BNF published revised charts in March 2009. Although a brief comment is made on the British Hypertension Society (BHS) website we feel that, given the charts’ extensive use, the change should have been publicised more widely. It is also concerning that this error should have persisted for so long. This probably reflects the lack of transparency surrounding the methodology employed to calculate risk in the original JBS2 publication. The lack of a widely available JBS risk calculator also hampers cross-checking of the calculation. We feel that use of a computer calculator should be preferred regardless; these can be individualised for patients whilst still providing a useful graphical representation of risk[4]. The JBS charts remain a valuable tool, and we are pleased to see that a correction has been made. However, we hope that there will be more openness surrounding the publication of the further revisions currently being proposed by the BHS. References: 1. Scott IA, Evaluating cardiovascular risk assessment for asymptomatic people. BMJ 2009;338:a2844 2. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91 Suppl 5:v1-52 3. Scottish Health Survey 2003, Scottish Executive, Edinburgh 4. University of Edinburgh Cardiovascular Risk Calculator website. http://cvrisk.mvm.ed.ac.uk/calculator/calc.asp?bnf Competing interests: Dr Payne is author of a website which produces patient-specific risk calculations including charts similar to those of the Joint British Societies
Joint British Societies Cardiovascular Risk Charts 22 October 2009
Paul N. Durrington, Professor of Medicine Cardiovascular Research Group, Core Technology Facility University of Manchester M13 9NT Send response to journal: Re: Joint British Societies Cardiovascular Risk Charts	Joint British Societies Cardiovascular Risk Charts Paul N. Durrington (corresponding author) Address: Cardiovascular Research Group Core Technology Facility (3rd Floor) 46 Grafton Street Manchester M13 9NT Payne and colleagues draw attention to the proposed revisions to the Joint British Societies 2 (JBS2) charts for cardiovascular disease (CVD) risk estimation to be found on the website of the British Hypertension Society [1] one of which has already been adopted in the British National Formulary. Their assertion that some 16% of 50-59 year old non-smoking men are at <10% 10 year risk of cardiovascular disease should, however, not be readily accepted, because the Health Survey for England showed that considerably fewer men are in this category [2], which generally requires them to have exceptionally low blood pressure and cholesterol, a finding which may indicate poor health rather than cardiovascular fitness. Moreover, the JBS2 Cardiovascular Risk Assessor computer programme which transparently explains the basis of calculation is widely available [3]. The main purpose of the proposed revision to the charts was to bring them in-line with the recent NICE guidance [4]. This endorses the JBS2 recommendations [5] in advocating a CVD risk threshold of 20% over the next 10 years for the introduction of statin therapy and agrees that this risk should be estimated using epidemiological data such as those generated from the Framingham Study. NICE, however, further proposes that the upper age limit at which CVD risk is estimated by such a method be 75 years rather than the 70 years in JBS2. The revised charts permit this (Figure). For the age-under-50-years chart, risk has been calculated for the age of 49 years, for 50-59 years for 59 years for 60-69 for 69 years and for 70 years and over for 75 years. The 30% 10 year risk lines have been removed, because earlier guidelines recommending this as a threshold for statins have now been superseded . Both NICE and JBS2 recommend increasing risk by 1.4 times if the individual whose risk is being assessed has South Asian ancestry. NICE recommends that if there is a family history of premature CVD in a first degree relative (male aged 55 years or less or female aged 65 years or less) the risk should be increased by 1.5 times and that it should be doubled if 2 or more first degree relatives have such a history. References 1. British Hypertension Society http://www.bhsoc.org/Cardiovascular_Risk_Charts_and_Calculators.stm 2. Choudhury, M. Blood analytes. In Health Survey for England 2003. Risk Factors for Cardiovascular Disease Vol2 (eds K. Sproston, P. Primatesta) London: The Stationery Office 2004, 241-87 3. http://www.heartuk.org.uk/HealthProfessionals/index.php/jbs_cv_risk_assessor/ 4. National Institute of Health and Clinical Excellence Lipid Modification: Cardiovascular risk assessment and the modifications of blood lipids for the primary and secondary prevention of cardiovascular disease. Full Guidelines London: National Collaborating Centre for Primary Care May 2008 5. Wood, D.A., Wray, R., Poulter, N., Williams, B., Kirby, M., Patel, V. et al JBS2: Joint British guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91(Suppl V): V1-52. Ethics: None required. Funding: None Competing interests: Prof. Durrington has been closely involved in the development of earlier versions of the charts.