The residual risk of stroke in subjects with nonvalvular atrial fibrillation(NVAF) is, in part, attributable to coexistence of nonvalvular atrial fibrillation(NVAF) and high-grade(stenosis(50% or more severity) involving the intracranial arterial circulation(1). In the latter study concomitant high-grade cerebrovascular stenosis was identified in 231 of 780 consecutive subjects of mean age 69.5 who had undergone angiographic studies at index stroke(1). Coexistence of extracranial carotid artery stenosis(CAS) and NVAF is also a risk factor for residual stroke(2). In the latter study Chang et al identified high-grade CAS(>50% severity) which was ipsilateral to the index ischemic cerebral infarct in 15 out of 25 patients presenting with stroke(2).
Secondary prevention of stroke in NVAF patients who have the association of either high-grade stenotic intracranial cerebrovascular disease or high-grade CAS to which the index stroke can be attributed would entail coprescription of low-dose aspirin and an oral anticoagulant drug. Edoxaban would be a suitable candidate, given the fact that the 15 mg/day dose significantly mitigates the risk of stroke ( of presumably cardioembolic origin) in NVAF subjects aged 80 or more(3). That dose is even lower than the 30 mg/day dose which is associated with significantly(p < 0.001) lower risk of gastrointestinal bleeding than warfarin(4).
Primary prevention would require strict abstinence from smoking, str...
The residual risk of stroke in subjects with nonvalvular atrial fibrillation(NVAF) is, in part, attributable to coexistence of nonvalvular atrial fibrillation(NVAF) and high-grade(stenosis(50% or more severity) involving the intracranial arterial circulation(1). In the latter study concomitant high-grade cerebrovascular stenosis was identified in 231 of 780 consecutive subjects of mean age 69.5 who had undergone angiographic studies at index stroke(1). Coexistence of extracranial carotid artery stenosis(CAS) and NVAF is also a risk factor for residual stroke(2). In the latter study Chang et al identified high-grade CAS(>50% severity) which was ipsilateral to the index ischemic cerebral infarct in 15 out of 25 patients presenting with stroke(2).
Secondary prevention of stroke in NVAF patients who have the association of either high-grade stenotic intracranial cerebrovascular disease or high-grade CAS to which the index stroke can be attributed would entail coprescription of low-dose aspirin and an oral anticoagulant drug. Edoxaban would be a suitable candidate, given the fact that the 15 mg/day dose significantly mitigates the risk of stroke ( of presumably cardioembolic origin) in NVAF subjects aged 80 or more(3). That dose is even lower than the 30 mg/day dose which is associated with significantly(p < 0.001) lower risk of gastrointestinal bleeding than warfarin(4).
Primary prevention would require strict abstinence from smoking, strict control of the lipid profile and strict control of blood pressure.
I have no funding and no conflict of interest.
References
(1) Kim YD., Cha MJ., Kim J et al
Increases in cerebral atherosclerosis according to CHADS2 scores in patients with stroke with nonvalvular atrial fibrillation
STROKE 2011;42:930-934
(2)Chang Y-J., Ryu S-J., Lin S-K
Carotid artery stenosis in ischemic stroke patients with nonvalvuar atrial fibrillation
Cerebrovascular Disease 2002;13:16020
(3)Okumura K., Akao M., Yoshida T et al
Low-dose edoxaban in very elderly patients with atrial fibrillation
N Engl J Med2020;383:1735-1745
(4)Guigliano RP., Ruff CT., Braunwald E et al
Edoxaban versus warfarin in patients with atrial fibrillation
N Engl J Med 2013;369:2093-2104
To the Editor,
We have recently read with great interest the article by Kim et al entitled ‘‘Exclusion versus preservation of the left atrial appendage in rheumatic mitral valve surgery’’ [1]. We appreciate the authors for their study describing the relationship of preservation of the left atrial appendage (LAA) to the risk of adverse clinical events in patients with rheumatic mitral valve disease. On the other hand, we believe that there are several major drawbacks that need to be addressed.
First of all, the LAA can be excluded from the systemic circula¬tion by obliterating its orifice with or without excising the body of the appendage [2]. During the two decades, mechanical occlusion of the LAA including the surgical approach has been adopted by clinicians as a potential approach for stroke prevention in selected patients with atrial fibrillation (AF) [2]. Surgical LAA ligation has been attempted with or without enabling devices. Although routine surgical LAA occlusion has been recommended by some, the evidence base for its actual benefit remains limited and conflicting. Surgical closure particularly using suture ligation can yield incomplete surgical left atrial appendage closure (iSLC) in more than one-third of the patients [2, 3]. Previously, Katz et al evaluated 50 patients who underwent surgical LAA closure in association with mitral valve surgery and similarly reported iSLC in 36% of their patients [3]. The readers may wonder whether routine p...
To the Editor,
We have recently read with great interest the article by Kim et al entitled ‘‘Exclusion versus preservation of the left atrial appendage in rheumatic mitral valve surgery’’ [1]. We appreciate the authors for their study describing the relationship of preservation of the left atrial appendage (LAA) to the risk of adverse clinical events in patients with rheumatic mitral valve disease. On the other hand, we believe that there are several major drawbacks that need to be addressed.
First of all, the LAA can be excluded from the systemic circula¬tion by obliterating its orifice with or without excising the body of the appendage [2]. During the two decades, mechanical occlusion of the LAA including the surgical approach has been adopted by clinicians as a potential approach for stroke prevention in selected patients with atrial fibrillation (AF) [2]. Surgical LAA ligation has been attempted with or without enabling devices. Although routine surgical LAA occlusion has been recommended by some, the evidence base for its actual benefit remains limited and conflicting. Surgical closure particularly using suture ligation can yield incomplete surgical left atrial appendage closure (iSLC) in more than one-third of the patients [2, 3]. Previously, Katz et al evaluated 50 patients who underwent surgical LAA closure in association with mitral valve surgery and similarly reported iSLC in 36% of their patients [3]. The readers may wonder whether routine postoperative screening can be performed in AF patients with LAA exclusion.
