Displaying 1-10 letters out of 631 published
Bicuspid aortopathy: searching for the answer in "non- progressors"
Evaldas Girdauskas1, Michael A. Borger2
1- Department of Cardiac Surgery, Central Hospital Bad Berka, Germany 2- Department of Cardiac Surgery, Heart Center Leipzig, University Leipzig, Germany
Keywords: bicuspid aortic valve, aortic aneurysm, aortopathy
Corresponding author: Evaldas Girdauskas, MD, PhD (Address: Department of Cardiac Surgery, Central Hospital Bad Berka, Robert-Koch- Allee 9, 99437 Bad Berka, Germany. Tel.: +49 3645851101; Fax: +49 3645853510 E-mail address: email@example.com)
We read with a great interest the manuscript by Detaint and co- authors published in the last issue of Heart . The authors should be congratulated for their efforts to shine some light on the controversial issue of bicuspid aortic valve (BAV)-associated aorthopathy in their current longitudinal echocardiographic study. Indeed, there are some novel and intriguing findings in this manuscript which may deserve a more extensive commentary.
The authors were able to demonstrate the fastest aortic dilatation rate at the ascending aortic level and smaller baseline aortic diameter being predictor of rapid aortic progression. Importantly, no correlation was found between aortic dilatation rate and BAV morphology as well as basic aortic phenotype. Typical morphology of BAV (i.e., L-R BAV fusion pattern) was independently associated with the baseline dilatation of the entire aortic root, which may reflect specific patterns of transvalvular flow in this BAV subtype .
The BAV population analyzed in this study is quite distinct from the "typical" surgical BAV population and these differences should be highlighted. First of all, 113/353 (32%) BAV patients without raphe were identified in the current study. In our experience, it is rather rare to find a BAV without raphe during aortic valve replacement (AVR) surgery. Similarly, BAV without raphe was identified in only 7% patients in the surgical series by Sievers and co-authors . Another major difference is the low proportion of patients with a BAV stenosis in the study (i.e., 14% of the study population). Calcific stenosis is the most common fate of congenital BAV (i.e., accounts for up 85% of surgically treated patients ) which is clearly underrepresented in the current series. As opposed to this, the authors revealed significant (i.e., at least moderate) BAV insufficiency in 123/353 (35%) study patients. Therefore, BAV cohort analyzed in this manuscript may represent a specific referral pattern of the tertiary care center. How many patients underwent AVR surgery during study period? Were these patients excluded from further echocardiographic follow-up? Is there any role of the variable "AVR surgery" in the progression of aortic diameters?
Was there a subgroup of BAV patients with the maximal progression of aortic diameters at the level of the sinuses of Valsalva? There is some evidence in the literature that patients with so-called "root phenotype" (i.e., Valsalva sinuses > ascending aorta) may represent a predominantly congenital form of BAV disease which is associated with a higher risk of adverse aortic events . What was the proportion of BAV patients in the subgroup of "sinuses phenotype" which showed stable aortic diameters at follow-up echocardiography?
However, the most intriguing question from this manuscript - why did aortic diameters remain stable in nearly half of the BAV patients? Is this only a function of limited echocardiographic follow-up interval (i.e., aortopathy would progress over longer follow-up periods) or a real phenotypic difference in BAV patients? Provided that it is a real phenotypic difference- what are the predictors of non-progressive aortopathy in BAV disease? Obviously, this issue was not the main focus of the current manuscript and no specific analysis has been performed. However, based on the presented data, risk stratification for aortic events based on BAV morphology and baseline aortic diameter would be inadequate. A higher level of complexity in determinants of BAV-associated aortopathy has been proposed by the authors. In our opinion, this question will be impossible to address without knowing the precise haemodynamic profile of transvalvular flow in these BAV patients. Moreover, the presented data underscore still significant gaps in knowledge in the development of BAV aortopathy.
