To the Editor:
We read with great interest the editorial by Dr. James J DiNicolantonio and colleagues.1 In their editorial, the authors have expressed their opinions that ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. However, we want to highlight some concerns about the use of ivermectin for late-stage COVID-19.
First, we do agree with the authors that ivermectin can be a potential drug for late-stage COVID-19 considering its anti-inflammatory effects. The authors stated that it is reasonable to suspect that, in doses at or modestly above the standard clinical dose, ivermectin may have important clinical potential for managing disorders associated with life-threatening respiratory distress and cytokine storm—such as advanced COVID-19.
Second, a usual dose or modestly above the standard clinical dose of ivermectin may induce neurologic disorders, which can be fatal.2 Encephalopathy and coma are well-known side effects of ivermectin treatment in animals. But few cases of neurologic disorders after ivermectin treatment have been reported in humans.3 Neurologic disorders may include coma, ataxia, pyramidal signs, and binocular diplopia. Thus, the seriousness of the adverse reaction in humans implies that caution is warranted regarding medical prescriptions of ivermectin.
We declare no competing interests.
Contributors: All authors contributed to the final manuscript.
To the Editor:
We read with great interest the editorial by Dr. James J DiNicolantonio and colleagues.1 In their editorial, the authors have expressed their opinions that ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. However, we want to highlight some concerns about the use of ivermectin for late-stage COVID-19.
First, we do agree with the authors that ivermectin can be a potential drug for late-stage COVID-19 considering its anti-inflammatory effects. The authors stated that it is reasonable to suspect that, in doses at or modestly above the standard clinical dose, ivermectin may have important clinical potential for managing disorders associated with life-threatening respiratory distress and cytokine storm—such as advanced COVID-19.
Second, a usual dose or modestly above the standard clinical dose of ivermectin may induce neurologic disorders, which can be fatal.2 Encephalopathy and coma are well-known side effects of ivermectin treatment in animals. But few cases of neurologic disorders after ivermectin treatment have been reported in humans.3 Neurologic disorders may include coma, ataxia, pyramidal signs, and binocular diplopia. Thus, the seriousness of the adverse reaction in humans implies that caution is warranted regarding medical prescriptions of ivermectin.
We declare no competing interests.
Contributors: All authors contributed to the final manuscript.
Funding: The authors have not declared a specific grant for this letter from any funding agency in the public, commercial or not-for-profit sectors.
Patient consent for publication: Not applicable.
References
1. DiNicolantonio JJ, Barroso J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. Open Heart 2020;7(2):e001350.
2. Mealey KL. Therapeutic implications of the MDR-1 gene. Journal of veterinary pharmacology and therapeutics 2004;27(5):257-264.
3. Baudou E, Lespine A, Durrieu G, André F, Gandia P, Durand C, Cunat S. Serious Ivermectin Toxicity and Human ABCB1 Nonsense Mutations. New England Journal of Medicine 2020;383(8):787-789.
Five years ago, our group at the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) published an analysis exploring the impact of day light saving time (DST) changes on the state -wide volume of percutaneous coronary intervention in patients presenting with acute myocardial infarction (AMI-PCI) in the weekdays following the time change.1 Using data from our clinical registry reflecting all PCIs performed at non-Federal hospitals throughout Michigan between 1/1/2010 and 9/15/2013, we identified a significant increase in AMI-PCI on Mondays following the Spring DST change (RR = 1.24, p = 0.011), and a significant reduction in cases on Tuesdays following fall DST changes (RR = 0.79, p = 0.044), adjusting for seasonal and weekday effects, and for an overall time trend. We have now repeated the analysis using registry data for the subsequent 5 ½ years, from 9/16/2013 – 3/31/2019 using the same methodology and obtained results inconsistent with our prior publication. In our analysis of more recent data, both of the previously reported effects were substantially attenuated and are no longer statistically significant (Spring Monday after change: RR = 1.095, p = 0.207; Fall Tuesday after change: RR = 0.96, p = 0.553). Our prior publication garnered a great deal of attention in the popular media2,3, often with alarming, sensational headlines. It has also been included in meta-analysis along with other publications identifying a similar Spring time change effect4...
Five years ago, our group at the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) published an analysis exploring the impact of day light saving time (DST) changes on the state -wide volume of percutaneous coronary intervention in patients presenting with acute myocardial infarction (AMI-PCI) in the weekdays following the time change.1 Using data from our clinical registry reflecting all PCIs performed at non-Federal hospitals throughout Michigan between 1/1/2010 and 9/15/2013, we identified a significant increase in AMI-PCI on Mondays following the Spring DST change (RR = 1.24, p = 0.011), and a significant reduction in cases on Tuesdays following fall DST changes (RR = 0.79, p = 0.044), adjusting for seasonal and weekday effects, and for an overall time trend. We have now repeated the analysis using registry data for the subsequent 5 ½ years, from 9/16/2013 – 3/31/2019 using the same methodology and obtained results inconsistent with our prior publication. In our analysis of more recent data, both of the previously reported effects were substantially attenuated and are no longer statistically significant (Spring Monday after change: RR = 1.095, p = 0.207; Fall Tuesday after change: RR = 0.96, p = 0.553). Our prior publication garnered a great deal of attention in the popular media2,3, often with alarming, sensational headlines. It has also been included in meta-analysis along with other publications identifying a similar Spring time change effect4, and our findings were concordant with other work 5. We believe that in light of the extensive coverage and attention paid to our prior work, it was important to share the results of our updated analysis. The reason for the different findings merit further investigation and could relate to temporal changes in risk factor profile of the broader population, changes in how the general population adjusts to DST, or could simply reflect the presence of Type I error in our original work. We also must acknowledge the very real presence of publication bias in the research community , and the fact that if our initial analysis had produced the same null findings we found 5 years later, we very likely would not have presented and probably would not have been able to publish those results.