Second, surgical closure particularly using suture ligation can yield iSLC in more than one-third of the patients, which, in turn, may be associated with increased thromboembolic complications (TECs) [2, 4]. In another trial, Garcia-Fernandez et al [5] similarly evaluated 58 patients who underwent surgical LAA ligation and determined that lack of LAA ligation served as an independent predictor of embolic events. When identification of iSLC was taken into account, the estimated embolic risk further increased to approximately 12-fold. Previously, Aryana et al indicated that the incidence of iSLC among 72 AF patients who underwent surgical suture ligation of LAA in conjunction with mitral valve surgery was 36% [4]. Hence, these findings support the hypothesis that the presence of iSLC may be ‘worse’ than no ligation at all [2]. Although the specific reasons for this are not clearly defined, it is conceivable that due to its ‘stenotic’ neck, iSLC may be associated with a ‘low-flow’ state and increased stasis, in turn promoting a greater risk for the development of TECs. The presence of extensive trabeculation and reduced peak flow have both been proposed to influence LAA stasis and thrombus formation [2, 4]. Recently, we have reported that a small LAA neck size as a predictor of thromboembolic stroke in patients with iSLC [2]. The mechanism for this probably related to a higher degree of stasis within the LAA. This is also consistent with our observation that patients with larger LAA neck diameters exhibit a lower risk of TEC [2]. Therefore, long-term strict anticoagulation therapy and follow-up are strongly encouraged in this high-risk group of patients. In this study, the authors did not provide detailed information about the anticoagulation treatments of these patients in the post-operative period.
REFERENCES
1.Kim WK, Kim HJ, Kim JB, et al. Exclusion versus preservation of the left atrial appendage in rheumatic mitral valve surgery. Heart 2020; 106:1839-1846.
2.Güner A, Kalçık M, Gündüz S, et al. The relationship between incomplete surgical obliteration of the left atrial appendage and thromboembolic events after mitral valve surgery (from the ISOLATE Registry). J Thromb Thrombolysis 2020 Sep 30. doi: 10.1007/s11239-020-02291-5. Online ahead of print.
3.Katz ES, Tsiamtsiouris T, Applebaum RM, et al. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiographic study. J Am Coll Cardiol 2000; 36:468–471.
4.Aryana A, Singh SK, Singh SM, et al. Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization. Heart Rhythm 2015; 12:1431-1437.
5.García-Fernández MA, Pérez-David E, Quiles J, et al. Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Coll Cardiol 2003; 42:1253-1258.
The observation that transient constrictive pericarditis(CP) is associated with a significantly higher erythrocyte sedimentation rate than its counterpart, persistent pericarditis, is consistent with the hypothesis that, in the former disorder, an active inflammatory process is at play, which might be responsive to corticosteroid therapy, whereas, in the latter context, irreversiible pericardial fibrosis or even pericardial calcification might have become firmly established.
This hypothesis can be tested in a disorder such as IgG4-related constrictive pericarditis, where corticosteroids are the only treatment modality available. In IgG4-related CP the disease spectrum includes, at one extreme,, effusive-constrictive pericarditis without pericardial calcification(1), and, at the other extreme, CP with pericardial calcification(2).In between, there may be gradations of acute inflammatory response..
The 79-year old man with IgG4-related effusive CP reported by Yuriditsky et al had stigmata of CP identified by simultaneous left and right-sided catheterisation. He had an initially good response to corticostroids, characterised by good diuresis over the course of 10 days. However, he had a subsequent relapse, and was eventually treated by pericardiectomy(1).
By contrast, the 29 year old woman with IgG4-related CP reported by Sekigushi et al had a consistently good response to corticosteroids. In her case, as well, there was no pericardial calcification. E...
The observation that transient constrictive pericarditis(CP) is associated with a significantly higher erythrocyte sedimentation rate than its counterpart, persistent pericarditis, is consistent with the hypothesis that, in the former disorder, an active inflammatory process is at play, which might be responsive to corticosteroid therapy, whereas, in the latter context, irreversiible pericardial fibrosis or even pericardial calcification might have become firmly established.
This hypothesis can be tested in a disorder such as IgG4-related constrictive pericarditis, where corticosteroids are the only treatment modality available. In IgG4-related CP the disease spectrum includes, at one extreme,, effusive-constrictive pericarditis without pericardial calcification(1), and, at the other extreme, CP with pericardial calcification(2).In between, there may be gradations of acute inflammatory response..
The 79-year old man with IgG4-related effusive CP reported by Yuriditsky et al had stigmata of CP identified by simultaneous left and right-sided catheterisation. He had an initially good response to corticostroids, characterised by good diuresis over the course of 10 days. However, he had a subsequent relapse, and was eventually treated by pericardiectomy(1).
By contrast, the 29 year old woman with IgG4-related CP reported by Sekigushi et al had a consistently good response to corticosteroids. In her case, as well, there was no pericardial calcification. Echocardiography showed "constrictive hemodynamics" without evidence of pericardial effusion. Computed tomography showed pericardial thickening. When repeated after 10 weeks of corticosteroid treatment echocardiography no longer showed "constrictive hemodynamics"(3). In both cases(10(3) the diagnosis of CP had, arguably, been made at trhe inflammatory stage, hence the demonstration of some degree of response to corticosteroids, albeit the response was more enduring in the patient reported by Sekiguchi et all(3).
I have no funding and no conflict of interest.
References
(1)Yuriditsky E., Dwivedi A., Narula N et al
Constrictive pericarditis caused by IgG4-related disease rquiring pericardiectomy after partial response to corticosteroids
JACC Case Report 2020;2:1558-1563
(2)Luo W-Q., Fang F., Zhen W-J et al
A case of immunoglobulin G4-related constrictive pericarditis
AnnTransl Med 2016;4(3):57
(3)Sekiguchi H., Horie R., Utz J., Ryu JH
IgG4-related systemic disease presenting with lung entrapment and constrictive pericarditis
CHEST 2012;142:781-783
For the sake of completeness, the evaluation of the deficit in knowledge and awareness and treatment of hypertension (1) should include an inquiry about two issues that are fundamental to the relationship between hypertension and stroke. For those issues to be addressed, the questionnaire should include the following items:-
(i)Did you ever have your blood pressure taken in both arms?