1. Detaint D, Michelena HI, Nkomo VT, Vahanian A, Jondeau G, Sarano ME. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart. 2014;100:126-34.
2. Mahadevia R, Barker AJ, Schnell S, Entezari P, Kansal P, Fedak PW, Malaisrie SC, McCarthy P, Collins J, Carr J, Markl M. Bicuspid Aortic Cusp Fusion Morphology Alters Aortic 3D Outflow Patterns, Wall Shear Stress and Expression of Aortopathy. Circulation. 2013 Dec 17.
3. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg. 2007;133:1226-33.
4. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases. Mayo Clin Proc. 1999;74:14-26.
5. Girdauskas E, Disha K, Secknus M, Borger M, Kuntze T. Increased risk of late aortic events after isolated aortic valve replacement in patients with bicuspid aortic valve insufficiency versus stenosis. J Cardiovasc Surg (Torino). 2013;54:653-9.
Conflict of Interest:
Don't forget radiotherapy
This is an excellent article which will help many of us who have to manage patients who are undergoing cancer treatment.
It must be remembered that many patients also undergo radiotherapy, as is acknowledged in the article. High dose radiotherapy to the thorax can cause heart failure, both systolic and restrictive, valvular dysfunction and coronary artery disease, which often presents many years later. In lymphoma survivors who have received such therapy, cardiovascular disease is the most common cause of death.
A history of thoracic radiotherapy is important to elicit when assessing patients with cardiovascular symptoms. Such patients may present with symptoms of cardiac disease at a younger age than is typical, with few traditional risk factors, and are therefore potentially at higher risk of initial misdiagnosis.
Conflict of Interest:
Cardiac Imaging Training in the United Kingdom - Rise of the Machines.
Cardiac Imaging Training in the United Kingdom - Rise of the Machines
Anna Marciniak PhD MRCP, Jessica Webb MRCP BM BCh, Ronak Rajani MD MRCP FSCCT.
Department of Cardiology, Guy's and St Thomas' NHS Foundation Trust, London. SE1 7EH. United Kingdom
Address for correspondence: Dr Ronak Rajani MD MRCP FSCCT BM, Department of Cardiology, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH. United Kingdom. Tel: +44 7866 258 572 Fax: +44 208 399 4699 Email: Ronak.Rajani@gstt.nhs.uk
There has been a steady growth in the number of cardiology trainees electing to pursue cardiac imaging as a subspecialty after achieving their core competencies. Whereas in 2004, only 12% of cardiology trainees selected cardiac imaging as a subspecialty in the United Kingdom, this has increased to 23% in less than a decade (1). This has placed cardiac imaging on par with coronary intervention as one of the premier choices of cardiology subspecialisation.
Although contemporary surveys do not explore the reasons for this increasing popularity, it is likely that this stems from the rapid evolution in computer technology and processing power over the last decade. Prior to this, cardiac imaging was often perceived to be predominantly isolated to nuclear cardiology and echocardiography. Only a handful of centres nationally had access to cardiac magnetic resonance imaging and electron beam computed tomography. In these centres, scans were largely confined to the research domain and for well-defined clinical indications. As a consequence sub-specialty cardiac imaging was a generally a less attractive option for trainees in contrast to the allure of the developments in interventional cardiology and electrophysiology.
Rise of the Machines.
By Moore's Law it is expected that the overall processing power for computers will double every two years (2). In the year 2000, a high-end computer had a processing speed of 1.3 GHz for one core, with 37.5 million transistors in a computer-processing unit. Within ten years this had increased to 2.8 GHz for a quad-core, with a staggering 904 million transistors per computer processing unit, equating to an 862% increase in power [1.3 GHz to 11.2 GHz (2.8 x 4)]. It is clear that this progress has also translated to almost simultaneous advancements in cardiac imaging.
Cardiac computed tomography.
