APICAL ANEURYSM ? OR TRANSIENT APICAL BALLOONING ? : A POTENTIAL DILEMMA IN RISK-STRATIFICATION OF HYPERTROPHIC CARDIOMYOPATHY
Kenan YALTA, MD a
Muhammet GURDOGAN, MD a
Orkide PALABIYIK, MD b
a,Trakya University, Cardiology Department, Edirne, TURKEY
b Trakya University, Department of Biophysics, Edirne, TURKEY
Corresponding Author: Kenan YALTA Trakya University, Cardiology Department, Edirne, TURKEY
Email- kyalta@gmail.com, akenanyalta@trakya.edu.tr Phone: 00905056579856
Left ventricular apical aneurysm (LVAA) formation in the setting of hypertrophic cardiomyopathy (HCM) usually appears to be associated with a significant mid-ventricular obstruction, and is potentially associated with adverse cardiovascular events (1). In their recently published article (1), Ramchand J et al have suggested LVAA as a major risk marker in this setting. Though we fully agree with the authors on this point, we would like to draw attention to certain other conditions including transient LV apical ballooning that might strongly mimick LVAA leading to a potential misdiagnosis in patients with HCM:
Takotsubo cardiomyopathy (TTC) presenting with a transient apical ballooning pattern has been recently suggested to have a pure mechanical basis in certain patients with pre-existing structural heart diseas...
APICAL ANEURYSM ? OR TRANSIENT APICAL BALLOONING ? : A POTENTIAL DILEMMA IN RISK-STRATIFICATION OF HYPERTROPHIC CARDIOMYOPATHY
Kenan YALTA, MD a
Muhammet GURDOGAN, MD a
Orkide PALABIYIK, MD b
a,Trakya University, Cardiology Department, Edirne, TURKEY
b Trakya University, Department of Biophysics, Edirne, TURKEY
Corresponding Author: Kenan YALTA Trakya University, Cardiology Department, Edirne, TURKEY
Email- kyalta@gmail.com, akenanyalta@trakya.edu.tr Phone: 00905056579856
Left ventricular apical aneurysm (LVAA) formation in the setting of hypertrophic cardiomyopathy (HCM) usually appears to be associated with a significant mid-ventricular obstruction, and is potentially associated with adverse cardiovascular events (1). In their recently published article (1), Ramchand J et al have suggested LVAA as a major risk marker in this setting. Though we fully agree with the authors on this point, we would like to draw attention to certain other conditions including transient LV apical ballooning that might strongly mimick LVAA leading to a potential misdiagnosis in patients with HCM:
Takotsubo cardiomyopathy (TTC) presenting with a transient apical ballooning pattern has been recently suggested to have a pure mechanical basis in certain patients with pre-existing structural heart disease including hypertensive heart disease and HCM largely attributable to acute increments in intraventricular pressure gradient leading to substantially elavated apical wall stress in these patients (2,3). Interestingly, TTC in this setting might have no preceding overt stressors (emotional, etc.) (3), and might be clinically silent generally with vague symptoms and signs along with a relatively delayed recovery pattern (hence; might potentially arise as a sole incidental finding on cardiac imaging). Nevertheless, there might still exist certain imaging clues to differentiate between true LVAA and transient apical ballooning in the setting of HCM:
Firstly; pronounced wall thinning is mostly present in true LVAA (excluding cases with severe apical hypertrophy at baseline) as opposed to transient apical ballooning that generally presents with normal or increased wall thickness.
Secondly; LVAA generally emerges due to a chronic and significant mid-ventricular gradient (1) leading to progressive structural remodeling in the apex. However, mid-ventricular gradient is relatively mild in the setting of apical ballooning that might have been induced by an abrupt, yet; transient elevation of this mild gradient to excessive levels leading to stunning in apical segments (2,3) usually without any preconditioning to such pressure elevations.
And lastly; late gadolinium enhancement (LGE) on MRI is an expected finding in LVAA (1) while it is relatively rare (and with a low-intensity pattern) in TTC (4) presenting with an apical ballooning pattern.
In summary; transient apical ballooning should also be taken into consideration in HCM patients suggestive of having a LVAA pattern on initial imaging. Therefore, a single echocardiographic examination might not suffice for decision-making for primary implantable cardiac defibrillator (ICD) therapy suggesting detailed and serial examinations along with MRI for absolute confirmation of an irreversible true LVAA in these patients.
Conflict of interest: None
REFERENCES:
1- Ramchand J, Fava AM, Chetrit M, Desai MY. Advanced imaging for risk stratification of sudden death in hypertrophic cardiomyopathy. Heart. 2020 Jan 16. pii: heartjnl-2019-315176. doi: 10.1136/heartjnl-2019-315176. [Epub ahead of print]
2- Yalta K, Yilmaztepe M, Zorkun C. Left Ventricular Dysfunction in the Setting of Takotsubo Cardiomyopathy: A Review of Clinical Patterns and Practical Implications. Card Fail Rev. 2018; 4(1): 14-20.
3- Azzarelli S, Galassi AR, Amico F, et al. Intraventricular obstruction in a patient with tako-tsubo cardiomyopathy. Int J Cardiol. 2007; 121(2): e22-4.
4- Abbas A, Sonnex E, Pereira RS, Coulden RA. Cardiac magnetic resonance assessment of takotsubo cardiomyopathy. Clin Radiol. 2016; 71(1): e110-9.
As a physician dealing with patients with confirmed or suspected Fabry disease, I've read with great interest this editorial. This is a very thought-provoking article, which introduces the process of reclassification of a prevalent variant in the GLA gene associated with the cardiac variant of Fabry disease. I would like to make only a minor correction regarding the nomenclature of the variant mentioned. As written in the article of Valtola et al, the referred variant is c.427G> A and not c.472G> A¹ (transcript NM_000169.2).