(ii)When you commenced antihypertensive treatment did you and your doctor agree on a "goal" blood pressure?
The rationale for those two lines of inquiry is the following:-
According to one meta analysis(10 cohorts; 13,317 patients) interarm blood pressure difference > 15 mm Hg is associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke(hazard ratio, 2.42: 95% Confidence Interval, 1.27-4.60; p < 0.01) (2).
Furthermore, antihypertensive medication should be titrated against the higher of the two inter arm blood pressure measurements otherwise the patient will run the risk of suboptimal drug dosing and the risk of missed diagnosis of resistant hypertension.
A mutually agreed "goal" blood pressure should be specified from the outset otherwise there will be a risk of insidious onset of "physician inertia" which could contribute to the subsequent development of stroke.
Younger patients have the most o gain from an ambitious "goal " blood pressure which sets the target...
For the sake of completeness, the evaluation of the deficit in knowledge and awareness and treatment of hypertension (1) should include an inquiry about two issues that are fundamental to the relationship between hypertension and stroke. For those issues to be addressed, the questionnaire should include the following items:-
(i)Did you ever have your blood pressure taken in both arms?
(ii)When you commenced antihypertensive treatment did you and your doctor agree on a "goal" blood pressure?
The rationale for those two lines of inquiry is the following:-
According to one meta analysis(10 cohorts; 13,317 patients) interarm blood pressure difference > 15 mm Hg is associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke(hazard ratio, 2.42: 95% Confidence Interval, 1.27-4.60; p < 0.01) (2).
Furthermore, antihypertensive medication should be titrated against the higher of the two inter arm blood pressure measurements otherwise the patient will run the risk of suboptimal drug dosing and the risk of missed diagnosis of resistant hypertension.
A mutually agreed "goal" blood pressure should be specified from the outset otherwise there will be a risk of insidious onset of "physician inertia" which could contribute to the subsequent development of stroke.
Younger patients have the most o gain from an ambitious "goal " blood pressure which sets the target at a systolic blood pressure(SBP) of < 120 mm Hg(3) because they are less likely to incur the antihypertensive drug side effects that might inhibit attainment of optimum SBP. Another benefit of intensive blood pressure lowering is that it mitigates the risk of atrial fibrillation(4), thereby also mitigating the risk of cardioembolic stroke.
I have no funding and no conflict of interest.
References
(1)O'Donnell M., Hankey GJ., Rangarajan S., Chin SL., Rao-Melacini P., Ferguson J., Xavier D et al
Variations in knowledge , awareness and treatment of hypertension and stroke risk by country income level
Heart 2019. doi:10.1136/heartjnl-2019-316515
(2)Tomiyama H., Ohkuma T., Ninomiya T., Masumoto C., Kario K., Hoshide S., Kita Y., Inoguchi T et al
Simultaneously measured interarm blood pressure difference and stroke
An Individual Participants Data Meta-Analysis
Hypertension 2018;71:1030-1038
(3)SPRINT Research Group, Wright JT., Williamson JD et al
A randomized trial of intensive versus standard blood pressure control
N Engl J Med 2015;373:2103-2116
(4)Soliman EZ., Rahman AKM F., Zhang Z-m., Rodriguez CJ., Chang TI., Bate JT et al
Effect of intensive blood pressure lowering on the risk of atrial fibrillation
Hypertension 2020;75:1491-1496
A corollary to the recommendation for anticoagulant persistence is a recognition that the time is long overdue for inclusion of evaluation of the extracranial carotid artery for evidence of high grade(ie >50 occlusion) carotid artery stenosis(CAS). The following is the rationale for the latter recommendation:-
Among patients aged > 70 high-grade CAS has a prevalence of 12% among men and 11% among women(1).
A systematic review of 9 studies(2611 patients) reporting presumed pathophysiological stroke mechanisms in patients with nonvalvular atrial fibrillation(NVAF) disclosed that 11%-24% of patients with the association of stroke and NVAF have high-grade CAS(2).
Some stroke patients with NVAF have high-grade CAS ipsilateral to the culprit cerebral infarct, implying an aetiological role for the CAS in the pathogenesis of the incident stroke(3).
During the entire history of the CHA2DS2 Vasc score we have squandared the opportunity to include ultrasonography of the extracranial carotid artery in the routine work up of newly diagnosed patients with NVAF. This was a missed opportunity to identify CAS as the potential aetiological agent in the event of the occurrence of manifestations of symptomatic CAS such as amaurosis fugax, transient ischemic attack, or non disabling stroke.. Without prior knowledge of the status of the carotid arteries those manifestations might have been missed opportunities to implement strategies such as carotid arte...
A corollary to the recommendation for anticoagulant persistence is a recognition that the time is long overdue for inclusion of evaluation of the extracranial carotid artery for evidence of high grade(ie >50 occlusion) carotid artery stenosis(CAS). The following is the rationale for the latter recommendation:-
Among patients aged > 70 high-grade CAS has a prevalence of 12% among men and 11% among women(1).
A systematic review of 9 studies(2611 patients) reporting presumed pathophysiological stroke mechanisms in patients with nonvalvular atrial fibrillation(NVAF) disclosed that 11%-24% of patients with the association of stroke and NVAF have high-grade CAS(2).
Some stroke patients with NVAF have high-grade CAS ipsilateral to the culprit cerebral infarct, implying an aetiological role for the CAS in the pathogenesis of the incident stroke(3).
