Dear Sir,
The article is interesting. We in the UAE are using high-sensitivity Troponin I for the last 8 years in all patients suspected of the acute coronary syndrome and all cardiovascular emergencies (for risk stratification) presenting in the emergency units. We observed many patients who presented after 3-hour of symptoms-onset with negative first high-sensitivity Troponin I (<5ng/L) showed positive second or a third repeat test, when we had high-index of suspicion clinically, largely because of chronic comorbidities like diabetes mellitus and expatriates from Bangaldesh. Therefore the message must be evaluated in light of overall picture and value of Troponin should be used only as one of the important markers.
According to Steffens et al.,1 patients with cardiovascular disease (CVD) whose cholesterol is too high despite ongoing cholesterol-lowering treatment should be treated with the PCSK9-inhibitor alirocumab. They base their conclusion on twelve weeks of treating 244 middle-aged and elderly patients (half of whom had familial hypercholesterolemia), where the LDL-cholesterol (LDL-C) was lowered by around 50% without any serious side effects. A relevant question is whether or not such treatment provide clinic benefit.
The optimal way to demonstrate the benefits of any drug is through the use of double-blinded placebo-controlled trials. More than 30 PCSK9-inhibitor-trials have now been published,2,3 and none of them has demonstrated a reduction in overall or CV mortality. Only three, which included 73 936 patients with CVD, were performed correctly.2 Although LDL-cholesterol was lowered by more than 50%, none of them achieved a statistically significant reduction in either total or CVD mortality. In the longest trial (the 2.8 year long ODYSSEY-trial), which included almost 19,000 statin-treated patients, total mortality was a little lower in the alirocumab-group (3.5% vs 4.1%),2 which means that to save one life per year, it is necessary to treat more than 550 patients at a cost of more than five million US dollars.
That such a strong cholesterol-lowering is ineffective is not unexpected, because there is much evidence that CVD is not caused by elevated...
According to Steffens et al.,1 patients with cardiovascular disease (CVD) whose cholesterol is too high despite ongoing cholesterol-lowering treatment should be treated with the PCSK9-inhibitor alirocumab. They base their conclusion on twelve weeks of treating 244 middle-aged and elderly patients (half of whom had familial hypercholesterolemia), where the LDL-cholesterol (LDL-C) was lowered by around 50% without any serious side effects. A relevant question is whether or not such treatment provide clinic benefit.
The optimal way to demonstrate the benefits of any drug is through the use of double-blinded placebo-controlled trials. More than 30 PCSK9-inhibitor-trials have now been published,2,3 and none of them has demonstrated a reduction in overall or CV mortality. Only three, which included 73 936 patients with CVD, were performed correctly.2 Although LDL-cholesterol was lowered by more than 50%, none of them achieved a statistically significant reduction in either total or CVD mortality. In the longest trial (the 2.8 year long ODYSSEY-trial), which included almost 19,000 statin-treated patients, total mortality was a little lower in the alirocumab-group (3.5% vs 4.1%),2 which means that to save one life per year, it is necessary to treat more than 550 patients at a cost of more than five million US dollars.
That such a strong cholesterol-lowering is ineffective is not unexpected, because there is much evidence that CVD is not caused by elevated LDL-C, neither in people with FH, nor in other people.4,5 In the following we shall shortly mention the most striking contradictions.
In a meta-analysis of 37 statin-trials, there was no exposure-response between LDL-C lowering and cardiovascular or total mortality. In contrast, CV mortality increased in seven trials and total mortality in ten, although not with statistical significance.5
Several studies have shown that people with or without FH and with low LDL-C become just as atherosclerotic as those with high LDL-C.4,5
In 38 studies, where the authors had followed more than six million individuals after having measured their LDL-cholesterol, almost all studies found, that those with high LDL-cholesterol lived just as long or longer than those with normal or low LDL-C.6,7
In a study of almost 140,000 patients with acute myocardial infarction, LDL-C was lower than normal, and in a study with the same result, increased cholesterol-lowering resulted in increased mortality.5
Furthermore, LDL-C of FH-people who die early from CVD is not higher than the others; in fact, people with FH have lifespans that are equivalent to the rest of the population.4 The few who die prematurely have inherited increased coagulation factors, whereas their LDL-C does not differ from those who survive.