1. Valtola K, Nino-Quintero J, Hedman M, et al. Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene. Heart 2020;:heartjnl-2019-315933. doi:10.1136/heartjnl-2019-315933
In clinical practice, coronary artery aneurysms (CAAs) in the setting of Kawasaki disease (KD) mostly evolve in the earlier stages, and generally reach their maximum size by 6 weeks after disease onset (1). Importantly, they are mostly encountered in untreated cases, and are strongly associated with the disease severity (and in particular; the degree of acute necrotizing vasculitis) (1). In their recently published enlightening report (2), Brogan P have discussed long-term management of KD patients with a particular emphasis on CAAs in this setting (2). However, we would like to comment on a specific phenomenon, namely ‘late CAA’ formation that might emerge even several months to years after the index KD:
Firstly, late CAAs were previously defined as new CAAs emerging at the same location of a previously regressed CAA, and were attributed to hemodynamic and residual pathological abnormalities along the arterial wal...
In clinical practice, coronary artery aneurysms (CAAs) in the setting of Kawasaki disease (KD) mostly evolve in the earlier stages, and generally reach their maximum size by 6 weeks after disease onset (1). Importantly, they are mostly encountered in untreated cases, and are strongly associated with the disease severity (and in particular; the degree of acute necrotizing vasculitis) (1). In their recently published enlightening report (2), Brogan P have discussed long-term management of KD patients with a particular emphasis on CAAs in this setting (2). However, we would like to comment on a specific phenomenon, namely ‘late CAA’ formation that might emerge even several months to years after the index KD:
Firstly, late CAAs were previously defined as new CAAs emerging at the same location of a previously regressed CAA, and were attributed to hemodynamic and residual pathological abnormalities along the arterial wall (3). However, we hold the opinion that these aneurysms mostly arise as a ‘de novo’ phenomenon in apparently normal or mildly affected coronary segments (and hence not associated with severe necrotizing vasculitis at the onset), and might potentially be associated with dysfunctional vascular healing in the long-term (potential under-healing due to prolonged steroid use for KD or other purposes, diabetes, etc).
Secondly, as analogous to progressive aortic remodeling in connective tissue disease, an over-healing process leading to excessive vascular remodeling in the long-term (largely through genetically determined and enhanced actions of certain profibrotic substances including transforming growth factor-beta (TGF-ß) (1), ,etc.and certain enzymes including matrix metalloproteinase-9 (MMP-9)) has been previously reported in KD, and might also serve as an alternative mechanism of late CAA evolution (4-6) particularly in coronary segments with pre-existing mild vasculitis as well.
Thirdly, based on potential favorable impact of captopril on prevention of classical early CAA formation (through inhibition of MMP-9) (5), blockade of renin-angiotensin system might also be indicated indefinitely in the presence of high-risk features (persistently high levels of profibrotic mediators and MMP-9, etc.) for prevention of late CAA evolution.
Lastly, even though late CAA, reportedly appears to have a more favorable prognosis (3) (due to its smaller size and low incidence of intramural thrombus formation, etc as compared with classical CAA), close supervision of long-term changes in coronary morphology (even in the presence of normal or near-normal coronary arteries at 6 weeks) may also be indicated in high-risk patients for timely initiation of further management strategies (anticoagulation, etc.). Interestingly, since late CAAs might be associated with progressive arterial remodeling involving intima and media layers (4,6), they may possibly be more prone to specific complications including spontaneous coronary artery dissection (SCAD) in comparison to classical CAAs with substantial multi-layer necrosis.
In conclusion, late CAA formation in KD might be regarded as an under-recognized phenomenon with important implications, and might constitute a significant portion of idiopathic coronary aneurysms on routine coronary imaging regardless of confirmed KD history. However, further insights of this phenomenon still remain to be established.
Conflict of interest: None
REFERENCES:
1- Newburger JW, Takahashi M, Burns JC. Kawasaki Disease. J Am Coll Cardiol. 2016 ;67(14):1738-49.
2- Brogan P, Burns JC, Cornish J, et al. Lifetime cardiovascular management of patients with previous Kawasaki disease. Heart 2019;0:1–10. doi:10.1136/heartjnl-2019-315925
3- Tsuda E, Kamiya T, Ono Y, et al. Dilated coronary arterial lesions in the late period after Kawasaki disease. Heart. 2005; 91(2): 177-82.
4- Suzuki A, Miyagawa-Tomita S, et al. Remodeling of coronary artery lesions due to Kawasaki disease: comparison of arteriographic and immunohistochemical findings. Jpn Heart J. 2000 ;41(3):245-56.
5- Inoue N, Takai S, Jin D, et al. Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease. Clin Chim Acta. 2010; 411(3-4): 267-9.
6- Toyono M, Shimada S, Aoki-Okazaki M, et al. Expanding coronary aneurysm in the late phase of Kawasaki disease. Pediatr Int. 2012; 54(1): 155-8.
We thank Dr Althouse for his letter and the interests in our article and for taking time to send us his comments. We appreciate it very much.
In Figure 1, in scenario C, we incorporated the findings of “equivalence” in cases of equivalence trials. We stated in the article under the section of “Equivalence trials versus non-inferiority trials” that, in equivalence trials, the significance level is set as a two-sided p value of 0.05. We agree that, in non-inferiority trials, a one-sided p value of 0.025 is usually set as the significant level, although in some non-inferiority trials in cardiology, a significance level of one-sided p value of 0.05 was used. This is also mentioned under the same section. We have considered using a separate figure in the submission. However, we decided to submit a single figure as the separate figure incorporating only equivalence trials may be too simple and not the focus of the discussion.
In scenario E, the lower limit of the confidence intervals is below 1 and the upper limit of the confidence interval is above the non-inferior margin. Therefore, the null hypothesis that the new treatment is inferior to standard treatment cannot be rejected and the alternative hypothesis that the new treatment is non-inferior to standard treatment cannot be accepted. We agree that the interpretation is more correctly stated as “New treatment not non-inferior to standard treatment”. Alternatively, as Dr Althouse suggested “New treatment...