References:
1) Sandhu A, Seth M, Gurm HS. Daylight savings time and myocardial infarction
Open Heart 2014;1:e000019. doi: 10.1136/openhrt-2013-000019
2) Brueck H, Daylight-savings time is literally killing us, Business Insider, 2019 https://www.businessinsider.com/daylight-saving-time-is-deadly-2018-3
3) Leasca, Stacey, Daylight savings Time Seems to be Really Bad For our Health, MensHealth 2018 https://www.menshealth.com/health/a26764185/daylight-savings-time-heart-...
4) Manfredini R, Fabbian F, Cappadona R, De Giorgi A, Bravi F, Carradori T, Flacco ME, Manzoli L. Daylight Saving Time and Acute Myocardial Infarction: A Meta-Analysis. Journal of Clinical Medicine. 2019; 8(3):404.
5) Janszky I, Ljung R. Shifts to and from daylight saving time and incidence of myocardial infarction. The New England Journal of Medicine. 2008 Oct;359(18):1966-1968. DOI: 10.1056/nejmc0807104.
Table 1: Initial and follow up analysis results
A) Initial analysis (Sandhu et. al.)
Week of Spring time change Week of Fall time change
Relative Risk p-value Relative Risk p-value
Sunday 0.97 0.766 1.02 0.875
Monday 1.24 0.011 0.94 0.589
Tuesday 0.98 0.816 0.79 0.044
Wednesday 0.97 0.770 0.94 0.605
Thursday 0.97 0.790 1.10 0.348
Friday 0.97 0.794 0.91 0.427
Saturday 1.04 0.715 1.15 0.200
B) Recent analysis (9/16/2013 – 6/30/2019)
Week of Spring time change Week of Fall time change
Relative Risk p-value Relative Risk p-value
Sunday 1.11 0.171 0.97 0.731
Monday 1.09 0.207 1.08 0.261
Tuesday 1.08 0.330 0.96 0.553
Wednesday 0.97 0.714 1.00 0.966
Thursday 1.03 0.665 1.00 0.968
Friday 1.07 0.345 0.90 0.204
Saturday 1.12 0.139 0.82 0.020
The prospective matched-cohort study by Joshi et al., investigated inflammation in both AAA and atherosclerosis using 18-FDG PET to generate non-invasive imaging biomarkers for aneurysm expansion and destabilization[1]. Such work is of great importance as atherosclerosis and AAA often co-exist and share many of the same underlying risk factors and pathologies including vascular inflammation and calcification. However, the magnitude and distribution of these processes both locally and globally were not previously investigated and could provide novel insight into AAA progression.
It was shown that asymptomatic aortic aneurysms had greater inflammatory activity not only in the aneurysmal region but also throughout the entire aorta when compared to the atherosclerotic cohort. This diffuse inflammation of the aorta in AAA patients is supported by our ongoing work investigating the role of the aneurysm in affecting systemic endothelial change. This is assessed by measuring the flow-mediated dilatation (FMD) of the brachial artery [2, 3]. FMD decreases with increased maximum diameter of the aneurysmal sac and reverses following surgical intervention. This suggests that the local aneurysm itself to be a nidus of stimulus for inciting global change during the aneurysm’s natural history[4].
Furthermore, they show that aneurysms with intra-luminal thrombi (ILT) demonstrated lower 18-FDG uptake both within the thrombus and in the adjacent aortic wall. Here, the authors...
The prospective matched-cohort study by Joshi et al., investigated inflammation in both AAA and atherosclerosis using 18-FDG PET to generate non-invasive imaging biomarkers for aneurysm expansion and destabilization[1]. Such work is of great importance as atherosclerosis and AAA often co-exist and share many of the same underlying risk factors and pathologies including vascular inflammation and calcification. However, the magnitude and distribution of these processes both locally and globally were not previously investigated and could provide novel insight into AAA progression.
It was shown that asymptomatic aortic aneurysms had greater inflammatory activity not only in the aneurysmal region but also throughout the entire aorta when compared to the atherosclerotic cohort. This diffuse inflammation of the aorta in AAA patients is supported by our ongoing work investigating the role of the aneurysm in affecting systemic endothelial change. This is assessed by measuring the flow-mediated dilatation (FMD) of the brachial artery [2, 3]. FMD decreases with increased maximum diameter of the aneurysmal sac and reverses following surgical intervention. This suggests that the local aneurysm itself to be a nidus of stimulus for inciting global change during the aneurysm’s natural history[4].