Therefore, Steffens et al.’s recommendation that patients with high cholesterol should be treated with the PCSK9-inhibitor alirocumab is not supported by evidence that the patients will benefit from the treatment.
References
1. Steffens D, Bramlage P, Müller J, et al. Intensified lipid- lowering treatment with alirocumab in patients with coronary heart disease. Open Heart 2021;8:e001572. doi:10.1136/ openhrt-2021-001572
2. Rabaeus M, de Lorgeril M. A systematic review of clinical trials testing CETP and PCSK9 inhibitors: the cholesterol-heart theory—time for a requiem? J Controvers Biomed Res 2019;5,4–11. doi.org/10.36255/jcbmr.2019.35
3. Van Bruggen FH, Nijhuis GB, Zuidema SU, Luijendijk H. Serious adverse events and deaths in PCSK9 inhibitor trials reported on Clinical-Trials.gov: a systematic review. Exp Rev Clin Pharmacol 2020;13:787–96.
4. 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: 60-3. PMID: 30396495 DOI: 10.1016/j.mehy.2018.09.019
5. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharmacol 2018;11:959-70. doi.org/10.1080/17512433.2018.1519391
6. Ravnskov U, Diamond D, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein and mortality in the elderly. A systematic review. BMJ Open 2016;6:e010401https://doi.org/10.1136/ bmjopen-2015-010401.cholesterol.
7. Ravnskov U, de Lorgeril M, Diamond DM, et al. The LDL paradox: higher LDL-cholesterol is associated with greater longevity. A Epidemiol Public Health 2020;3:1040-7. https://meddocsonline.org/annals-of- epidemiology-and-public-health/the-LDL-paradox-higher-LDL-cholesterol-is-associated-with- greater-longevity.pdf
In their recent discussion on the anti-inflammatory activity of ivermectin in sepsis, DiNicolantonio et al. [1] left open the question on how ivermectin may protect against COVID-19 initial symptoms and progression.
Insight was published by Li et al. [2] in their derivation of an ivermectin host protein and SARS-CoV-2 host protein interaction network (PPI). For this they metabolically labelled proteins in an ovarian cancer cell line and determined which proteins were upregulated and downregulated related to a 24 hour exposure to ivermectin versus no exposure. There were 4,447 identified proteins differentially regulated by ivermectin. When compared with the 284 host proteins known to be affected by SARS-CoV-2, this left 52 proteins in common, 50 of which were downmodulated. Only two proteins, HMOX1 and IL1F10 were upregulated by ivermectin.
This protein-protein interaction (PPI) network revealed EGFR at the center of the pathway with connections to mTOR/APOE, NFKB1/APP, AKT, MAPK1, and CASP3 through TGFB1 interacting with the protein ALB (albumin). BSG, recently shown to be absolutely essential for foam cell formation in macrophages [3] was also captured in the PPI network. Moreover, foam cell formation has been shown in macrophages to be mediated under the direction of EGFR [4] as well as for the foamy sebocytes of sebaceous glands which line the mucosal surfaces and may be an important site of viral entry [5]. Foam cell formation is important in ho...
In their recent discussion on the anti-inflammatory activity of ivermectin in sepsis, DiNicolantonio et al. [1] left open the question on how ivermectin may protect against COVID-19 initial symptoms and progression.
Insight was published by Li et al. [2] in their derivation of an ivermectin host protein and SARS-CoV-2 host protein interaction network (PPI). For this they metabolically labelled proteins in an ovarian cancer cell line and determined which proteins were upregulated and downregulated related to a 24 hour exposure to ivermectin versus no exposure. There were 4,447 identified proteins differentially regulated by ivermectin. When compared with the 284 host proteins known to be affected by SARS-CoV-2, this left 52 proteins in common, 50 of which were downmodulated. Only two proteins, HMOX1 and IL1F10 were upregulated by ivermectin.
This protein-protein interaction (PPI) network revealed EGFR at the center of the pathway with connections to mTOR/APOE, NFKB1/APP, AKT, MAPK1, and CASP3 through TGFB1 interacting with the protein ALB (albumin). BSG, recently shown to be absolutely essential for foam cell formation in macrophages [3] was also captured in the PPI network. Moreover, foam cell formation has been shown in macrophages to be mediated under the direction of EGFR [4] as well as for the foamy sebocytes of sebaceous glands which line the mucosal surfaces and may be an important site of viral entry [5]. Foam cell formation is important in host defense as it relates to induction of a foamy virus of humans which may protect against emerging RNA viruses [6].