We thank Dr Althouse for his letter and the interests in our article and for taking time to send us his comments. We appreciate it very much.
In Figure 1, in scenario C, we incorporated the findings of “equivalence” in cases of equivalence trials. We stated in the article under the section of “Equivalence trials versus non-inferiority trials” that, in equivalence trials, the significance level is set as a two-sided p value of 0.05. We agree that, in non-inferiority trials, a one-sided p value of 0.025 is usually set as the significant level, although in some non-inferiority trials in cardiology, a significance level of one-sided p value of 0.05 was used. This is also mentioned under the same section. We have considered using a separate figure in the submission. However, we decided to submit a single figure as the separate figure incorporating only equivalence trials may be too simple and not the focus of the discussion.
In scenario E, the lower limit of the confidence intervals is below 1 and the upper limit of the confidence interval is above the non-inferior margin. Therefore, the null hypothesis that the new treatment is inferior to standard treatment cannot be rejected and the alternative hypothesis that the new treatment is non-inferior to standard treatment cannot be accepted. We agree that the interpretation is more correctly stated as “New treatment not non-inferior to standard treatment”. Alternatively, as Dr Althouse suggested “New treatment is neither inferior nor non-inferior” can be used.
I submit this comment on the recent publication by Leung et al entitled “Non-inferiority trials in cardiology: what clinicians need to know” (1) which I believe has a slight error that merits correction.
On Figure 1 in the original publication, the label says that Result E shows “New treatment inferior” but that is not a correct interpretation. The text in the footnote (“the upper bound of the 95% CI exceeds the predetermined non-inferior margin. Therefore, the new treatment is inferior to standard treatment”) is also incorrect. The data shown in Result E are not sufficient to declare a non-inferiority hypothesis met (the upper limit of the CI for relative risk is above the non-inferiority margin) but nor are they sufficient to declare the new treatment inferior (the lower limit of the CI for relative risk is below the null value). Therefore, the correct label for Result E is “New treatment neither inferior nor non-inferior.” The new treatment would only be declared inferior to the standard treatment in cases F and G (where the lower limit of the 95% CI for relative risk is above the null).
REFERENCE
1. Leung JT, Barnes SL, Lo ST, Leung DY. Non-inferiority trials in cardiology: what clinicians need to know. Heart 2019 [epub ahead of print]
Some of the risk factors for atrial fibrillation(AF) mentioned by the authors, such as hypertension, diabetes, sleep apnoea, older age, and lack of exercise, respectively(1), are also risk factors for myocardial stiffness(2)(3)(4)(5)(6). Myocardial stiffness, in turn, is a risk factor for atrial remodeling in the canine heart(7), and a parameter associated with paroxysmal AF in structurally normal human hearts(8). What is more, exercise has been shown to be capable of reversing myocardial stiffness, both in animals(9), and in human subjects(10).
In the more specific context of left atrial stiffness, obesity has emerged as a risk factor for left atrial stiffness(11)(12). Among patients with obesity, hypertension, and diabetes, respectively, a link has been hypothesised between the twin entities of left ventricular stiffness and depressed atrial compliance, on the one hand, and the development of myocardial fibrosis.(12) . The authors of the latter hypothesis proposed that obesity, hypertension and diabetes generated a systemic proinflammatory state which culminated in the emergence of the coexistence of stiff cardiomyocytes and interstitial fibrosis(12). Furthermore, in a study where the assumption was made that the existence of low voltage areas was a surrogate for left atrial fibrosis, the presence of a left atrial low voltage burden exceeding 10% was shown to be associated with significantly(p < 0.0001) higher left atrial stiffness index((LASI)(13)....
Some of the risk factors for atrial fibrillation(AF) mentioned by the authors, such as hypertension, diabetes, sleep apnoea, older age, and lack of exercise, respectively(1), are also risk factors for myocardial stiffness(2)(3)(4)(5)(6). Myocardial stiffness, in turn, is a risk factor for atrial remodeling in the canine heart(7), and a parameter associated with paroxysmal AF in structurally normal human hearts(8). What is more, exercise has been shown to be capable of reversing myocardial stiffness, both in animals(9), and in human subjects(10).
In the more specific context of left atrial stiffness, obesity has emerged as a risk factor for left atrial stiffness(11)(12). Among patients with obesity, hypertension, and diabetes, respectively, a link has been hypothesised between the twin entities of left ventricular stiffness and depressed atrial compliance, on the one hand, and the development of myocardial fibrosis.(12) . The authors of the latter hypothesis proposed that obesity, hypertension and diabetes generated a systemic proinflammatory state which culminated in the emergence of the coexistence of stiff cardiomyocytes and interstitial fibrosis(12). Furthermore, in a study where the assumption was made that the existence of low voltage areas was a surrogate for left atrial fibrosis, the presence of a left atrial low voltage burden exceeding 10% was shown to be associated with significantly(p < 0.0001) higher left atrial stiffness index((LASI)(13). The relationship between left atrial stiffness and AF is exemplified by the observation that patients with a burden of left atrial low voltage areas(LA-LVA) exceeding 10% had a significantly(p=0.0002) higher prevalence of non-paroxysmal AF than counterparts without LV-LVA(13). Furthermore, meta-analysis has confirmed that left atrial stiffness is a risk factor for recurrence of AF in patients undergoing radiofrequency catheter ablation(14). Arguably in view of these observations(12)(13(14) the hypothesis has emerged that "atrial fibrosis is a disease process that triggers the initiation and maintenance of the syndrome of AF"(15). Accordingly lifestyle modification is mandatory, not only for treatment of atrial fibrillation(1) but also , as far as is practicable, for its prevention.