Furthermore, they show that aneurysms with intra-luminal thrombi (ILT) demonstrated lower 18-FDG uptake both within the thrombus and in the adjacent aortic wall. Here, the authors claim that the ILT is metabolically inert and that its inactivity is linked with overall thrombus burden. This question of the ILT’s inflammatory profile and its physiological role in AAA progression is an area of active research that has presented many conflicting reports [5-7]. When examining the biological and mechanical properties of the aortic wall, prior studies have often excluded the ILT from analysis. However, recent in-vitro experiments have begun to characterize its heterogenous inflammatory cell infiltrate and metabolic activity[8]. Our group is currently performing a systematic review investigating the extent of inflammation within the ILT and its impact on the aortic wall and peri-aortic tissue. A majority of studies highlight the ILT as a biologically active structure that secretes a variety of proteolytic factors into the aneurysmal environment[9-12]. Ultimately, this leads to local changes in the underlying vessel wall as well as systemic vascular change [13]. This directly conflicts with the results of this study. Although, it is also possible that there may be insufficient localized metabolic activity to garner a positive signal on an 18-FDG-Uptake PET scan. This finding needs to be elucidated in a larger cohort of AAA patients and such work is underway.
Finally, the authors investigated the extent of calcification throughout the aorta in AAA patients. In general, vascular calcification has been extensively validated as a risk factor in the cardiovascular field and has been shown to strengthen the AAA rupture risk assessment[14, 15]. However, this is the first study to differentiate calcification patterns in AAA and atherosclerotic patients. They concluded that aortic wall calcification is prominent within the aneurysmal sac, relatively non-existent in the remainder of the aorta, and may be used as a biomarker to gauge AAA progression.
This study introduces a new method to stratify asymptomatic AAA patients, which may be a powerful addition to current tools for AAA disease management. However, as the authors clearly mentioned, future studies are required to assess their prognostic value.
References
1. Joshi, N.V., et al., Greater aortic inflammation and calcification in abdominal aortic aneurysmal disease than atherosclerosis: a prospective matched cohort study. Open Heart, 2020. 7(1): p. e001141.
2. Bellamkonda, K., et al., Flow Mediated Dilatation as a Biomarker in Vascular Surgery Research. Journal of atherosclerosis and thrombosis, 2017. 24: p. 779-787.
3. Lee, R., et al., Integrated Physiological and Biochemical Assessments for the Prediction of Growth of Abdominal Aortic Aneurysms in Humans. Annals of surgery, 2019. 270: p. e1-e3.
4. Lee, R., et al., Flow Mediated Dilatation and Progression of Abdominal Aortic Aneurysms. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 2017. 53: p. 820-829.
5. Haller, S.J., et al., Intraluminal thrombus is associated with early rupture of abdominal aortic aneurysm. Journal of Vascular Surgery, 2018. 67: p. 1051-1058.e1.
6. Leach, J.R., et al., On the Relative Impact of Intraluminal Thrombus Heterogeneity on Abdominal Aortic Aneurysm Mechanics. Journal of Biomechanical Engineering, 2019. 141.
7. Wang, D.H., et al., Mechanical properties and microstructure of intraluminal thrombus from abdominal aortic aneurysm. J Biomech Eng, 2001. 123(6): p. 536-9.
8. Cassimjee, I., R. lee, and J. Patel, Inflammatory Mediators in Abdominal Aortic Aneurysms. IntechOpen, 2017.
9. Koole, D., et al., Intraluminal abdominal aortic aneurysm thrombus is associated with disruption of wall integrity. J Vasc Surg, 2013. 57(1): p. 77-83.
10. Kazi, M., et al., Influence of intraluminal thrombus on structural and cellular composition of abdominal aortic aneurysm wall. J Vasc Surg, 2003. 38(6): p. 1283-92.
11. Kazi, M., et al., Difference in matrix-degrading protease expression and activity between thrombus-free and thrombus-covered wall of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol, 2005. 25(7): p. 1341-6.
12. Piechota-Polanczyk, A., et al., The Abdominal Aortic Aneurysm and Intraluminal Thrombus: Current Concepts of Development and Treatment. Frontiers in cardiovascular medicine, 2015. 2: p. 19.
13. Touat, Z., et al., Renewal of mural thrombus releases plasma markers and is involved in aortic abdominal aneurysm evolution. Am J Pathol, 2006. 168(3): p. 1022-30.
14. Buijs, R.V., et al., Calcification as a risk factor for rupture of abdominal aortic aneurysm. Eur J Vasc Endovasc Surg, 2013. 46(5): p. 542-8.
15. Lindholt, J.S., Aneurysmal wall calcification predicts natural history of small abdominal aortic aneurysms. Atherosclerosis, 2008. 197(2): p. 673-8.