In 2000, computed tomography scanners had a temporal resolution of 0.5 seconds with a slice count of 4 to 8. By 2005, 32/64 slice scanners began to emerge and reliable coronary imaging became a reality. Nowadays, contemporary CT scanners can achieve a temporal resolution of 75 ms with a spatial resolution of <0.6mm. The slice count has increased to 320 and other novel innovations such as dual-source and dual energy x-ray sources, high-definition detectors, iterative reconstruction techniques and advancements in the post-processing of CT datasets have also emerged. Computer power has also permitted the application of computational fluid dynamics to cardiac CT datasets to measure pressure, velocity and arterial wall stress. This development has now made it possible to evaluate lesion specific fractional flow reserve by CT and also valve haemodynamics. In the future, the prospect of being able to able non-invasively assess the coronary anatomy and its functional significance at sub 0.5 mSv doses with <20 mls of contrast is likely to become a distinct reality.
Cardiac magnetic resonance imaging.
Although magnetic resonance imaging has been available for almost twenty years, it is only up until relatively recently that it has been possible to image the beating heart. Advancements in computer processing power have had a significant impact upon this capability. Alongside high- strengths magnets and novel contrast agents, improvements in computing power have permitted extremely rapid cardiac acquisitions, advancements in respiratory compensation techniques and the assessment of tissue characteristics without the need for peripherally administered contrast (T1 mapping). We are also now witnessing advancements in coronary motion correction techniques that will enable the more widespread use of coronary magnetic resonance imaging, detailed plaque characterisation with novel contrast agents, and the development of magnetic resonance spectroscopy to assess myocardial metabolism in vivo.
Nuclear cardiology has also benefitted from computer processing power improvements over the last decade. There have been vast changes from planar to single-photon emission computed tomography, and to now ultrafast SPECT, positron emission tomography (PET), and hybrid SPECT-CT and PET-CT. Gamma camera technology has also evolved with the emergence of solid-state detectors using cadmium zinc telluride in place of conventional sodium iodide based systems. These detectors are smaller in size and offer better energy resolution and spatial resolution than conventional detectors. In addition, owing to their compact nature, new configurations with multiple detectors are now possible. These permit shorter imaging times by almost five-fold to two minutes and a substantial reduction in radiation dose owing to smaller doses of radioactive isotope being required. There has also been progress in developing newer automated quantitative methods for image processing and interpretation, molecular and hybrid imaging and perfusion tracers.
There has also been a change in the landscape of echocardiography. With technological advancements we have seen the miniaturisation of echocardiography machines to hand-held devices. This has permitted the migration of cardiac ultrasound to other specialities outside of cardiology and the emergence of "focussed", "point-of-care" or "screening" echocardiograms to facilitate early decision-making. In addition, the capability of "standard sized" echocardiography machines has also vastly increased. Cardiologists now have access to ultrasound machines that can perform 3-dimensional imaging to provide an accurate quantitative assessment of the left ventricle and heart valves. There are also novel quantitative measures of myocardial function such as myocardial strain and speckle tracking to evaluate regional and global myocardial deformation properties.
Cardiac Imaging - salvation.
For cardiology trainees these developments in cardiac imaging have had a number of effects. Firstly, we have seen rapid rise in the number of cardiology journals and international conferences dedicated solely to cardiac imaging. This reflects the substantial investment of research in these areas and the increasing profile of cardiac imaging as a sub- speciality. Secondly, there has been an increase in the number of cardiac centres within the UK providing 3 or more of these imaging modalities. In order to capitalise on this, the number of suitably trained consultants with experience in multimodality imaging experience has had to increase. Thirdly, the profile of an imaging cardiologist within a cardiology unit has evolved. They are now seen to be vitally important to clinical decision making across a wide spectrum of cardiac conditions, including patient suitability for cardiac resynchronisation therapy, electrophysiological procedures, revascularisation, structural intervention and cardiothoracic surgery. Finally, reflecting the changes to the cardiology core curriculum in 2010, there has been a propagation of cardiac imaging training opportunities within the UK. There are now dedicated training days and annual meetings hosted by the British Society of Cardiovascular Imaging, British Society of Echocardiography and the British Society of Cardiac Magnetic Resonance, and a host of training courses and regular meetings available for trainees (3). The net result is that the perception of cardiac imaging as a subspecialty has changed substantially over the years. It is a growing subspecialty with excellent career prospects, and looking at the developments on the horizon, it is likely to be so for the foreseeable future.