I have no funding and no conflict of interest
References
(1`) Middeldorp ME., Ariyaratnam J., Lau D., Sanders P
Lifestyle modification for treatment of atrial fibrillation
Heart 2019 doi:10.1136/heartjnl-2019-315327
(2)Cvijic M., Bezy S., Petrescu A et al
Interplay of cardiac remodelling and myocardial stiffness in hypertensive heart disease: a shear wave imaging study using high-frame rate echocardiography
Eur Heart J Cardiovasc Imaging 2019;Epub ahead of print. doi:10.1093/ehjci/jez205
(3)Benech JC., Benech N., Zambrana AI et al
Diabetes increases stiffness of live cardiomyocytes measured by atomic force microscopy nanoindentation
Am J Physiol Cell Physiol 2014;307:C910-C919
(Farre N., Otero J., Falcones B et al
Intermittent hypoxia mimicking sleep apnea increases passive stiffness of myocardial extracellular matrix. A multiscale study
Frontiers in Physiology doi:10.3389/phys.2018.01143
(5) Lieber SC., Aubry N., Pain J et al
Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation
Am J Physiol Heart Circ Physiol 2004;287:I1645-I1651
(6) Lalande S., Mueller PJ., Chung CS
The link between exercise and Titin passive stiffness
Exp Physiol 2017;102;1055-1066
(7) Zakeri R., Moulay G., Chai Q et al
Left atrial remodeling and atrioventricular coupling in a canine model of early heart failure with preserved ejection fraction
Circ Haert Fail 2016;9:doi:10.1161/CIRCHEARTFAILURE:115;003238
(8)Uetake S., Maruyama M., Yamamoto T et al
Left ventricular stiffness estimated by diastolic wall strain is associated with paroxysmal atrial fibrillation in structurally normal hearts
Clinical Cardiology 2016;39:728-732
(9) Slater RE., Strom JG., Granzier H
Effect of exercise on passive myocardial stiffness in mice with diastolic dysfunction
J Mol Cell Cardiol 2017;108:24-33
(10) Howden EJ., Sarma S., Lawley JS et al
Reversing the cardiac effects of sedentary aging in middle age .A randomized controlled trial
circulation 2018;137:1549-1560
(11) Mahfouz RA., Gomma A., Goda M., safwat M
Relation of left atrial stiffness to insulin resistance in obese children: Doppler strain imaging study
Echocardiography 2018;32:1157-1163
(12) Paulus WJ., Tschope C
A novel paradigm for heart failure with preserved ejection fraction
JACC 2013;62:263-271
(13)Kishima H., Mine T., Fukuhara E., Ashida K., Ishihara M
The association between left atrial stiffness and low-grade areas of left atrium in patients with atrial fibrillation
Heart and Vessels 2019;34;1830-1838
(14) de Oliveira Correia E., dos Santos Barbetta l., da Silva CMP., Mesquita ET
Left atrial stiffness A predictor of atrial fibrillation recurrence after radiofrequency catheter ablation. A systematic review and meta-analysis
Arq Bras Cardiol 2019;112:501-508
(15) gal P., Marrouche NF
Magnetic resonance imaging of atrial fibrosis : redefining atrial fibrillation to a syndrome
Eur Heart J 2017;38;14-19
We have read with interest the review published by Goldsweig et al of predictors of readmission after transcatheter aortic valve replacement (TAVR) (1). We agree that identifying factors linked with a higher rate of readmission is of utmost importance. In this review, several clinical and procedural factors have been identified as predictors of adverse events after TAVR. However, the potential value of biomarkers for risk stratification in this setting has also been suggested in the literature. Several biomarkers have been tested for prognostic purposes; among them, we would like to highlight the role of Carbohydrate Antigen 125 (CA125). CA125 is a glycoprotein released by the mesothelial cells in response to increased hydrostatic pressures and/or inflammatory stimuli (2). Their levels are elevated in up to two-thirds of decompensated patients and correlated to parameters of clinical and echocardiographic congestion including pulmonary artery and right atrial pressures. Interestingly, its changes after discharge are strongly associated with the risk of adverse clinical events (2). In the setting of TAVR, baseline (pre-implant) CA125 levels were independent predictors of death and MACE (death, myocardial infarction, stroke, and readmission), even after adjusting for well-established prognostic factors, in an observational study (3). Interestingly, increases of CA125 at any time in the follow-up after TAVR were independently related to events, suggesting its usefulness not...
We have read with interest the review published by Goldsweig et al of predictors of readmission after transcatheter aortic valve replacement (TAVR) (1). We agree that identifying factors linked with a higher rate of readmission is of utmost importance. In this review, several clinical and procedural factors have been identified as predictors of adverse events after TAVR. However, the potential value of biomarkers for risk stratification in this setting has also been suggested in the literature. Several biomarkers have been tested for prognostic purposes; among them, we would like to highlight the role of Carbohydrate Antigen 125 (CA125). CA125 is a glycoprotein released by the mesothelial cells in response to increased hydrostatic pressures and/or inflammatory stimuli (2). Their levels are elevated in up to two-thirds of decompensated patients and correlated to parameters of clinical and echocardiographic congestion including pulmonary artery and right atrial pressures. Interestingly, its changes after discharge are strongly associated with the risk of adverse clinical events (2). In the setting of TAVR, baseline (pre-implant) CA125 levels were independent predictors of death and MACE (death, myocardial infarction, stroke, and readmission), even after adjusting for well-established prognostic factors, in an observational study (3). Interestingly, increases of CA125 at any time in the follow-up after TAVR were independently related to events, suggesting its usefulness not only to identify higher-risk patients before the procedure but also as a tool to anticipate events during follow-up (3). Moreover, CA125 showed to be a useful tool for improving risk stratification beyond EuroSCORE and natriuretic peptides (4; 5). Additionally, this biomarker offers some important logistic advantages. First, CA125 levels, conversely to natriuretic peptides, are not influenced by common confounders in TAVR patients such as renal dysfunction and age. Second, their wide availability and low cost make feasible its implantation in daily clinical practice.
In summary, we believe biomarkers may improve clinical evaluation in TAVR decision-making work out, adding valuable information to identify patients with worse prognosis after TAVR in which the procedure could be dismissed (considered as futile) or postposed after medical treatment optimization. Following TAVR, biomarkers may also play a relevant role in clinical monitoring. All these assumptions must be confirmed in prospective further studies.