Dear editor,
I have read with great interest the results of nordic baltic bifurcation study-4 by Kumsar et al (1), in which study clinical outcomes after treatment of lesions in large bifurcations by simple or complex stent implantation were compared. In the 6-month results of this study, compared to the provisional method, a decrease in major adverse cardiac event (MACE) was observed in the complex group, although it was not statistically significant. Again, in the comparison of the 2-year results, no difference was observed between the two groups. The fact that complex stenting is not found to be superior to simple stenting for true bifurcation lesions with such a wide side branch can be due to several reasons:
1- All patients did not receive a final kissing balloon inflation (FKBI). It is well known that the FKBI should be performed in two-stenting techniques for full treatment of the true bifurcation lesion. In addition, why was the high rate of FKBI application required in simple stenting? It is well known that in simple stenting, POT should be used instead of FKBI unless the there is a TIMI flow <3, and / or a dissection in the side branch (2).
2- Interestingly, no proximal optimization technique (POT) was used in any patient. In any complex two-stent technique without POT, the lesion is not considered to be truly treated (3,4). I think this is the most important limitation of the study. POT provides optimal positioning of the main vascular ste...
Dear editor,
I have read with great interest the results of nordic baltic bifurcation study-4 by Kumsar et al (1), in which study clinical outcomes after treatment of lesions in large bifurcations by simple or complex stent implantation were compared. In the 6-month results of this study, compared to the provisional method, a decrease in major adverse cardiac event (MACE) was observed in the complex group, although it was not statistically significant. Again, in the comparison of the 2-year results, no difference was observed between the two groups. The fact that complex stenting is not found to be superior to simple stenting for true bifurcation lesions with such a wide side branch can be due to several reasons:
1- All patients did not receive a final kissing balloon inflation (FKBI). It is well known that the FKBI should be performed in two-stenting techniques for full treatment of the true bifurcation lesion. In addition, why was the high rate of FKBI application required in simple stenting? It is well known that in simple stenting, POT should be used instead of FKBI unless the there is a TIMI flow <3, and / or a dissection in the side branch (2).
2- Interestingly, no proximal optimization technique (POT) was used in any patient. In any complex two-stent technique without POT, the lesion is not considered to be truly treated (3,4). I think this is the most important limitation of the study. POT provides optimal positioning of the main vascular stent prior to carina and facilitates rewiring of the side branch. The superiority of this method has been demonstrated in the studies conducted. In the vast majority of cases of true bifurcation lesions involving large side branch, complex stenting without POT is resulted in malapposition and underexpansion, which are associated with coronary thrombosis and neo-atherosclerosis (closely related to stent restenosis and / or MACE) (3,4).
For this reason, I think that the two-stent strategy is likey superior to the single-stent strategy in true bifurcation lesions with a wide side branch provided that POT - FKBI - POT sequence should be performed in all bifurcation lesions treated with the two-stent strategy.
REFERENCES
1- Kumsars I, Holm NR, Niemelä M On behalf of the Nordic Baltic bifurcation study group, et al. Randomised comparison of provisional side branch stenting versus a two-stent strategy for treatment of true coronary bifurcation lesions involving a large side branch: the Nordic-Baltic Bifurcation Study IV. Open Heart 2020;7:e000947. doi: 10.1136/openhrt-2018-000947.
2- Sawaya FJ, Lefèvre T, Chevalier B, et al. Contemporary Approach to Coronary Bifurcation Lesion Treatment. JACC Cardiovasc Interv. 2016;9(18):1861‐1878. doi:10.1016/j.jcin.2016.06.056.
3- Hoye A. The Proximal Optimisation Technique for Intervention of Coronary Bifurcations. Interv Cardiol. 2017;12(2):110‐115. doi:10.15420/icr.2017:11:2.
4- Yurtdaş M, Asoğlu R, Özdemir M, Asoğlu E. An Upfront Two-Stent Strategy for True Coronary Bifurcation Lesions with A Large Side Branch in Acute Coronary Syndrome: A Two-Year Follow-Up Study. Medicina (Kaunas). 2020;56(3):102. doi:10.3390/medicina56030102.
The authors of the metanalysis "Pharmacological interventions for the prevention of contrast-induced acute kidney injury in high-risk adult patients undergoing coronary angiography: a systematic review and meta-analysis of randomised controlled trials" conclude that "several drugs are renoprotective in patients with CKD [...] the evidence is strongest for NAC".
This conclusion is at odds with previous research and metanalyses. The same authors report 10 papers (over a total of 27) which show potentially harmful effects of NAC (OR >1). Furthermore, the paper they cite with the largest sample size (by Weisbord et al, n>2000) does not show any beneficial effect of NAC. Notwithstanding these data, the authors "recommend that NAC should be used when a high dose of contrast is anticipated". I believe the readers should be aware about the poor evidence supporting this conclusion.
NAC is a well-tolerated substance and, clearly, its use is unlikely to represent harm for patients (even though 1/3 of the studies reported by the authors would suggest that some negative effect might exist). Therefore, the main reason for its recommendation is its anxiolytic effect on physicians, who are convinced to use a "renoprotective" drug.