Acknowledgments. In 2010 Dr Rajani was the recipient of the BCS/ACC jointly funded 1-year Fellowship in Advanced Cardiac Imaging.
1.Keenan NG. 2012 BJCA trainee survey. Br J Cardiol 2013;20:8-9. 2.Moore G E. Cramming more components onto integrated circuits. Electronics Magazine. 1965. 3.Rajani R, Berman D, Underwood R. Cardiac imaging training in the United Kingdom - time for a New Dawn. Heart. 2010;96:1427.
Conflict of Interest:
Conclusions about elderly people need real elderly people
We really appreciate the clarifications offered by Alexandros Briasoulis concerning his article, but in our opinion our claim about the importance of including in the meta-analysis information only (or mostly) from elderly patients remains well founded. In this regard, the Cochrane Hypertension Group encourages to accept only studies if 70% or more of the participants meet the definition, or individual patient data are available, or data of relevant patients are provided separately allowing specific inclusion of the population as defined (1). Moreover, the inclusion of INVEST trial (2) in the ACCF/AHA 2011 (3) cannot be claimed as a relevant argument to support proceeding in the same manner in the meta-analysis, because of the inherent low level of evidence showed by consensus. On the other hand, the INVEST trial has a very high risk of bias. It is an open trial and no information on the sequence generation nor the allocation concealment is provided.
We agree with the author in the conclusion showed by the secondary analysis (4). But in fact this provides to us compelling evidence of the importance of separating the information between young and older people. Furthermore, it is not clear to us why these findings are said to be "in accordance" with the results of the sensitivity analysis performed by the author. According to the Discussion (1), the subgroup analysis of studies with patients over 70 years showed that "the beneficial effects of antihypertensive treatment remained significant in the first group of studies (treatment versus placebo group)" but the meta-analysis did not take into account blood pressure levels, thereby both papers seem to be focused on very different issues. Also, we have not been able to read in the last article cited (5) the assertion made on the J-curve association in patients above or below age of 65. In fact, this study did not compare different age subgroups any time but different blood pressure strata, and the mean age values in each 10-mm Hg blood pressure stratum were very similar (66-67 years).
In short, if elderly age begins at 65, we need to found our practices on studies including real elderly people. Evidence based on the results of studies with patients of a mean age close to 65 is not trustworthy.
(1) Gorricho J, Garjon J, Celaya MC, Muruzabal L, Montoya R, Lopez A, Malon MDM, Saiz LC. Blood pressure targets for the treatment of patients with hypertension and cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD010315. DOI: 10.1002/14651858.CD010315. (2) Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil- Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805-16. (3) Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123:2434-2506. (4) Denardo SJ, Gong Y, Nichols WW, et al. Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an international verapamil ST-Trandolapril (INVEST) substudy. Am J Med. 18 2010;123:719-26. (5) Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-93.
Luis Carlos Saiz, Pharm D Pharmacotherapy Research Coordinator Navarre Health Service, Spain
Juan Erviti, Pharm D, PhD Head of Unit, Drug Information Navarre Health Service, Spain
Conflict of Interest:
Pre-test probability in the new ESC guidelines or appropriateness criteria.
We read with great interest the recent article by Bhattacharyya et. al.1 They state that a high proportion (71/250) of stress echocardiograms (SE) were performed on low risk patients and were inappropriate, concluding that implementation of diagnostic appropriateness criteria2 would reduce this.