References
1. Goldsweig A, Aronow HD. Identifying patients likely to be readmitted after transcatheter aortic valve replacement. Heart. 2019 Oct 24. pii: heartjnl-2019-315381.
2. Núñez J, Miñana G, Núñez E, Chorro FJ, Bodí V, Sanchis J. Clinical utility of antigen carbohydrate 125 in heart failure. Heart Fail Rev. 2014 Sep;19(5):575-84.
3. Husser O, Núñez J, Núñez E, Holzamer A, Camboni D, Luchner A et al. Tumor marker carbohydrate antigen 125 predicts adverse outcome after transcatheter aortic valve implantation. JACC Cardiovasc Interv. 2013 May;6(5):487-96.
4. Husser O, Núñez J, Burgdorf C, Holzamer A, Templin C, Kessler T et al. Improvement in Risk Stratification in Transcatheter Aortic Valve Implantation Using a Combination of the Tumor Marker CA125 and the Logistic EuroSCORE. Rev Esp Cardiol. 2017 Mar;70(3):186-193.
5. Rheude T, Pellegrini C, Schmid H, Trenkwalder T, Mayr NP, Joner M et al. Comparison of Carbohydrate Antigen 125 and N-Terminal Pro-Brain Natriuretic Peptide for Risk Prediction After Transcatheter Aortic Valve Implantation. Am J Cardiol. 2018 Feb 15;121(4):461-468.
This is a really important and interesting article. I would like to congratulate the authors with their work.
I do have one question with regard to figure 3B. The numbers needed to treat to harm (NNTH) in this table seem to have counterintuitive values, for instance see the value from the direct thrombin inhibitor, which is listed as 153, with a corresponding OR of harm of 2.63. This NNTH value is more or less equal to that of aspirin, which has a listed NNTH of 155, however, its corresponding OR for harm is much lower, namely 1.07. Similarly, the point estimate of the NNTH for standard dose Xa is 270 which is higher than that listed for low dose Xa inhibitor (187), while the respective ORs for harm show that standard-dose Xa inhibitor has a higher odds for harm. I realize that there is a possible logical explanation for these counterintuitive results, namely that the base rates of the placebo/observation condition vary significantly, but that would not be expected. Could the authors elaborate on this? Thank you very much in advance.
This is our response to a concern raised by a reader regarding the estimates and credible intervals of those numbers needed to treat to harm presented in our article titled “Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.”
First, we confirm that data published in the Journal are valid and correct.
We also like to thank the reader to point it out as a number needed (either for benefit or harm) derived from an effect estimate that crosses the unity has been intuitively challenging to visualize (Hutton JL. Br J Haematol. 2009;146:27-30). Because it is given by the reciprocal of the absolute risk difference, a number needed can never include zero but straddles plus and minus infinity ∞ when the absolute risk difference include zero. By the frequentist approach based on inverting the confidence interval of the absolute risk difference, it represents that the number needed encompasses two disjoint regions: one from upper confidence interval to plus ∞ and the other from lower confidence interval to minus ∞ (Altman DG. BMJ. 1998;317:1309-12). Some had argued that for those non-significant results, a number needed should be presented as a single number without its confidence interval as it includes the possibility of no benefit or harm (McQuay HJ. Ann Intern Med. 1997;126:712-20). Other had suggested that it should not be reported when being non-significant (McAlister FA. CMAJ. 2008;179:549-53).
This is our response to a concern raised by a reader regarding the estimates and credible intervals of those numbers needed to treat to harm presented in our article titled “Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.”
First, we confirm that data published in the Journal are valid and correct.
We also like to thank the reader to point it out as a number needed (either for benefit or harm) derived from an effect estimate that crosses the unity has been intuitively challenging to visualize (Hutton JL. Br J Haematol. 2009;146:27-30). Because it is given by the reciprocal of the absolute risk difference, a number needed can never include zero but straddles plus and minus infinity ∞ when the absolute risk difference include zero. By the frequentist approach based on inverting the confidence interval of the absolute risk difference, it represents that the number needed encompasses two disjoint regions: one from upper confidence interval to plus ∞ and the other from lower confidence interval to minus ∞ (Altman DG. BMJ. 1998;317:1309-12). Some had argued that for those non-significant results, a number needed should be presented as a single number without its confidence interval as it includes the possibility of no benefit or harm (McQuay HJ. Ann Intern Med. 1997;126:712-20). Other had suggested that it should not be reported when being non-significant (McAlister FA. CMAJ. 2008;179:549-53).
Our analyses with the Bayesian approach based on probability derived a number needed from the posterior distribution of the reciprocal of the absolute risk difference. Mathematically, its distribution stretches from minus ∞ to plus ∞ and can be bi-modal (as the probability of a number needed being zero is zero) (Thabane L. Biostatistics. 2003;4:365-70). The median of a number needed falls within its credible interval.
We also provided the estimates of the absolute risk difference in Supplementary table 3. When using them by the frequentist approach, the number needed to treat to harm (95% credible interval) is 4560 (-368, 110), 95 (16, 3461), 87(23, 348), 805 (-381, 56), 363 (-854, 56), and 184 (-1103, 17) for aspirin, low-intensity vitamin K antagonist, standard-intensity vitamin K antagonist, low-dose factor Xa inhibitor, standard-dose factor Xa inhibitor, and direct thrombin inhibitor, respectively.
We opted for presenting all numbers needed with their credible intervals by the Bayesian approach. However, neither the frequentist approach nor the Bayesian approach is ideal when reporting non-significant results. It should take extra caution when using and interpreting a number needed derived from an effect estimate that crosses the unity.
Finally, thank you for letting us clarify this.