The arguments for using pre- race aspirin for cardio protection are quite tenable and strong. But since many cardiac arrests occur in the training period, are we to advise aspirin during training period too?
Granada neglects to mention that prior to publication of my blog post I had emailed him, offering him the opportunity to clarify or respond to the questions I raised prior to publication and to prevent any misunderstanding. Granada did not respond to my emails. In fact, after I emailed my questions to Granada I received a “cease-and-desist” letter from Julio Palmaz's attorneys. Is this his idea of "very high ethical and academic standards”?
In his statement Granada also fails to address the differences between the listing of the study on ClinicalTrials.Org (https://clinicaltrials.gov/ct2/show/record/NCT02759406), in which the stents are described as Palmaz stents, and the Open Heart publication, in which they are described as Abbott stents. This discrepancy may, potentially, raise troubling issues, including questions about the IRB evaluation of the study and how the study was described to potential subjects during the informed consent process. Granada also offers no explanation for the discrepanc...
Granada neglects to mention that prior to publication of my blog post I had emailed him, offering him the opportunity to clarify or respond to the questions I raised prior to publication and to prevent any misunderstanding. Granada did not respond to my emails. In fact, after I emailed my questions to Granada I received a “cease-and-desist” letter from Julio Palmaz's attorneys. Is this his idea of "very high ethical and academic standards”?
In his statement Granada also fails to address the differences between the listing of the study on ClinicalTrials.Org (https://clinicaltrials.gov/ct2/show/record/NCT02759406), in which the stents are described as Palmaz stents, and the Open Heart publication, in which they are described as Abbott stents. This discrepancy may, potentially, raise troubling issues, including questions about the IRB evaluation of the study and how the study was described to potential subjects during the informed consent process. Granada also offers no explanation for the discrepancy between the number of patients randomized (48 on ClinicalTrials.Govand 40 in Open Heart).
Granada also completely ignores another potentially explosive issue I raised in my blog post. While it was on the verge of bankruptcy Palmaz Scientific invested more than $443,000 in Triventures, a venture capital company co-founded by Martin Leon. Leon is also the Founder and Chairman Emeritus of the Cardiovascular Research Foundation, the organization for which Granada is now the chairman. There may be a perfectly innocent explanation for this investment, but it is fair to ask what role if any role did Triventures play in the Palmaz/CRF relationship? Why would a company in dire financial straits invest so much money in a VC fund?
We agree with DiNicolantonio´s and O´Keefe´s hypothesis that a high intake of omega-6 vegetable oils may promote coronary heart disease (CHD).1 However, we think that the mechanism is not oxidation of LDL-cholesterol (LDL-C). It is a solidly documented but little-known fact that LDL partake in the immune system by adhering to and inactivating almost all types of microorganisms.2 As the LDL-covered microorganisms are oxidized after having been taken up by macrophages, we think that the oxidation of LDL is a secondary phenomenon. The crucial event is most likely, as explained in our papers,2,3 that complexes of LDL-covered microorganisms may aggregate, in particular in the presence of
hyperhomocysteinemia, because homocysteine thiolactone causes aggregation and precipitation of thiolated LDL. Because of the high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum of the major arteries and result in ischemia of the arterial wall. The reason why omega-6 oils promote CHD may be that these oils may result in increased coagulation,4 which is a well-known risk factor for CHD, even among individuals with familial hypercholesterolemia.5
References
1. DiNicolantonio JJ, O’Keefe JH. Omega-6 vegetable oils as a driver of coronary heart
disease: the oxidized linoleic acid hypothesis. Open Heart 2018;5:e000898. doi:10.1136/openhrt-2018-000898
2. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of...
We agree with DiNicolantonio´s and O´Keefe´s hypothesis that a high intake of omega-6 vegetable oils may promote coronary heart disease (CHD).1 However, we think that the mechanism is not oxidation of LDL-cholesterol (LDL-C). It is a solidly documented but little-known fact that LDL partake in the immune system by adhering to and inactivating almost all types of microorganisms.2 As the LDL-covered microorganisms are oxidized after having been taken up by macrophages, we think that the oxidation of LDL is a secondary phenomenon. The crucial event is most likely, as explained in our papers,2,3 that complexes of LDL-covered microorganisms may aggregate, in particular in the presence of
hyperhomocysteinemia, because homocysteine thiolactone causes aggregation and precipitation of thiolated LDL. Because of the high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum of the major arteries and result in ischemia of the arterial wall. The reason why omega-6 oils promote CHD may be that these oils may result in increased coagulation,4 which is a well-known risk factor for CHD, even among individuals with familial hypercholesterolemia.5
References
1. DiNicolantonio JJ, O’Keefe JH. Omega-6 vegetable oils as a driver of coronary heart
disease: the oxidized linoleic acid hypothesis. Open Heart 2018;5:e000898. doi:10.1136/openhrt-2018-000898
2. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of
vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates
complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab
Sci 2009;39:3-16.
3. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of
atherosclerosis. Am J Med Sci 2012;344:391-4. doi 10.1097/MAJ.0b013e31824ba6e0.