During the entire history of the CHA2DS2 Vasc score we have squandared the opportunity to include ultrasonography of the extracranial carotid artery in the routine work up of newly diagnosed patients with NVAF. This was a missed opportunity to identify CAS as the potential aetiological agent in the event of the occurrence of manifestations of symptomatic CAS such as amaurosis fugax, transient ischemic attack, or non disabling stroke.. Without prior knowledge of the status of the carotid arteries those manifestations might have been missed opportunities to implement strategies such as carotid artery endarterectomy or carotid artery stenting for secondary prevention of disabling stroke.
It is unconscionable that we should allow such a state of affairs to continue indefinitely.
I have no funding and no conflict of interest.
References
(1)Kanter MC., Tegeler CH., Peasrce LA et al
Carotid stenosis in patients with atrial fibrillation. Prevalence, risk factors, and relationship to stroke in Stroke Prevention in Atrial Fibrillation Study
Arch Intern Med 1994;154:1372-1377
(2)Katsi V., Georgiopoulos G., Skafida A et al
Noncardioembolic stroke in patients with nonvalvular atrial fibrillation
Angiology 2019;70:299-304
(3)Chang Y-J., Ryu S-J., Lin S-K
Carotid artery stenosis in ischemic stroker patients with nonvalvular atrial fibrillation
Cerebrovasc Dis 2002;13:16-20
We have read with great interest the article written by Jolicoer et al. (1) about the concordant domain analysis, a new method to interpret early phase trials and we applaud their initiative which expands the horizons in the current context of progressive diffuculties to ran studies.
Randomized controlled trials (RCT) and meta-analysis constitute the highest level of evidence and the chances to succeed are high when there is a strong financial support to launch projects as Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) with 27,564 patients, which in addition to demonstrate the hypothesis of the study, it ensures the external validity and the study of subgroups.
However, recently we are witnessing a progressively more tortuous environment to launch adequately powered RCTs due to economic restrictions, lower margin to demonstrate cost-effectivity of the new treatments and more strict legal requirements and as the authors quote, only 1 in 10 investigational agents tested in phase III trials reaches the market. Some authors have already raisen concerns about the future of research and the protagonism of new methods as adaptive studies(2) or approaches to emulate RCT (3) are foreseen in the near future.
In our opinion, the combination of pilot randomized studies with new iniciatives as the described by Jolicoer may be a promising pathway when the conditions to launch large RCTs are not possible and in fa...
We have read with great interest the article written by Jolicoer et al. (1) about the concordant domain analysis, a new method to interpret early phase trials and we applaud their initiative which expands the horizons in the current context of progressive diffuculties to ran studies.
Randomized controlled trials (RCT) and meta-analysis constitute the highest level of evidence and the chances to succeed are high when there is a strong financial support to launch projects as Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) with 27,564 patients, which in addition to demonstrate the hypothesis of the study, it ensures the external validity and the study of subgroups.
However, recently we are witnessing a progressively more tortuous environment to launch adequately powered RCTs due to economic restrictions, lower margin to demonstrate cost-effectivity of the new treatments and more strict legal requirements and as the authors quote, only 1 in 10 investigational agents tested in phase III trials reaches the market. Some authors have already raisen concerns about the future of research and the protagonism of new methods as adaptive studies(2) or approaches to emulate RCT (3) are foreseen in the near future.
In our opinion, the combination of pilot randomized studies with new iniciatives as the described by Jolicoer may be a promising pathway when the conditions to launch large RCTs are not possible and in fact, we have recently seen examples of small pilot randomized trials with clinical endpoints published in journals of very high impact factor(4). In this way, our group has recently received financial support from a large company of devices to run a pilot study with 400 patients to explore a research question that requires a large and expensive trial of 2000 patients (ANGiographic Evaluation of Left main coronary INtErvention, ANGELINE, NCT04604197).
In summary, we are assisting to relevant changes in the field of research and although RCTs and meta-analysis will be and will have to be always the first goal, new initiatives as the one that Jolicoer et al. share with us deserve our attention and are very welcome.
REFERENCES
1. Jolicoeur EM, Verheye S, Henry TD et al. A novel method to interpret early phase trials shows how the narrowing of the coronary sinus concordantly improves symptoms, functional status and quality of life in refractory angina. Heart 2021;107:41-46.
2. Rapezzi C, Maggioni AP, Ferrari R. Adapting to survive. Eur Heart J 2020;41:3981-3983.
3. Franklin JM, Patorno E, Desai RJ et al. Emulating Randomized Clinical Trials with Nonrandomized Real-World Evidence Studies: First Results from the RCT DUPLICATE Initiative. Circulation 2020.
4. Yannopoulos D, Bartos J, Raveendran G et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet 2020;396:1807-1816.
In clinical practice, timing of aortic valve intervention in asymptomatic severe aortic stenosis (ASAS) has been a challenging task particularly in the absence of overt high-risk features (low ejection fraction, etc.) (1,2). The recently published article by Bing R, et al. (1), has discussed current strategies that might help risk-stratification and management of this precarious valvular phenomenon. In this context, we fully agree with the authors that serum biomarkers including natriuretic peptides, as opposed to certain imaging modalities, generally have significant limitations (1). However, serum copeptin (the surrogate marker of arginine-vasopressine (AVP) axis) might serve as a promising guide to prognostication and clinical decision-making for aortic valve intervention in patients with ASAS (2) largely due to pathophysiological implications of AVP axis in these patients:
Firstly; copeptin elevation in patients with ASAS might help ide...
In clinical practice, timing of aortic valve intervention in asymptomatic severe aortic stenosis (ASAS) has been a challenging task particularly in the absence of overt high-risk features (low ejection fraction, etc.) (1,2). The recently published article by Bing R, et al. (1), has discussed current strategies that might help risk-stratification and management of this precarious valvular phenomenon. In this context, we fully agree with the authors that serum biomarkers including natriuretic peptides, as opposed to certain imaging modalities, generally have significant limitations (1). However, serum copeptin (the surrogate marker of arginine-vasopressine (AVP) axis) might serve as a promising guide to prognostication and clinical decision-making for aortic valve intervention in patients with ASAS (2) largely due to pathophysiological implications of AVP axis in these patients:
Firstly; copeptin elevation in patients with ASAS might help identify a subgroup with a state of subtle systemic hypoperfusion (potentially associated with the failure to increase cardiac output sufficiently under stress) that might lead to unexpected coronary ischemic events and sudden cardiac death (SCD) particularly during exercise (2). Copeptin elevation due to valvular stenosis might also suggest progressive ventricular remodeling and eventual heart failure in the long term as a consequence of enhanced AVP actions on myocardium (2). However, potential confounding factors (dehydration, infections, etc.) should also be sought before associating ASAS with copeptin elevation (2).