Appropriateness criteria2 published in 2011 reviewed clinical scenarios warranting SE and graded these on a scale of 1 to 9. Classifying patients into 3 categories, appropriate (grade 7-9), uncertain (grade 4-6) and inappropriate (grade 1-3). The 2013 ECS guidelines3 for investigation of stable coronary artery disease (CAD) recommends functional testing for patients with intermediate (15-85%) pre-test probability (PTP). However, Bhattacharyya et. al. do not elaborate on the PTP of patients in each classification. Thus, in accordance with new ESC guideline SE may have been appropriate in some of the patients classified as uncertain or inappropriate.
Furthermore, a proportion of patients classified as inappropriate included previously revascularised patients with stable symptoms. Cardiologists may feel obliged to perform investigations on symptomatic previously revascularised patients, often with invasive coronary angiography, even if they are stable with a negative SE within the previous two years. To reduce the burden on SE, cardiac CT is a viable alternative that demonstrates grafts and proximal stent patency.
Finally, NICE, ESC and ACC/AHA guidelines all differ in diagnostic guidelines, enabling cardiologists to use their experience and local expertise to select the most appropriate investigation for individual patients.
Conflict of Interest:
Re:Scaling cardiac dimensions to body size is crucial in the cardiovascular care of elite athletes
Dear Professor Pressier,
Thank you for your correspondence with respect to our study (1). We have read your paper (2) with interest and congratulate you on an important paper providing further empirical evidence to support more appropriate methods of generating body size independent cardiac indices. We are delighted your data demonstrated the importance of fat free mass something we and others have proposed empirically before and represented in previous review articles (3, 4). Your recent study is a very insightful contribution to this field and we hope others in the clinical field read this work and follow suit. We feel our additional comments in the meta- analysis support a revisionist approach to the use of cardiac indices.
We would go further though and not stop at structural data and charge all interested groups to look at how key functional data are indexed. We have some empirical data published in respect of longitudinal tissue velocities (5) and we feel this work should be extended.
References 1. Utomi V, Oxborough D, Whyte GP, Somauroo J, Sharma S, Shave R, et al. Systematic review and meta-analysis of training mode, imaging modality and body size influences on the morphology and function of the male athlete's heart. Heart 2013;99:1727-1733. 2. Pressler A, Haller B, Scherr J, Heitkamp D, Esefeld K, Boscheri A, et al. Association of body composition and left ventricular dimensions in elite athletes. European Journal of Preventive Cardiology. 2012;19(5):1194 -204. 3. Batterham A, George K, Whyte G, Sharma S, McKenna W. Scaling cardiac structural data by body dimensions: a review of theory, practice, and problems. Int J Sports Med. 1999;20(8):495-502. 4. Dewey F, Rosenthal D, Murphy DJ, Froelicher V, Ashley E. Does size matter? Clinical applications of scaling cardiac size and function for body size. Circulation. 2008;117(17):2279-87. 5. Oxborough D, Batterham AM, Shave R, Artis N, Birch KM, Whyte G, et al. Interpretation of two-dimensional and tissue Doppler-derived strain (?) and strain rate data: is there a need to normalize for individual variability in left ventricular morphology? Eur J Echocardiogr. 2009;10(5):677-82.
Conflict of Interest:
Re:Scaling cardiac dimensions to body size is crucial in the cardiovascular care of elite athletes
Dear Professor Pressier,
Many thanks for your correspondence. Your recent study is a very important contribution to this field of research.
A meta-analysis is of course dependent on the validity of the study- level metrics that are reported by authors, and this is why we inserted the very important point about allometric scaling in our discussion.
I have been confronted with this issue also when meta-analysing studies on percentage flow mediated dilation, which may not be the most precise scaling index to employ for the change in arterial diameter.
So thank you again and I personally agree with everything you say.