4. Caligiuri SPB, Parikh M, Stamenkovic A et al. Dietary modulation of oxylipins in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol. doi:10.1152/ajpheart.00201.2017 (In press)
5. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-6. doi.org/10.1016/j.mehy.2018.09.019
Clinical practice has been historically driven by evidence-based medicine. Properly sized randomized controlled trials have been the basis of accepting or rejecting research hypotheses, and clinical guidelines are developed based on data reported in such trials. Clinical research is not perfect. However, most clinical trials are conducted in a highly regulated environment and accepted for publication following a strict peer review process led by independent experts. While limitations exist in conducting and reporting clinical trials, investigators are judged at very high ethical and academic standards.
A blog posted on September 11, 2017[1] questioned the integrity of the data and ethical conduct of the investigators of this study published in Open Heart. Due to the respect I have for the editor and this journal, I am obliged to respond on behalf of the authors.
First, I did not receive ANY type of financial compensation as the principal investigator for this study. Second, no financial obligations or equity arrangements exist between the sponsor of the study, myself or my current Institution. Third, although all financial disclosures of all authors were properly disclosed to the journal at the time of submission, they were unfortunately not included in the final published article and therefore published subsequently as a correction[2]. Fourth, the objective of the study was to assess the 3-week healing properties of a surface-modified stent. The patient wi...
Clinical practice has been historically driven by evidence-based medicine. Properly sized randomized controlled trials have been the basis of accepting or rejecting research hypotheses, and clinical guidelines are developed based on data reported in such trials. Clinical research is not perfect. However, most clinical trials are conducted in a highly regulated environment and accepted for publication following a strict peer review process led by independent experts. While limitations exist in conducting and reporting clinical trials, investigators are judged at very high ethical and academic standards.
A blog posted on September 11, 2017[1] questioned the integrity of the data and ethical conduct of the investigators of this study published in Open Heart. Due to the respect I have for the editor and this journal, I am obliged to respond on behalf of the authors.
First, I did not receive ANY type of financial compensation as the principal investigator for this study. Second, no financial obligations or equity arrangements exist between the sponsor of the study, myself or my current Institution. Third, although all financial disclosures of all authors were properly disclosed to the journal at the time of submission, they were unfortunately not included in the final published article and therefore published subsequently as a correction[2]. Fourth, the objective of the study was to assess the 3-week healing properties of a surface-modified stent. The patient with pancreatitis mentioned in the article died from non-cardiovascular causes several months beyond the reported follow up period, which is why the patient was not included in the study results. Finally, the study was properly approved and conducted according to the recommendations and guidelines of local investigators, ethics committees and regulatory authorities.
As leaders in the medical community, we are bound by a strong code of ethics. Medical innovation thrives when there is collaboration among physicians, engineers, business people and funding sources. The innovation ecosystem, although far from perfect, has been responsible for the development of truly disruptive technologies that have made a real impact on humanity. Medical media outlets have a responsibility to ensure that all developments in the field, including successes and failures, are reported based on facts and in an accurate and professional fashion.
References
1. Husten L. Julio Palmaz Really Doesn’t Want You To Read This Story. http://www.cardiobrief.org/2017/09/11/julio-palmaz-really-doesnt-want-yo...
2. Correction: Biological effect of microengineered grooved stents on strut healing: a randomised OCT-based comparative study in humans. Open Heart 2018;5:e000521corr1. doi: 10.1136/openhrt-2016-000521corr1
Lee et al in trying to define the accuracy of one method illustrate the huge weakness in echo vs MRI comparative data. First and foremost neither FAC or TAPSE correlated that well with RVEF ( FAC only slightly better) although statistically significant this difference is clinically of negligible importance. Secondly in assuming that MRI provides a gold standard for RVEF. As with echo there are strengths and weaknesses of MRI. On is the rather lower sensitivity to long axis abnormalities because ventricular volumes are usually defined using the short axis plane. So a reduced correlation between a purely long axis technique, a moderate correlation with a technique that has both long and short axis components and one which is defined using predominantly radial function is entirely to be expected. Long axis dysfunction is usually the first sign of ventricular deterioration with short axis hyperactivity to compensate - exactly the example cited post cardiac surgery. Finally in their conclusions they state that FAC provides a better guide to RV systolic function. This is not justified - what it does do is provide a slightly better estimate of RVEF -these two are not synonymous. So as there are no clinical correlates - prognosis, symptoms, exercise performance, hospitalisations , the comparison between the techniques tells us nothing we did not already know - all methods of defining systolic function are different - we have not answered which one is best.
To the Editor:
We read with great interest the editorial by Dr. James J DiNicolantonio and colleagues.1 In their editorial, the authors have expressed their opinions that ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. However, we want to highlight some concerns about the use of ivermectin for late-stage COVID-19.
First, we do agree with the authors that ivermectin can be a potential drug for late-stage COVID-19 considering its anti-inflammatory effects. The authors stated that it is reasonable to suspect that, in doses at or modestly above the standard clinical dose, ivermectin may have important clinical potential for managing disorders associated with life-threatening respiratory distress and cytokine storm—such as advanced COVID-19.