Secondly; augmented myocardial baroreceptor reactivity (namely Bezold-Jarish reflex) is well known to be associated with syncopal attacks and, if substantial, SCD in the setting of severe aortic stenosis largely through induction of bradyarrhythmias and peripheral vasodilatation (2). Interestingly, AVP was previously demonstrated to exert a significant stimulatory impact on baroreceptor reactivity (3,4). Therefore, substantial copeptin elevation might help identify ASAS patients who might particularly be prone to excessive Bezold-Jarish reflex (and hence; to SCD risk) on follow-up. (2).
Thirdly; AVP axis has a significant correlation with adrenergic system partly attributable to the central impact of adrenergic substances on AVP release (2). Therefore, copeptin elevation denotes a state of adrenergic hyperactivation that might account for arrhythmias in patients with ASAS, particularly in those with left ventricular hypertrophy (2).
Finally; copeptin elevation in patients with ASAS might also predict rapid progression of transaortic gradient owing to profibrotic effects of augmented AVP actions on aortic valvular tissue (2).
In summary; copeptin elevation might potentially signify a higher risk for adverse events in patients with ASAS due to the hemodynamic, autonomic and fibrogenic implications of enhanced AVP actions (2). Therefore, adjunctive evaluation of serum copeptin at regular intervals might help dynamic risk-stratification, and might further optimize the timing of aortic valve intervention in these patients (2). However, this needs to be tested in large-scale clinical studies.
Conflict of Interest: None
REFERENCES:
1- Bing R, Dweck MR. Management of asymptomatic severe aortic stenosis: check or all in?
Heart Published Online First: 04 November 2020. doi: 10.1136/heartjnl-2020-317160
2- Yalta K, Palabiyik O, Gurdogan M, Gurlertop Y. Serum copeptin might improve risk stratification and management of aortic valve stenosis: a review of pathophysiological insights and practical implications. Ther Adv Cardiovasc Dis. 2019 Jan-Dec;13:1753944719826420. doi: 10.1177/1753944719826420. PMID: 30803406; PMCID: PMC6376527.
3- Roul G, Riehl-Aleil V, Germain P, Bareiss P. Neurohormonal profile before and after beta-blockade in patients with neurocardiogenic syncope. Pacing Clin Electrophysiol. 1999; 22(7): 1020-30.
4- Mosqueda-Garcia R, Furlan R, Tank J, Fernandez-Violante R. The elusive pathophysiology of neurally mediated syncope. Circulation. 2000; 102(23): 2898-906.
We thank Güner and colleagues for their comments1 and their interest on our study.1
It is very common in the low to middle come countries to observe women with more than one pregnancy and the proposed risk stratification score (Devi’s Score) took this scenario into consideration.2 Analyses took into consideration the non-independent nature of the data structure occurring from women having more than one pregnancy and generalized estimating equations were used to produce regression models to account for the clustering occurring due to more than one pregnancy in the same patient.
Prosthetic heart valve, especially the mechanical heart valves are highly thrombogenic and are associated with complications. On univariate analysis, use of anticoagulation was found to be associated with the adverse cardiac events and since they showed high collinearity with the prosthetic heart valve, it was decided to include prosthetic heart valve in the multivariate analysis. Despite following the guidelines on managing the anticoagulation regimen during pregnancy, we experience multiple challenges in day to day practice. Monitoring and maintaining the International normalised ratio(INR) /prothrombin time within the optimal range during a dynamic hemodynamic, variability in the actual timing in switching over to heparin and the clearly evident risk of thrombo-embolic phenomena during the switch-over time till heparin takes full control are some of the real wor...
We thank Güner and colleagues for their comments1 and their interest on our study.1
It is very common in the low to middle come countries to observe women with more than one pregnancy and the proposed risk stratification score (Devi’s Score) took this scenario into consideration.2 Analyses took into consideration the non-independent nature of the data structure occurring from women having more than one pregnancy and generalized estimating equations were used to produce regression models to account for the clustering occurring due to more than one pregnancy in the same patient.
Prosthetic heart valve, especially the mechanical heart valves are highly thrombogenic and are associated with complications. On univariate analysis, use of anticoagulation was found to be associated with the adverse cardiac events and since they showed high collinearity with the prosthetic heart valve, it was decided to include prosthetic heart valve in the multivariate analysis. Despite following the guidelines on managing the anticoagulation regimen during pregnancy, we experience multiple challenges in day to day practice. Monitoring and maintaining the International normalised ratio(INR) /prothrombin time within the optimal range during a dynamic hemodynamic, variability in the actual timing in switching over to heparin and the clearly evident risk of thrombo-embolic phenomena during the switch-over time till heparin takes full control are some of the real world concerning scenarios we have observed. A detailed analysis of the outcomes of the mechanical heart valves based on the anticoagulant regimes is under manuscript preparation for submission.
The present study included women with arrythmias which were present or diagnosed prior to pregnancy, including those with atrial fibrillation, under the broad category of prior cardiovascular event and those women with new onset atrial fibrillation requiring treatment during the course of pregnancy as a part of the composite maternal cardiovascular outcome. The prior cardiovascular event was found to be a significant factor and is included in the proposed score. Chokesuwattanaskul et al3 in the metanalysis included studies reporting women with prevalent and incident cases of atrial fibrillation; the effect of which may vary on the pregnancy outcomes. They also fail to describe the exact nature of the structural heart disease included in the meta-analysis, as the reasons leasing to development of atrial fibrillation as well as it effects on the outcome may be influenced by the primary structural lesion. So, the effect of atrial fibrillation on pregnant women with RHD need to be explored further in future studies.