Interestingly, foamy sebocytes have the distinct highly vacuolated morphology of the lipid body negative foamy macrophages (LB-FMs) which produce human endogenous retrovirus K102 (HERV-K102), the elusive, protector foamy virus of humans [6]. In this regard, an examination of the GEO profiles [https://www.ncbi.nlm.nih.gov/geo/tools/profileGraph.cgi?ID=GDS3215:38935] for sebocytes reveals that sebocytes indeed express HERV-K102 (ERVK-7) along with BSG and bear all the relevant differentially expressed genes of the LB-FMs [7] including CD14, CD16 and CD68. Technically this definitively establishes the sebocytes as macrophages. As sebocytes undergo programmed cell death on day 7, just like the LB-FMs [6], this may be the first realization that sebocytes are LB-FMs which constitutively produce HERV-K102 particles. Thus, it seems HERV-K102 is positioned to provide the first line of defense against SARS-CoV-2 an emerging pandemic RNA virus. The relevance of this in terms of immunosenescence is discussed below.
The damage associated molecular pattern high mobility group box 1 (HMGB1) released by dying cells and which acts as a ligand stimulating TLR4 was also captured in the ivermectin SARS-Cov-2 host PPI network. DiNicolantonio et al, had in an earlier paper discussed how ivermectin may counteract sepsis by the inhibition of the LPS-like TLR4 responses in murine models [8].
However, Li et al [2] may have mistakenly labelled alpha-fetoprotein (AFP) as albumin (ALB) in the PPI network. First, 8 of the 8 sequenced peptides for ALB did not distinguish it from AFP which is related with 45% amino acid homology [9]. Second, AFP is a better fit than ALB since 1) TGFB1 is known to bind and activate AFP [10,11], 2) AFP binds and inactivates CASP3 inhibiting apoptosis [12,13], 3) the main AFP signalling pathway involves PI3K/Akt/mTOR signalling [14] but also TGFB1 and MAPK pathways [15], 4) ovarian cancer cells express AFP but not ALB [16] and 5) SARS-CoV-2 infection upregulates AFP mRNA and protein in HuH-7 cells associated with hyperactivation of the Erbb2/EGFR pathway via PI3K/Akt/mTOR [17, and Dr. Ujjwal Neogi, personal communication]. Assuming that AFP replaces ALB in the PPI network of Li et al [2], it is remarkable then that ivermectin blocked AFP protein expression by 100% [2]. This identifies ivermectin as a potent AFP antagonist. Overall, this PPI network is in agreement with previous reports that ivermectin binds EGFR and reverses drug resistance in cancer cells via EGFR/ERK/Akt/NFKB1 [18] and that it may downregulate Akt/mTOR hyperactivity [19]. Thus, this helps to explain the reports of anti-tumor activity of ivermectin in addition to its potential biological effects against SARS-CoV-2.
How this connects to immunosenescence and COVID-19 pathogenesis is as follows. First immunosenescence was defined in the new immunosenescence paradigm of 2015 as the failed lytic release of human endogenous retrovirus K102 (HERV-K102) protector foamy virus particles from LB-FMs [20]. Failure to release the protector foamy virus by lysis on day 7 was proposed to be due to active AFP. In part the activity of AFP relates to the DHEA/cortisol ratio which notably declines with age and/or with onset and progression of chronic illness. In this regard, DHEA but not DHEA-S was shown to bind and inactivate AFP blocking its ability to inhibit programmed cell death in primary cells [20]. As well, AFP contains glucocorticoid response elements in its promoter [21] and is upregulated by corticosteroids in humans [22]. Accordingly, AFP activity relates in part to the DHEA/cortisol ratio and may help explain the age/stress connection with immunosenescence and COVID-19 susceptibility. In COVID-19 hospitalized patients, 70% showed elevated cortisol levels between days 1-2 and 3-5 [23] consistent with a role of SARS-Cov-2 infection mediating a heightened risk of immunosenescence.