Second, a usual dose or modestly above the standard clinical dose of ivermectin may induce neurologic disorders, which can be fatal.2 Encephalopathy and coma are well-known side effects of ivermectin treatment in animals. But few cases of neurologic disorders after ivermectin treatment have been reported in humans.3 Neurologic disorders may include coma, ataxia, pyramidal signs, and binocular diplopia. Thus, the seriousness of the adverse reaction in humans implies that caution is warranted regarding medical prescriptions of ivermectin.
We declare no competing interests.
Contributors: All authors contributed to the final manuscript.
Funding: The authors have...
Show MoreFive years ago, our group at the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) published an analysis exploring the impact of day light saving time (DST) changes on the state -wide volume of percutaneous coronary intervention in patients presenting with acute myocardial infarction (AMI-PCI) in the weekdays following the time change.1 Using data from our clinical registry reflecting all PCIs performed at non-Federal hospitals throughout Michigan between 1/1/2010 and 9/15/2013, we identified a significant increase in AMI-PCI on Mondays following the Spring DST change (RR = 1.24, p = 0.011), and a significant reduction in cases on Tuesdays following fall DST changes (RR = 0.79, p = 0.044), adjusting for seasonal and weekday effects, and for an overall time trend. We have now repeated the analysis using registry data for the subsequent 5 ½ years, from 9/16/2013 – 3/31/2019 using the same methodology and obtained results inconsistent with our prior publication. In our analysis of more recent data, both of the previously reported effects were substantially attenuated and are no longer statistically significant (Spring Monday after change: RR = 1.095, p = 0.207; Fall Tuesday after change: RR = 0.96, p = 0.553). Our prior publication garnered a great deal of attention in the popular media2,3, often with alarming, sensational headlines. It has also been included in meta-analysis along with other publications identifying a similar Spring time change effect4...
Show MoreThe prospective matched-cohort study by Joshi et al., investigated inflammation in both AAA and atherosclerosis using 18-FDG PET to generate non-invasive imaging biomarkers for aneurysm expansion and destabilization[1]. Such work is of great importance as atherosclerosis and AAA often co-exist and share many of the same underlying risk factors and pathologies including vascular inflammation and calcification. However, the magnitude and distribution of these processes both locally and globally were not previously investigated and could provide novel insight into AAA progression.
It was shown that asymptomatic aortic aneurysms had greater inflammatory activity not only in the aneurysmal region but also throughout the entire aorta when compared to the atherosclerotic cohort. This diffuse inflammation of the aorta in AAA patients is supported by our ongoing work investigating the role of the aneurysm in affecting systemic endothelial change. This is assessed by measuring the flow-mediated dilatation (FMD) of the brachial artery [2, 3]. FMD decreases with increased maximum diameter of the aneurysmal sac and reverses following surgical intervention. This suggests that the local aneurysm itself to be a nidus of stimulus for inciting global change during the aneurysm’s natural history[4].
Furthermore, they show that aneurysms with intra-luminal thrombi (ILT) demonstrated lower 18-FDG uptake both within the thrombus and in the adjacent aortic wall. Here, the authors...
Show MoreDear editor,
Show MoreI have read with great interest the results of nordic baltic bifurcation study-4 by Kumsar et al (1), in which study clinical outcomes after treatment of lesions in large bifurcations by simple or complex stent implantation were compared. In the 6-month results of this study, compared to the provisional method, a decrease in major adverse cardiac event (MACE) was observed in the complex group, although it was not statistically significant. Again, in the comparison of the 2-year results, no difference was observed between the two groups. The fact that complex stenting is not found to be superior to simple stenting for true bifurcation lesions with such a wide side branch can be due to several reasons:
1- All patients did not receive a final kissing balloon inflation (FKBI). It is well known that the FKBI should be performed in two-stenting techniques for full treatment of the true bifurcation lesion. In addition, why was the high rate of FKBI application required in simple stenting? It is well known that in simple stenting, POT should be used instead of FKBI unless the there is a TIMI flow <3, and / or a dissection in the side branch (2).
2- Interestingly, no proximal optimization technique (POT) was used in any patient. In any complex two-stent technique without POT, the lesion is not considered to be truly treated (3,4). I think this is the most important limitation of the study. POT provides optimal positioning of the main vascular ste...
The authors of the metanalysis "Pharmacological interventions for the prevention of contrast-induced acute kidney injury in high-risk adult patients undergoing coronary angiography: a systematic review and meta-analysis of randomised controlled trials" conclude that "several drugs are renoprotective in patients with CKD [...] the evidence is strongest for NAC".
This conclusion is at odds with previous research and metanalyses. The same authors report 10 papers (over a total of 27) which show potentially harmful effects of NAC (OR >1). Furthermore, the paper they cite with the largest sample size (by Weisbord et al, n>2000) does not show any beneficial effect of NAC. Notwithstanding these data, the authors "recommend that NAC should be used when a high dose of contrast is anticipated". I believe the readers should be aware about the poor evidence supporting this conclusion.