Kang-Ling Wang and Marc Carrier
General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
Given the fact that some of the patients studied by Chou et al were characterised by the coexistence of , at least, four CHADS2 parameters, namely, Congestive heart failure, Hypertension, Age 75 or more, and Diabetes(1), it is to be expected that some of those patients will have stenotic cerebrovascular disease(both intracranial and extracranial)(2). In the latter study of 780 subjects presenting with stroke in the presence of nonvalvular atrial fibrillation(NVAF), concomitant cerebrovascular stenosis of 50% or more was identified in 231 patients. Multivariate analyses showed that CHADS2 score was an independent predictor of concomitant cerebral atherosclerosis(Odds Ratio 3.121; 95% Confidence Interval 1.770 to 5.504), and also a predictor of the presence of proximal stenosis at the symptomatic artery(OR, 3.043; 95% CI 1.458 to 6.350)(2).
When the CHADS2 score is associated with coronary heart disease(CHD) , as might have been the case in 1475 of the heart failure patients studied by Chou et al(1), CHADS2 predicts stroke in the total absence of NVAF(3). In the latter study, over a period of 5821 person-years of follow up, 40 out of 916 non anticoagulated patients with stable CHD and no NVAF suffered an ischaemic stroke/transient ischaemic attack. Compared with those with low(0-1) CHADS2 scores, those with progressively higher CHADS2 scores had a stepwise significant increase in rates of stroke/TIA(3). This increase in stroke rate might, arguably, hav...
Given the fact that some of the patients studied by Chou et al were characterised by the coexistence of , at least, four CHADS2 parameters, namely, Congestive heart failure, Hypertension, Age 75 or more, and Diabetes(1), it is to be expected that some of those patients will have stenotic cerebrovascular disease(both intracranial and extracranial)(2). In the latter study of 780 subjects presenting with stroke in the presence of nonvalvular atrial fibrillation(NVAF), concomitant cerebrovascular stenosis of 50% or more was identified in 231 patients. Multivariate analyses showed that CHADS2 score was an independent predictor of concomitant cerebral atherosclerosis(Odds Ratio 3.121; 95% Confidence Interval 1.770 to 5.504), and also a predictor of the presence of proximal stenosis at the symptomatic artery(OR, 3.043; 95% CI 1.458 to 6.350)(2).
When the CHADS2 score is associated with coronary heart disease(CHD) , as might have been the case in 1475 of the heart failure patients studied by Chou et al(1), CHADS2 predicts stroke in the total absence of NVAF(3). In the latter study, over a period of 5821 person-years of follow up, 40 out of 916 non anticoagulated patients with stable CHD and no NVAF suffered an ischaemic stroke/transient ischaemic attack. Compared with those with low(0-1) CHADS2 scores, those with progressively higher CHADS2 scores had a stepwise significant increase in rates of stroke/TIA(3). This increase in stroke rate might, arguably, have been attributable to left atrial dysfunction and its associated risk of concomitant left atrial prothrombotic milieu, given the fact that the study of 970 subjects(of whom only 35 had atrial fibrillation) showed that high CHADS2 score was associated with the lowest quartile of left atrial functional index (Odds Ratio 2.34, p=0.001)(4)
The association of older age and hypertension, also documented in the recent study(1), confers increased risk of carotid artery stenosis(CAS)(5). Given the fact that smoking also confers increased risk of CAS(5), it would be useful to ascertain the proportion of smokers in the study by Chou et al(1). Furthermore, according to the retrospective study of 3,435 NVAF patients who underwent carotid sonography, the prevalence of carotid plaques increased significantly with the increase in CHA2DS2-Vasc score(P for trend < 0.001). Multivariate logistic regression analysis showed that, for each 1 point increase in the CHA2DS2-Vasc score, there was a 37% increase in the prevalence of carotid plaques(6). Given the predictive power of CHADS2 for IS even in the absence of NVAF(3), the above observation could be extrapolated to heart failure patients who have a high CHADS2 score in the absence of NVAF. Occult paroxysmal atrial fibrillation(PAF), a parameter also not evaluated by Chou et al(1), may coexist with CAS, thereby compounding the risk of IS. The association of PAF and CAS was documented in a study which showed that CAS was prevalent in 13.5% of PAF patients of mean age 69(7).
In conclusion, for the sake of completeness, it would be useful to ascertain the proportion of smokers in the study by Chou et al(1). Documentation of PAF, left atrial functional index, and carotid artery sonography would also be useful indicators of the relative contributions of left atrial cardiomyopathy and CAS to IS prevalence in heart failure.