References
1. Güner A, Kalçık M, Güner EG, et al Challenges in the management of pregnant patients with cardiovascular diseases Heart Published Online First: 21 September 2020. doi: 10.1136/heartjnl-2020-317768.
2. Baghel J, Keepanasseril A, Pillai AA, et al. Prediction of adverse cardiac events in pregnant women with valvular rheumatic heart disease. Heart 2020; 106:1400–6.doi:10.1136/heartjnl-2020-316648.
3. Chokesuwattanaskul R, Thongprayoon C, Bathini T, O'Corragain OA, Sharma K, Prechawat S, Ungprasert P, Watthanasuntorn K, Pachariyanon P, Cheungpasitporn W. Incidence of atrial fibrillation in pregnancy and clinical significance: A meta-analysis. Adv Med Sci. 2019 Sep;64(2):415-422. doi: 10.1016/j.advms.2019.07.003.
The soul-searching analysis by Daniel McKenzie deals with the scenario where both the doctor and the patient recognise that something went wrong(1). The dynamics are different when it is only with the benefit of hindsight that it is only the professionals who realise that, all along, they have been inflicting iatrogenic harm on their patients. Even in that scenario what matters is "What will be done to prevent someone else being harmed in the future?".
The thrombolytic treatment of ST elevation myocardial infarction(STEMI) is a case in point. That treatment strategy was initiated in 1986, and it soon became the standard of care for STEMI(2). Further down the line, in September 2020, a literature review identified 138 cases(with accompanying case histories) of dissecting aortic aneurysm(DAA) characterised by STEMI-like ST segment elevation. These cases were published during the period January 2000 to March 2020(3). Arguably, there must have been, at least, the same number of cases of STEMI-like DAA in the 20 year period following the introduction of thrombolytic treatment of ST elevation myocardial infarction. At the very least, some of those cases must have been harmed by thrombolytic treatment.
Why does that matter in September 2020? It matters because thrombolysis is "back on the agenda" for some myocardial infarction patients with ST segment elevation(4). All this, without the precaution to rule out DAA either by point-of-c...
The soul-searching analysis by Daniel McKenzie deals with the scenario where both the doctor and the patient recognise that something went wrong(1). The dynamics are different when it is only with the benefit of hindsight that it is only the professionals who realise that, all along, they have been inflicting iatrogenic harm on their patients. Even in that scenario what matters is "What will be done to prevent someone else being harmed in the future?".
The thrombolytic treatment of ST elevation myocardial infarction(STEMI) is a case in point. That treatment strategy was initiated in 1986, and it soon became the standard of care for STEMI(2). Further down the line, in September 2020, a literature review identified 138 cases(with accompanying case histories) of dissecting aortic aneurysm(DAA) characterised by STEMI-like ST segment elevation. These cases were published during the period January 2000 to March 2020(3). Arguably, there must have been, at least, the same number of cases of STEMI-like DAA in the 20 year period following the introduction of thrombolytic treatment of ST elevation myocardial infarction. At the very least, some of those cases must have been harmed by thrombolytic treatment.
Why does that matter in September 2020? It matters because thrombolysis is "back on the agenda" for some myocardial infarction patients with ST segment elevation(4). All this, without the precaution to rule out DAA either by point-of-care transthoracic echocardiography(TTE) or by transoesophageal echocardiography(TOE). The former is non-invasive but suboptimally sensitive, the latter is invasive but much more sensitive.. To mitigate the suboptimal sensitivity of TTE one strategy would be to maximise the pretest probability of DAA by compiling a risk score which encompasses history of backache(which does not need to have a "rearing" quality), documentation of interarm blood pressure difference, presence of the murmur of aortic regurgitation(optimally detected by the Vivid-7 system; GE Medical, Milwauwkee, Wisconsin, USA)(5), focal neurological symptoms and signs, and mediastinal widening on chest radiography. A high pre-test probability of DAA would be sufficient to invalidate a TTE which had failed to detect stigmata of DAA.
Our patients are not aware of the dynamics that come into play when they present with chest pain and a STEMI-like electrocardiogram. They take everything on trust. It would be unconscionable for us to knowingly put them in the way of iatrogenic harm by not heeding the lessons that can be gleaned from the literature on STEMI-like DAA.
I have no funding, and no conflict of interest.
References
(1) McKenzie D
What to do when things go wrong
Heart 2020;doi.org/10.1136/heartjnl 2020.316539
(2) Van de Werf
The history of coronary reperfusion
Eur Heart J 2014;35:2510-2515
(3) Jolobe OMP
Clinical characteristics in STEMI-like aortic dissection versus STEMI-like pulmonary embolism
Archives of Vascular Medicine 2020;4:019-130
DOI:29328/journal.avm.1001013
(4) Vallabhajosyula S., Verghese D., Subramanian AV et al
Management and outcome of uncomplicated ST segment elevation myocardial infarction patients transferred after fibrinolytic treatment
Int J Cardiol IJCA-28800(Article in Press)
(5)Draper J., Subbiah S., Bailey R., Chambers J
Murmur clinic. Validation of a new model for detecting heart valve disease
Heart 2019;105;56-59
There had been controversies raging whether Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blocking Agents may be harmful, neutral or protective to the people affected by SARS-CoV-2.
The findings of this study, especially because it encompasses such huge study population will provide great relief from uncertainty and anxiety to the doctor's prescribing these class of medicines to their hypertensive patients and to the people alrady taking these medicines.
Great many sinceremost thanks to the investigators of this study!
-Arvind Joshi;
MBBS, MD; FCGP, FAMS, FICP;
Founder Convener and President:
Our Own Discussion Group (OODG);
602-C, Megh Apartments;
Ganesh Peth Lane, Dadar West, Mumbai; Maharashtra State,INDIA, PIN 400028;
Consultant Physician at:
Ruchi Clinical Laboratory/Ruchi Diagnostic Center, Sunshine CHS,
Plot 58, Sector 21, Kharghar;
Maharashtra State, INDIA, PIN 410210.