Although the PPI network elaborated by Li et al [2] was not informative for p53, possibly due to its inactivation in ovarian cancers which are notably aggressive, nevertheless, in vivo and in vitro evidence suggests SARS-CoV-2 downmodulates TP53 [24,25]. One of the most important malignancy conferring genes downregulated by TP53 is AFP [26,27]. Pathogenic viruses such as Hepatitis B Virus may specifically target p53 resulting in the upregulation of AFP such as by HBx protein [28]. On the other hand, silencing AFP leads to the upregulation of TP53 [13] and the downmodulation of TGFB1 [29]. SARS-CoV-2 also strongly upregulates TGFB1 in monocytes and macrophages in vitro [30] and in vivo associated with COVID-19 severity [31]. An emerging picture of failed lytic release of the protector HERV-K102 particles from foamy macrophages by SARS-CoV-2 appears to involve the upregulation of TGFB1 which may bind and activate AFP (with [17] or without [24] upregulation at the protein/mRNA level) and the concomitant downregulation of TP53.
In addition to failed lytic release of HERV-K102 particles from LB-FMs, there is also evidence for the inhibition of foam cell formation in vitro. For example, as shown in ACE2 transfected A549 cells, not only is TP53 significantly downmodulated by SARS-CoV-2 infection but also BSG [25]. Moreover, the mevalonate pathway which generates cholesterol for the production of vacuoles and HERV-K102 particles is uniquely negatively affected by SARS-CoV-2 infection amongst respiratory viruses [25]. As well, hypoxia inducing factor -1A which induces foam cell formation in response to hypoxia was downregulated by SARS-CoV-2 infection in HuH-7 cells [17]. In vivo Chow et al [24] have shown that BSG is downmodulated when bronchoalveolar lavage fluids (BALF) from healthy controls are compared with patients with severe COVID-19.
The induction of HERV-K102 proviral genomic RNA is initiated by interferon-gamma (IFNG) which induces the transcription factor Interferon Regulatory Factor 1 (IRF1) which binds to the HERV-K102 LTR [32]. DDX6 is needed for the export of the RNA genomes to the cytoplasm for incorporation into particles [32]. An alternative activation of IRF1 is through the LPS or LPS-like response via TLR4 [33]. However here, this response not only downmodulates IFNG signalling but also interferes with lipogenesis needed for foam cell formation and HERV-K102 particle production [33]. Consistent with this notion, while IRF1 is upregulated in BALF in patients with severe COVID-19 [24,31], DDX6 is downmodulated [24]. Indeed, in a 33 differentially expressed gene (DEG) classification system of COVID-19 sepsis into 3 groups according to clinical parameters and mortality, the coagulopathic category that had the highest levels of D-dimer and ferritin, had the highest mortality at 42.3 %. Here the downregulation of DDX6 was part of the classification DEGS for this category [34]. Potentially this implies little if any HERV-K102 particle production or foam cell formation. The inflammopathic group featured the highest levels of CRP and IL-6 and presented with 17. 9 % mortality [34]. Here elevated LCN2 was part of the defining DEGS for this group, and LCN2 was shown to be upregulated on day 7 associated with the induction of apoptosis in sebocytes [5]. Potentially this may indicate particle production but failed lytic release of the HERV-K102 particles. The adaptive category with 0 % mortality, younger age and the best clinical laboratory findings featured the upregulation of TP53BP1 which is involved in apoptosis [35]. All together the sepsis endotype groups appear to categorize COVID-19 risks based on HERV-K102 activity: adaptive (0% mortality): no issues with the production and release of HERV-K102; inflammopathic (17.9% mortality): issues with the release of HERV-K102 particles but production might be okay; and coagulopathic (42.3 % mortality) and possible problems with HERV-K102 particle production and thus little foam cell formation. Clearly it will be important to determine HERV-K102 particle production (release versus macrophage content) for the different categories of sepsis endotypes.