I have no funding and no conflict of interest
References
(1)Chou Y-L., Liou J-T., Cheng C-C., Tsai M-C., Lin W-S., Cheng S-M et al
The association of ischaemic stroke in patients with heart failure without atrial flutter/fibrillation
Heart 2019;doi:10.1136/heartjnl 2019-315646
(2) Kim DY., Cha MJ., Kim J., Lee DH., Lee HS., Nam CM., Nam HS et al
Increases in cerebral atherosclerosis according to CHADS2 scores in patients with stroke with nonvalvular atrial fibrillation#
STROKE 2011;42:930-934
(3) Welles CC., Whooley MA., Na B., Ganz P., Schiller NB., Turakhia MP
The CHADS2 score predicts ischemic stroke in the absence of atrial fibrillation among patients with coronary heart disease:Data from the Heart and Soul Study
Am Heart J 2011;162:555-561
(4)Azarbal F., Welles CC., Wong JM., Whooley MA., Schiller MB., Turakhia MP
Association of CHADS2, CHADS2-Vasc, R2CHADS2 scores with left atrial dysfunction in patients with coronary heart disease(from the Heart and Soul Study)
Am J Cardiol 2014;113;1166-1172
(5)Woo SY., Joh JH., Han S-A., Park H-C
Prevalence and risk factors for atherosclerotic carotid stenosis and plaque. A population-based screening study
Medicine 2017;96:4(e5999)
(6) Shang L., Zhao Y., Shao M., Sun H., Feng M., Li Y et al
The association of CHA2DS2-Vasc score and carotid plaque in patients with nonvalvular atrial fibrillation
LOS one 2019;14(2);e0210945
(7) Gu Y., Feng L., Xu Y., Zhao Y
Co-prevalence of carotid stenosis and coronary artery disease in Chinese patients with paroxysmal atrial fibrillation
Journal of International Medical Research 2014;42:1294-1300
APICAL ANEURYSM ? OR TRANSIENT APICAL BALLOONING ? : A POTENTIAL DILEMMA IN RISK-STRATIFICATION OF HYPERTROPHIC CARDIOMYOPATHY
Kenan YALTA, MD a
Muhammet GURDOGAN, MD a
Orkide PALABIYIK, MD b
a,Trakya University, Cardiology Department, Edirne, TURKEY
b Trakya University, Department of Biophysics, Edirne, TURKEY
Corresponding Author: Kenan YALTA Trakya University, Cardiology Department, Edirne, TURKEY
Email- kyalta@gmail.com, akenanyalta@trakya.edu.tr Phone: 00905056579856
Left ventricular apical aneurysm (LVAA) formation in the setting of hypertrophic cardiomyopathy (HCM) usually appears to be associated with a significant mid-ventricular obstruction, and is potentially associated with adverse cardiovascular events (1). In their recently published article (1), Ramchand J et al have suggested LVAA as a major risk marker in this setting. Though we fully agree with the authors on this point, we would like to draw attention to certain other conditions including transient LV apical ballooning that might strongly mimick LVAA leading to a potential misdiagnosis in patients with HCM:
Show MoreTakotsubo cardiomyopathy (TTC) presenting with a transient apical ballooning pattern has been recently suggested to have a pure mechanical basis in certain patients with pre-existing structural heart diseas...
As a physician dealing with patients with confirmed or suspected Fabry disease, I've read with great interest this editorial. This is a very thought-provoking article, which introduces the process of reclassification of a prevalent variant in the GLA gene associated with the cardiac variant of Fabry disease. I would like to make only a minor correction regarding the nomenclature of the variant mentioned. As written in the article of Valtola et al, the referred variant is c.427G> A and not c.472G> A¹ (transcript NM_000169.2).
1. Valtola K, Nino-Quintero J, Hedman M, et al. Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene. Heart 2020;:heartjnl-2019-315933. doi:10.1136/heartjnl-2019-315933
LATE CORONARY ANEURYSM FORMATION IN KAWASAKI DISEASE: A SUBTLE PHENOMENON WITH POTENTIAL IMPLICATIONS
Kenan YALTA, MD
Muhammet GURDOGAN, MD
Gokay TAYLAN, MD
a,Trakya University, Cardiology Department, Edirne, TURKEY
Corresponding Author: Kenan YALTA Trakya University, Cardiology Department, Edirne, TURKEY
Email- kyalta@gmail.com, akenanyalta@trakya.edu.tr Phone: 00905056579856
In clinical practice, coronary artery aneurysms (CAAs) in the setting of Kawasaki disease (KD) mostly evolve in the earlier stages, and generally reach their maximum size by 6 weeks after disease onset (1). Importantly, they are mostly encountered in untreated cases, and are strongly associated with the disease severity (and in particular; the degree of acute necrotizing vasculitis) (1). In their recently published enlightening report (2), Brogan P have discussed long-term management of KD patients with a particular emphasis on CAAs in this setting (2). However, we would like to comment on a specific phenomenon, namely ‘late CAA’ formation that might emerge even several months to years after the index KD:
Show MoreFirstly, late CAAs were previously defined as new CAAs emerging at the same location of a previously regressed CAA, and were attributed to hemodynamic and residual pathological abnormalities along the arterial wal...
We thank Dr Althouse for his letter and the interests in our article and for taking time to send us his comments. We appreciate it very much.
In Figure 1, in scenario C, we incorporated the findings of “equivalence” in cases of equivalence trials. We stated in the article under the section of “Equivalence trials versus non-inferiority trials” that, in equivalence trials, the significance level is set as a two-sided p value of 0.05. We agree that, in non-inferiority trials, a one-sided p value of 0.025 is usually set as the significant level, although in some non-inferiority trials in cardiology, a significance level of one-sided p value of 0.05 was used. This is also mentioned under the same section. We have considered using a separate figure in the submission. However, we decided to submit a single figure as the separate figure incorporating only equivalence trials may be too simple and not the focus of the discussion.
In scenario E, the lower limit of the confidence intervals is below 1 and the upper limit of the confidence interval is above the non-inferior margin. Therefore, the null hypothesis that the new treatment is inferior to standard treatment cannot be rejected and the alternative hypothesis that the new treatment is non-inferior to standard treatment cannot be accepted. We agree that the interpretation is more correctly stated as “New treatment not non-inferior to standard treatment”. Alternatively, as Dr Althouse suggested “New treatment...
Show MoreI submit this comment on the recent publication by Leung et al entitled “Non-inferiority trials in cardiology: what clinicians need to know” (1) which I believe has a slight error that merits correction.
On Figure 1 in the original publication, the label says that Result E shows “New treatment inferior” but that is not a correct interpretation. The text in the footnote (“the upper bound of the 95% CI exceeds the predetermined non-inferior margin. Therefore, the new treatment is inferior to standard treatment”) is also incorrect. The data shown in Result E are not sufficient to declare a non-inferiority hypothesis met (the upper limit of the CI for relative risk is above the non-inferiority margin) but nor are they sufficient to declare the new treatment inferior (the lower limit of the CI for relative risk is below the null value). Therefore, the correct label for Result E is “New treatment neither inferior nor non-inferior.” The new treatment would only be declared inferior to the standard treatment in cases F and G (where the lower limit of the 95% CI for relative risk is above the null).