Conflict of Interest:
Baseline artery diameter confounds flow-mediated dilation only if a percentage change is selected as the size-scaling index
Dear Editor, Maruhashi et al. meticulously measured the flow-mediated changes in brachial artery diameter with a large sample of participants. The changes in diameter were quantified using the conventional percentage-based index (FMD%). As usual, baseline artery diameter (Dbase) was found to be substantially and negatively correlated with FMD%. So it seems that even the most robust protocols and precise measurements of arterial diameters cannot eradicate the FMD%-Dbase correlation. This is not surprising because it is the FMD% index itself that causes this Dbase-dependency .
It seems illogical to persist in quantifying endothelial "function" with FMD% when it is so erroneously dependent on the structural/morphological variable that is its denominator. The FMD% index was presumably selected to "normalise" the flow-mediated response for variability in Dbase. But the flow-mediated response itself (measured in mm) tends to be uncorrelated to Dbase, or is even inversely proportional to Dbase. The overriding problem is that FMD% "works" only if this flow -mediated response is consistently, substantially and positively proportional to Dbase. This incongruity between the nature of the physiological change and the index used to describe that change means that FMD% itself creates the substantial negative dependency of FMD% on Dbase .
Physiological explanations have been forwarded for the FMD%-Dbase correlation  but such explanations are putting the "cart before the horse". Because the output of the protocol, the FMD% index, is the source of the Dbase-dependency problem rather than the physiological changes that are occurring during the protocol, any further physiological explanations for FMD%-Dbase dependency are unsatisfactory. For example, the shear rate explanation for Dbase-dependency forwarded by Pyke et al. and repeated by Maruhashi et al. is inconsistent with the fact that FMD% depends on Dbase even when calculated from randomly-generated data with no physiological basis at all . If the flow-mediated response was scaled to Dbase properly in the first place, there would be no substantial negative correlation between these two variables, and so no need to explain and correct with other variables. Such circular logic is avoided by appropriate size scaling in the first place. Then the influence of other important variables, e.g., shear rate, on the flow-mediated response per se can be quantified more precisely.
I agree that Dbase should be taken into consideration as a confounder of FMD%. A full consideration of this problem has surfaced recently and, as in the study by Maruhashi et al., been applied to age- and sex- differences in the flow-mediated response . The FMD% index is higher in women than in men simply because FMD% does not scale properly for the lower Dbase in women. Similarly, Dbase increases with age, thus biasing age-related changes when FMD% is selected as the outcome of interest . As long as FMD% is the index used to quantify the relative flow-mediated response, such inferential errors will occur, and these errors cannot be corrected parsimoniously with any physiological mechanisms. If FMD% was replaced with a more accurate scaling index, Dbase-dependency, and the associated interpretive problems would be eradicated.
1. Maruhashi T, Soga J, Fujimura N, et al. Relationship between flow- mediated vasodilation and cardiovascular risk factors in a large community -based study. Heart 2013;991837-1842.
2. Atkinson G, Batterham AM. Allometric scaling of diameter change in the original flow-mediated dilation protocol. Atherosclerosis 2013;226:425 -427
3. Pyke KE, Dwyer EM, Tschakovsky ME. (2004) Impact of controlling shear rate on flow-mediated dilation responses in the brachial artery of humans. J Appl Physiol 97: 499-508
Conflict of Interest:
Hypertension in the Elderly
We read with interest the correspondence of Luis Carlos Saiz regarding our meta-analysis on the effects of antihypertensive treatment in patients over 65 years of age. The author asserts the INternational VErapamil SR-Trandolapril STudy (INVEST) trial  should not have been included in the meta-analysis as it did not recruit a predominantly elderly population.
INVEST enrolled a total of 22,576 patients from 862 sites with the majority of patients being women (52%) with a mean age of 66 years (in our analysis one of the inclusion criteria is mean age of 65 years or above). Approximately one third of patients were older than 70 years and more than 2,000 patients were >85 years old, making this one of the largest randomized subgroups to be reported among older patients. Therefore, it was reviewed and included in the ACCF/AHA 2011 expert consensus document on hypertension in the elderly .