The residual risk of stroke in subjects with nonvalvular atrial fibrillation(NVAF) is, in part, attributable to coexistence of nonvalvular atrial fibrillation(NVAF) and high-grade(stenosis(50% or more severity) involving the intracranial arterial circulation(1). In the latter study concomitant high-grade cerebrovascular stenosis was identified in 231 of 780 consecutive subjects of mean age 69.5 who had undergone angiographic studies at index stroke(1). Coexistence of extracranial carotid artery stenosis(CAS) and NVAF is also a risk factor for residual stroke(2). In the latter study Chang et al identified high-grade CAS(>50% severity) which was ipsilateral to the index ischemic cerebral infarct in 15 out of 25 patients presenting with stroke(2).
Show MoreSecondary prevention of stroke in NVAF patients who have the association of either high-grade stenotic intracranial cerebrovascular disease or high-grade CAS to which the index stroke can be attributed would entail coprescription of low-dose aspirin and an oral anticoagulant drug. Edoxaban would be a suitable candidate, given the fact that the 15 mg/day dose significantly mitigates the risk of stroke ( of presumably cardioembolic origin) in NVAF subjects aged 80 or more(3). That dose is even lower than the 30 mg/day dose which is associated with significantly(p < 0.001) lower risk of gastrointestinal bleeding than warfarin(4).
Primary prevention would require strict abstinence from smoking, str...
To the Editor,
Show MoreWe have recently read with great interest the article by Kim et al entitled ‘‘Exclusion versus preservation of the left atrial appendage in rheumatic mitral valve surgery’’ [1]. We appreciate the authors for their study describing the relationship of preservation of the left atrial appendage (LAA) to the risk of adverse clinical events in patients with rheumatic mitral valve disease. On the other hand, we believe that there are several major drawbacks that need to be addressed.
First of all, the LAA can be excluded from the systemic circula¬tion by obliterating its orifice with or without excising the body of the appendage [2]. During the two decades, mechanical occlusion of the LAA including the surgical approach has been adopted by clinicians as a potential approach for stroke prevention in selected patients with atrial fibrillation (AF) [2]. Surgical LAA ligation has been attempted with or without enabling devices. Although routine surgical LAA occlusion has been recommended by some, the evidence base for its actual benefit remains limited and conflicting. Surgical closure particularly using suture ligation can yield incomplete surgical left atrial appendage closure (iSLC) in more than one-third of the patients [2, 3]. Previously, Katz et al evaluated 50 patients who underwent surgical LAA closure in association with mitral valve surgery and similarly reported iSLC in 36% of their patients [3]. The readers may wonder whether routine p...
The observation that transient constrictive pericarditis(CP) is associated with a significantly higher erythrocyte sedimentation rate than its counterpart, persistent pericarditis, is consistent with the hypothesis that, in the former disorder, an active inflammatory process is at play, which might be responsive to corticosteroid therapy, whereas, in the latter context, irreversiible pericardial fibrosis or even pericardial calcification might have become firmly established.
Show MoreThis hypothesis can be tested in a disorder such as IgG4-related constrictive pericarditis, where corticosteroids are the only treatment modality available. In IgG4-related CP the disease spectrum includes, at one extreme,, effusive-constrictive pericarditis without pericardial calcification(1), and, at the other extreme, CP with pericardial calcification(2).In between, there may be gradations of acute inflammatory response..
The 79-year old man with IgG4-related effusive CP reported by Yuriditsky et al had stigmata of CP identified by simultaneous left and right-sided catheterisation. He had an initially good response to corticostroids, characterised by good diuresis over the course of 10 days. However, he had a subsequent relapse, and was eventually treated by pericardiectomy(1).
By contrast, the 29 year old woman with IgG4-related CP reported by Sekigushi et al had a consistently good response to corticosteroids. In her case, as well, there was no pericardial calcification. E...
For the sake of completeness, the evaluation of the deficit in knowledge and awareness and treatment of hypertension (1) should include an inquiry about two issues that are fundamental to the relationship between hypertension and stroke. For those issues to be addressed, the questionnaire should include the following items:-
Show More(i)Did you ever have your blood pressure taken in both arms?
(ii)When you commenced antihypertensive treatment did you and your doctor agree on a "goal" blood pressure?
The rationale for those two lines of inquiry is the following:-
According to one meta analysis(10 cohorts; 13,317 patients) interarm blood pressure difference > 15 mm Hg is associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke(hazard ratio, 2.42: 95% Confidence Interval, 1.27-4.60; p < 0.01) (2).
Furthermore, antihypertensive medication should be titrated against the higher of the two inter arm blood pressure measurements otherwise the patient will run the risk of suboptimal drug dosing and the risk of missed diagnosis of resistant hypertension.
A mutually agreed "goal" blood pressure should be specified from the outset otherwise there will be a risk of insidious onset of "physician inertia" which could contribute to the subsequent development of stroke.
Younger patients have the most o gain from an ambitious "goal " blood pressure which sets the target...
A corollary to the recommendation for anticoagulant persistence is a recognition that the time is long overdue for inclusion of evaluation of the extracranial carotid artery for evidence of high grade(ie >50 occlusion) carotid artery stenosis(CAS). The following is the rationale for the latter recommendation:-
Show MoreAmong patients aged > 70 high-grade CAS has a prevalence of 12% among men and 11% among women(1).
A systematic review of 9 studies(2611 patients) reporting presumed pathophysiological stroke mechanisms in patients with nonvalvular atrial fibrillation(NVAF) disclosed that 11%-24% of patients with the association of stroke and NVAF have high-grade CAS(2).
Some stroke patients with NVAF have high-grade CAS ipsilateral to the culprit cerebral infarct, implying an aetiological role for the CAS in the pathogenesis of the incident stroke(3).