NAC is a well-tolerated substance and, clearly, its use is unlikely to represent harm for patients (even though 1/3 of the studies reported by the authors would suggest that some negative effect might exist). Therefore, the main reason for its recommendation is its anxiolytic effect on physicians, who are convinced to use a "renoprotective" drug.
The arguments for using pre- race aspirin for cardio protection are quite tenable and strong. But since many cardiac arrests occur in the training period, are we to advise aspirin during training period too?
In his response to my CardioBrief blog post (http://www.cardiobrief.org/2017/09/11/julio-palmaz-really-doesnt-want-yo...) Juan Granada implies that my article was neither factual, nor accurate, nor professional. However, at no point does Granada give examples backing his assertions.
Granada neglects to mention that prior to publication of my blog post I had emailed him, offering him the opportunity to clarify or respond to the questions I raised prior to publication and to prevent any misunderstanding. Granada did not respond to my emails. In fact, after I emailed my questions to Granada I received a “cease-and-desist” letter from Julio Palmaz's attorneys. Is this his idea of "very high ethical and academic standards”?
In his statement Granada also fails to address the differences between the listing of the study on ClinicalTrials.Org (https://clinicaltrials.gov/ct2/show/record/NCT02759406), in which the stents are described as Palmaz stents, and the Open Heart publication, in which they are described as Abbott stents. This discrepancy may, potentially, raise troubling issues, including questions about the IRB evaluation of the study and how the study was described to potential subjects during the informed consent process. Granada also offers no explanation for the discrepanc...
Show MoreWe agree with DiNicolantonio´s and O´Keefe´s hypothesis that a high intake of omega-6 vegetable oils may promote coronary heart disease (CHD).1 However, we think that the mechanism is not oxidation of LDL-cholesterol (LDL-C). It is a solidly documented but little-known fact that LDL partake in the immune system by adhering to and inactivating almost all types of microorganisms.2 As the LDL-covered microorganisms are oxidized after having been taken up by macrophages, we think that the oxidation of LDL is a secondary phenomenon. The crucial event is most likely, as explained in our papers,2,3 that complexes of LDL-covered microorganisms may aggregate, in particular in the presence of
hyperhomocysteinemia, because homocysteine thiolactone causes aggregation and precipitation of thiolated LDL. Because of the high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum of the major arteries and result in ischemia of the arterial wall. The reason why omega-6 oils promote CHD may be that these oils may result in increased coagulation,4 which is a well-known risk factor for CHD, even among individuals with familial hypercholesterolemia.5
References
Show More1. DiNicolantonio JJ, O’Keefe JH. Omega-6 vegetable oils as a driver of coronary heart
disease: the oxidized linoleic acid hypothesis. Open Heart 2018;5:e000898. doi:10.1136/openhrt-2018-000898
2. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of...
Clinical practice has been historically driven by evidence-based medicine. Properly sized randomized controlled trials have been the basis of accepting or rejecting research hypotheses, and clinical guidelines are developed based on data reported in such trials. Clinical research is not perfect. However, most clinical trials are conducted in a highly regulated environment and accepted for publication following a strict peer review process led by independent experts. While limitations exist in conducting and reporting clinical trials, investigators are judged at very high ethical and academic standards.
A blog posted on September 11, 2017[1] questioned the integrity of the data and ethical conduct of the investigators of this study published in Open Heart. Due to the respect I have for the editor and this journal, I am obliged to respond on behalf of the authors.
First, I did not receive ANY type of financial compensation as the principal investigator for this study. Second, no financial obligations or equity arrangements exist between the sponsor of the study, myself or my current Institution. Third, although all financial disclosures of all authors were properly disclosed to the journal at the time of submission, they were unfortunately not included in the final published article and therefore published subsequently as a correction[2]. Fourth, the objective of the study was to assess the 3-week healing properties of a surface-modified stent. The patient wi...
Show MoreLee et al in trying to define the accuracy of one method illustrate the huge weakness in echo vs MRI comparative data. First and foremost neither FAC or TAPSE correlated that well with RVEF ( FAC only slightly better) although statistically significant this difference is clinically of negligible importance. Secondly in assuming that MRI provides a gold standard for RVEF. As with echo there are strengths and weaknesses of MRI. On is the rather lower sensitivity to long axis abnormalities because ventricular volumes are usually defined using the short axis plane. So a reduced correlation between a purely long axis technique, a moderate correlation with a technique that has both long and short axis components and one which is defined using predominantly radial function is entirely to be expected. Long axis dysfunction is usually the first sign of ventricular deterioration with short axis hyperactivity to compensate - exactly the example cited post cardiac surgery. Finally in their conclusions they state that FAC provides a better guide to RV systolic function. This is not justified - what it does do is provide a slightly better estimate of RVEF -these two are not synonymous. So as there are no clinical correlates - prognosis, symptoms, exercise performance, hospitalisations , the comparison between the techniques tells us nothing we did not already know - all methods of defining systolic function are different - we have not answered which one is best.
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