Secondary analysis from INVEST trial showed that for patients more than 70 years old higher systolic blood pressure was associated with less risk for death, myocardial infarction, or stroke then SBP lower than 130 mmHg . These findings are in accordance with the results of our sensitivity analysis for patients 70 years old or older, which did not include the INVEST study. Additionally, the J-curve association between blood pressure and primary outcomes was similar for those above and below the age of 65 .
We would agree with the author that more data from studies on exclusively elderly population are required. However, we believe that the currently available evidence is against author's assertion that the INVEST trial should have been excluded from the analysis.
1. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil- Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805-16.
2. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123:2434-2506.
3. Denardo SJ, Gong Y, Nichols WW, et al. Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an international verapamil ST-Trandolapril (INVEST) substudy. Am J Med. 18 2010;123:719-26.
4. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-93.
Conflict of Interest:
The possible impact of lack of ethnic and geographical diversity on the association of MTHFR mutations, homocysteine levels and heart disease outcomes
Methylenetetrahydrofolate reductase (MTHFR) plays an important role in conversion of homocysteine to methionine by catalyzing the production of 5-methyl tetrahydrofolate hence effectively decreasing plasma homocysteine levels. The MTHFR 677C>T nonsynonymous single nucleotide polymorphism (SNP) leads to a substitution of Valine for Alanine and results in the formation of a thermolabile variant of the enzyme with decreased basal enzymatic activity (1) resulting in increased homocysteine levels. The minor allele (T) of this SNP described in the study by Mehling at al was found to be associated with increased plasma homocysteine levels however the ancestral allele (C) was associated with an increased risk for coronary artery disease (CAD)(2). This finding is counter-intuitive and contrary to a large meta-analysis performed by Klerk et al involving a total of 11,162 cases and 12,758 controls that found that carriers of the minor allele T for this SNP had higher homocysteine levels and 16% higher risk of CAD (3). The increased risk for CAD in the TT genotype was related to lower folate concentrations.
The limitations of the study by Mehling et al are the failure to replicate their original findings in the INTERGENE cohort and a failure to measure folate levels. The study by Klerk et al did not find an increased risk for CAD in the minor allele carriers who had high folate concentrations. Another important limitation of this and other such studies due to the homogeneous European population studied is not to account for the racial diversity that exists with the MTHFR 677C>T genotype. The TT genotype is common in Mexico (32%), northern China (20%) and newborns of American Hispanic Ancestry (18%) as compared to a prevalence of 7% in the Swedish population studied by Mehling et al which could have accounted for the negative findings (4). Despite the higher prevalence of this SNP in these populations, studies examining the association of this genotype with homocysteine levels and CAD risk in these populations are scarce. The impact of such studies if performed in these countries or ethnic populations could potentially be far reaching by allowing assessment of preventive measures such as folate replacement on vascular and other complications associated with higher homocysteine levels in subjects carrying the susceptible TT genotype.
References (1)Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Denheijer M, Kluijtmans LAJ, Vandenheuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-113
(2)K Mehlig, K Leander, U de Faire, F Nyberg, C Berg, A Rosengren, L Bj?rck, H Zetterberg, K Blennow, G Tognon, K Tor?n, E Strandhagen, L Lissner, and D Thelle The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C>T polymorphism. Heart 2013;99:1761-1765
(3)Klerk, M., Verhoef, P., Clarke, R., Blom, H. J., Kok, F. J., Schouten, E. G., MTHFR Studies Collaboration Group. MTHFR 677C-T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288: 2023-2031
(4)Wilcken, B., Bamforth, F., Li, Z., Zhu, H., Ritvanen, A., Renlund, M., Stoll, C., Alembik, Y., Dott, B., Czeizel, A. E., Gelman-Kohan, Z., Scarano, G., and 19 others. Geographical and ethnic variation of the 677C- T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J. Med. Genet. 2003;40: 619-625
Conflict of Interest:
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