During the entire history of the CHA2DS2 Vasc score we have squandared the opportunity to include ultrasonography of the extracranial carotid artery in the routine work up of newly diagnosed patients with NVAF. This was a missed opportunity to identify CAS as the potential aetiological agent in the event of the occurrence of manifestations of symptomatic CAS such as amaurosis fugax, transient ischemic attack, or non disabling stroke.. Without prior knowledge of the status of the carotid arteries those manifestations might have been missed opportunities to implement strategies such as carotid arte...
We have read with great interest the article written by Jolicoer et al. (1) about the concordant domain analysis, a new method to interpret early phase trials and we applaud their initiative which expands the horizons in the current context of progressive diffuculties to ran studies.
Show MoreRandomized controlled trials (RCT) and meta-analysis constitute the highest level of evidence and the chances to succeed are high when there is a strong financial support to launch projects as Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) with 27,564 patients, which in addition to demonstrate the hypothesis of the study, it ensures the external validity and the study of subgroups.
However, recently we are witnessing a progressively more tortuous environment to launch adequately powered RCTs due to economic restrictions, lower margin to demonstrate cost-effectivity of the new treatments and more strict legal requirements and as the authors quote, only 1 in 10 investigational agents tested in phase III trials reaches the market. Some authors have already raisen concerns about the future of research and the protagonism of new methods as adaptive studies(2) or approaches to emulate RCT (3) are foreseen in the near future.
In our opinion, the combination of pilot randomized studies with new iniciatives as the described by Jolicoer may be a promising pathway when the conditions to launch large RCTs are not possible and in fa...
Kenan YALTA, MD a
Ertan YETKIN, MD b
Gokay TAYLAN, MD a
a,TrakyaUniversity, CardiologyDepartment, Edirne, TURKEY
b Derindere Hospital, Cardiology Department, Istanbul, TURKEY
Corresponding Author: Kenan YALTA Trakya University, Cardiology Department, Edirne, TURKEY
Email- kyalta@gmail.com, akenanyalta@trakya.edu.tr Phone: 00905056579856
In clinical practice, timing of aortic valve intervention in asymptomatic severe aortic stenosis (ASAS) has been a challenging task particularly in the absence of overt high-risk features (low ejection fraction, etc.) (1,2). The recently published article by Bing R, et al. (1), has discussed current strategies that might help risk-stratification and management of this precarious valvular phenomenon. In this context, we fully agree with the authors that serum biomarkers including natriuretic peptides, as opposed to certain imaging modalities, generally have significant limitations (1). However, serum copeptin (the surrogate marker of arginine-vasopressine (AVP) axis) might serve as a promising guide to prognostication and clinical decision-making for aortic valve intervention in patients with ASAS (2) largely due to pathophysiological implications of AVP axis in these patients:
Show MoreFirstly; copeptin elevation in patients with ASAS might help ide...
Dear Editor,
We thank Güner and colleagues for their comments1 and their interest on our study.1
Show MoreIt is very common in the low to middle come countries to observe women with more than one pregnancy and the proposed risk stratification score (Devi’s Score) took this scenario into consideration.2 Analyses took into consideration the non-independent nature of the data structure occurring from women having more than one pregnancy and generalized estimating equations were used to produce regression models to account for the clustering occurring due to more than one pregnancy in the same patient.
Prosthetic heart valve, especially the mechanical heart valves are highly thrombogenic and are associated with complications. On univariate analysis, use of anticoagulation was found to be associated with the adverse cardiac events and since they showed high collinearity with the prosthetic heart valve, it was decided to include prosthetic heart valve in the multivariate analysis. Despite following the guidelines on managing the anticoagulation regimen during pregnancy, we experience multiple challenges in day to day practice. Monitoring and maintaining the International normalised ratio(INR) /prothrombin time within the optimal range during a dynamic hemodynamic, variability in the actual timing in switching over to heparin and the clearly evident risk of thrombo-embolic phenomena during the switch-over time till heparin takes full control are some of the real wor...
The soul-searching analysis by Daniel McKenzie deals with the scenario where both the doctor and the patient recognise that something went wrong(1). The dynamics are different when it is only with the benefit of hindsight that it is only the professionals who realise that, all along, they have been inflicting iatrogenic harm on their patients. Even in that scenario what matters is "What will be done to prevent someone else being harmed in the future?".
Show MoreThe thrombolytic treatment of ST elevation myocardial infarction(STEMI) is a case in point. That treatment strategy was initiated in 1986, and it soon became the standard of care for STEMI(2). Further down the line, in September 2020, a literature review identified 138 cases(with accompanying case histories) of dissecting aortic aneurysm(DAA) characterised by STEMI-like ST segment elevation. These cases were published during the period January 2000 to March 2020(3). Arguably, there must have been, at least, the same number of cases of STEMI-like DAA in the 20 year period following the introduction of thrombolytic treatment of ST elevation myocardial infarction. At the very least, some of those cases must have been harmed by thrombolytic treatment.
Why does that matter in September 2020? It matters because thrombolysis is "back on the agenda" for some myocardial infarction patients with ST segment elevation(4). All this, without the precaution to rule out DAA either by point-of-c...
There had been controversies raging whether Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blocking Agents may be harmful, neutral or protective to the people affected by SARS-CoV-2.
The findings of this study, especially because it encompasses such huge study population will provide great relief from uncertainty and anxiety to the doctor's prescribing these class of medicines to their hypertensive patients and to the people alrady taking these medicines.
Great many sinceremost thanks to the investigators of this study!
-Arvind Joshi;
MBBS, MD; FCGP, FAMS, FICP;
Founder Convener and President:
Our Own Discussion Group (OODG);
602-C, Megh Apartments;
Ganesh Peth Lane, Dadar West, Mumbai; Maharashtra State,INDIA, PIN 400028;
Consultant Physician at:
Ruchi Clinical Laboratory/Ruchi Diagnostic Center, Sunshine CHS,
Plot 58, Sector 21, Kharghar;
Maharashtra State, INDIA, PIN 410210.
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