REFERENCE
1. Leung JT, Barnes SL, Lo ST, Leung DY. Non-inferiority trials in cardiology: what clinicians need to know. Heart 2019 [epub ahead of print]
Some of the risk factors for atrial fibrillation(AF) mentioned by the authors, such as hypertension, diabetes, sleep apnoea, older age, and lack of exercise, respectively(1), are also risk factors for myocardial stiffness(2)(3)(4)(5)(6). Myocardial stiffness, in turn, is a risk factor for atrial remodeling in the canine heart(7), and a parameter associated with paroxysmal AF in structurally normal human hearts(8). What is more, exercise has been shown to be capable of reversing myocardial stiffness, both in animals(9), and in human subjects(10).
Show MoreIn the more specific context of left atrial stiffness, obesity has emerged as a risk factor for left atrial stiffness(11)(12). Among patients with obesity, hypertension, and diabetes, respectively, a link has been hypothesised between the twin entities of left ventricular stiffness and depressed atrial compliance, on the one hand, and the development of myocardial fibrosis.(12) . The authors of the latter hypothesis proposed that obesity, hypertension and diabetes generated a systemic proinflammatory state which culminated in the emergence of the coexistence of stiff cardiomyocytes and interstitial fibrosis(12). Furthermore, in a study where the assumption was made that the existence of low voltage areas was a surrogate for left atrial fibrosis, the presence of a left atrial low voltage burden exceeding 10% was shown to be associated with significantly(p < 0.0001) higher left atrial stiffness index((LASI)(13)....
We have read with interest the review published by Goldsweig et al of predictors of readmission after transcatheter aortic valve replacement (TAVR) (1). We agree that identifying factors linked with a higher rate of readmission is of utmost importance. In this review, several clinical and procedural factors have been identified as predictors of adverse events after TAVR. However, the potential value of biomarkers for risk stratification in this setting has also been suggested in the literature. Several biomarkers have been tested for prognostic purposes; among them, we would like to highlight the role of Carbohydrate Antigen 125 (CA125). CA125 is a glycoprotein released by the mesothelial cells in response to increased hydrostatic pressures and/or inflammatory stimuli (2). Their levels are elevated in up to two-thirds of decompensated patients and correlated to parameters of clinical and echocardiographic congestion including pulmonary artery and right atrial pressures. Interestingly, its changes after discharge are strongly associated with the risk of adverse clinical events (2). In the setting of TAVR, baseline (pre-implant) CA125 levels were independent predictors of death and MACE (death, myocardial infarction, stroke, and readmission), even after adjusting for well-established prognostic factors, in an observational study (3). Interestingly, increases of CA125 at any time in the follow-up after TAVR were independently related to events, suggesting its usefulness not...
Show MoreThis is a really important and interesting article. I would like to congratulate the authors with their work.
I do have one question with regard to figure 3B. The numbers needed to treat to harm (NNTH) in this table seem to have counterintuitive values, for instance see the value from the direct thrombin inhibitor, which is listed as 153, with a corresponding OR of harm of 2.63. This NNTH value is more or less equal to that of aspirin, which has a listed NNTH of 155, however, its corresponding OR for harm is much lower, namely 1.07. Similarly, the point estimate of the NNTH for standard dose Xa is 270 which is higher than that listed for low dose Xa inhibitor (187), while the respective ORs for harm show that standard-dose Xa inhibitor has a higher odds for harm. I realize that there is a possible logical explanation for these counterintuitive results, namely that the base rates of the placebo/observation condition vary significantly, but that would not be expected. Could the authors elaborate on this? Thank you very much in advance.
This is our response to a concern raised by a reader regarding the estimates and credible intervals of those numbers needed to treat to harm presented in our article titled “Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.”
First, we confirm that data published in the Journal are valid and correct.
We also like to thank the reader to point it out as a number needed (either for benefit or harm) derived from an effect estimate that crosses the unity has been intuitively challenging to visualize (Hutton JL. Br J Haematol. 2009;146:27-30). Because it is given by the reciprocal of the absolute risk difference, a number needed can never include zero but straddles plus and minus infinity ∞ when the absolute risk difference include zero. By the frequentist approach based on inverting the confidence interval of the absolute risk difference, it represents that the number needed encompasses two disjoint regions: one from upper confidence interval to plus ∞ and the other from lower confidence interval to minus ∞ (Altman DG. BMJ. 1998;317:1309-12). Some had argued that for those non-significant results, a number needed should be presented as a single number without its confidence interval as it includes the possibility of no benefit or harm (McQuay HJ. Ann Intern Med. 1997;126:712-20). Other had suggested that it should not be reported when being non-significant (McAlister FA. CMAJ. 2008;179:549-53).
Our analyses with t...
Show MoreGiven the fact that some of the patients studied by Chou et al were characterised by the coexistence of , at least, four CHADS2 parameters, namely, Congestive heart failure, Hypertension, Age 75 or more, and Diabetes(1), it is to be expected that some of those patients will have stenotic cerebrovascular disease(both intracranial and extracranial)(2). In the latter study of 780 subjects presenting with stroke in the presence of nonvalvular atrial fibrillation(NVAF), concomitant cerebrovascular stenosis of 50% or more was identified in 231 patients. Multivariate analyses showed that CHADS2 score was an independent predictor of concomitant cerebral atherosclerosis(Odds Ratio 3.121; 95% Confidence Interval 1.770 to 5.504), and also a predictor of the presence of proximal stenosis at the symptomatic artery(OR, 3.043; 95% CI 1.458 to 6.350)(2).
Show MoreWhen the CHADS2 score is associated with coronary heart disease(CHD) , as might have been the case in 1475 of the heart failure patients studied by Chou et al(1), CHADS2 predicts stroke in the total absence of NVAF(3). In the latter study, over a period of 5821 person-years of follow up, 40 out of 916 non anticoagulated patients with stable CHD and no NVAF suffered an ischaemic stroke/transient ischaemic attack. Compared with those with low(0-1) CHADS2 scores, those with progressively higher CHADS2 scores had a stepwise significant increase in rates of stroke/TIA(3). This increase in stroke rate might, arguably, hav...
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