According to Liao et al. [36] and Ren et al. [37] there are two major subsets of macrophages in BALF from severe COVID-19 patients (sBALF) which appear to be alternative forms of the LB-FMs. These cells comprise over 50% of the major cell types in sBALF [37]. As well, it should be appreciated that in sBALF but interestingly, not BALF from patients with moderate COVID-19, the myeloid cells have more SARS-CoV-2 RNA than the epithelial cells, despite the absence of expression of ACE2 and TMPRSS2 [37]. From Liao et al, both macrophage subsets appear to exhibit epithelial mesenchymal transition (EMT, the malignant phenotype), and this is associated with glycolysis, apoptosis resistance, and dysfunctional p53 suggesting immunosenescence in both major groups. Group 3 may express more TGF-1 and exhibits more notable TGFBR dysfunction, which are also features of the malignant phenotype. While the Group 2 (Macro c2) features inflammation associated with mir155 expression which promotes M1 proinflammatory polarization [38], the Group 3 (Macro c1) which may be 1.7 times more dominant [37] features coagulation which is associated with higher PPARG and NR1H3 expression. NR1H3 is the liver x receptor alpha which controls cholesterol homeostasis and is considered anti-inflammatory [39]. PPARG encodes the protein peroxisome proliferator activated receptor gamma (glitazone receptor) which regulates fatty acid storage, glucose metabolism, and adipocyte/foam cell differentiation and is also considered anti-inflammatory [40]. When compared with the sepsis endotype categories [34], it appears Group 3 may be contributing to the coagulopathic highest mortality category (42.3%), while Group 2 may be contributing to the inflammopathic category with significant mortality (17.9%). The finding that TGFB1 may be more upregulated in the highest mortality category is consistent with the notion that TGFB1 binds and activates AFP [10, 11], and that AFP may drive immunosenescence as originally proposed [20] and COVID-19 mortality. Thus, SARS-CoV-2 infection itself may exacerbate pre-existing immunosenescence in parallel with its upregulation of cortisol [23].
Additional clinical evidence is consistent with SARS-CoV-2 targeting HERV-K102 particle production. Lieberman et al., [41] showed that both MX1 (elevates on day 7 with apoptosis of sebocytes[5]) and IRF1 (induces HERV-K102 proviral genomic RNA [32]) were significantly upregulated in nasopharyngeal swabs when SARS2 positive samples were compared with those that were SARS2 negative. On the other hand, when a comparison was made of high SARS2 viral load to low, neither MX1 nor IRF1 were elevated, suggesting SARS2 at higher inoculums may block apoptosis, HERV-K102 particle upregulation and/or that pre-existing immunosenescence may allow for higher viral loads.
As mentioned in the earlier paper by DiNicolantonio et al [8], Zhang et al had demonstrated that ivermectin prevented the lethality of intraperitoneal injection of LPS in mice where the IC50 was 4 mg/kg [42]. According to DiNicolantonio et al [8] this extrapolates to 18 mg for a 70 kg adult. A recent clinical trial (preprint) used 15 mg/70 kg and although underpowered for mortality, showed significance for ivermectin inhibition of CRP, D-dimers and ferritin in patients with severe COVID-19 [43]. As mentioned above, the TLR4 signalling which results in elevated IRF1 appears to abolish IFNG signalling and lipogenesis [33] needed for HERV-K102 genome expression [32]. Accordingly, this sepsis inducing TLR4 signalling may qualify under the umbrella of immunosenescence as it also leads to the failed lytic release of HERV-K102 particles through blocking foam cell formation. Thus, accumulating evidence suggests ivermectin may be useful for the treatment of all stages of COVID-19 as all stages may be related to immunosenescence.
In summary, from the PPI network, ivermectin may counteract the effects of SARS-CoV-2 in the dysregulation of the EGFR/ERBB2 pathway involved in foam cell formation of LB-FMs through its antagonism to AFP and/or the EGFR/ERBB2 mediated hyperactivity of the PI3K/Akt/mTOR pathway Ivermectin appears to reverse or prevent immunosenescence and EMT which re-establishes the HERV-K102 innate protector system. Since BSG has been demonstrated to mediate SARS-CoV-2 entry into cells [44], it appears that SARS-CoV-2 particularly with progression to severe COVID-19, may directly target the LB-FMs and sebocytes to block HERV-K102 particle production and/or release. Interestingly, HERV-K102 may also be the target of another pandemic RNA virus, HIV-1 [45,46]. Potentially this further substantiates the importance of HERV-K102 and ivermectin for pandemic preparedness.
References
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43. Okumus N, Demirtürk N, Cetinkaya RA, et al., Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. (preprint) https://www.researchsquare.com/article/rs-224203/v1 and see https://clinicaltrials.gov/ct2/show/results/NCT04646109.
44. Wang K, Chen W, Zhang Z, et al. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther. 2020 Dec 4;5(1):283. doi: 10.1038/s41392-020-00426-x.
45. Laderoute MP, Giulivi A, Larocque L, et al. The replicative activity of human endogenous retrovirus K102 (HERV-K102) with HIV viremia. AIDS. 2007 Nov 30;21(18):2417-24.
46. Laderoute MP. Clues to finding correlates of risk/protection for HIV-1 vaccines F1000 Research 2018, 6:868 (doi: 10.12688/f1000research.11818.2). https://f1000research.com/articles/6-868
The use of high dose melatonin early and aggressively for those infected with COVID-19 was the subject of an international symposium held in December 2020 (1). Dr Richard Neel reported on over 1000 cases that have responded to monotherapy with melatonin.
Why this works, as speculated upon in this article, is open to debate. What is most important is that people can benefit from this treatment modality. Thank you for the opportunity to raise awareness of this underappreciated therapeutic option.
References
(1) https://www.youtube.com/watch?v=p_4JeOj1JLc
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
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 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.
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?
Dear Sir,
The article is interesting. We in the UAE are using high-sensitivity Troponin I for the last 8 years in all patients suspected of the acute coronary syndrome and all cardiovascular emergencies (for risk stratification) presenting in the emergency units. We observed many patients who presented after 3-hour of symptoms-onset with negative first high-sensitivity Troponin I (<5ng/L) showed positive second or a third repeat test, when we had high-index of suspicion clinically, largely because of chronic comorbidities like diabetes mellitus and expatriates from Bangaldesh. Therefore the message must be evaluated in light of overall picture and value of Troponin should be used only as one of the important markers.
According to Steffens et al.,1 patients with cardiovascular disease (CVD) whose cholesterol is too high despite ongoing cholesterol-lowering treatment should be treated with the PCSK9-inhibitor alirocumab. They base their conclusion on twelve weeks of treating 244 middle-aged and elderly patients (half of whom had familial hypercholesterolemia), where the LDL-cholesterol (LDL-C) was lowered by around 50% without any serious side effects. A relevant question is whether or not such treatment provide clinic benefit.
Show MoreThe optimal way to demonstrate the benefits of any drug is through the use of double-blinded placebo-controlled trials. More than 30 PCSK9-inhibitor-trials have now been published,2,3 and none of them has demonstrated a reduction in overall or CV mortality. Only three, which included 73 936 patients with CVD, were performed correctly.2 Although LDL-cholesterol was lowered by more than 50%, none of them achieved a statistically significant reduction in either total or CVD mortality. In the longest trial (the 2.8 year long ODYSSEY-trial), which included almost 19,000 statin-treated patients, total mortality was a little lower in the alirocumab-group (3.5% vs 4.1%),2 which means that to save one life per year, it is necessary to treat more than 550 patients at a cost of more than five million US dollars.
That such a strong cholesterol-lowering is ineffective is not unexpected, because there is much evidence that CVD is not caused by elevated...
In their recent discussion on the anti-inflammatory activity of ivermectin in sepsis, DiNicolantonio et al. [1] left open the question on how ivermectin may protect against COVID-19 initial symptoms and progression.
Insight was published by Li et al. [2] in their derivation of an ivermectin host protein and SARS-CoV-2 host protein interaction network (PPI). For this they metabolically labelled proteins in an ovarian cancer cell line and determined which proteins were upregulated and downregulated related to a 24 hour exposure to ivermectin versus no exposure. There were 4,447 identified proteins differentially regulated by ivermectin. When compared with the 284 host proteins known to be affected by SARS-CoV-2, this left 52 proteins in common, 50 of which were downmodulated. Only two proteins, HMOX1 and IL1F10 were upregulated by ivermectin.
This protein-protein interaction (PPI) network revealed EGFR at the center of the pathway with connections to mTOR/APOE, NFKB1/APP, AKT, MAPK1, and CASP3 through TGFB1 interacting with the protein ALB (albumin). BSG, recently shown to be absolutely essential for foam cell formation in macrophages [3] was also captured in the PPI network. Moreover, foam cell formation has been shown in macrophages to be mediated under the direction of EGFR [4] as well as for the foamy sebocytes of sebaceous glands which line the mucosal surfaces and may be an important site of viral entry [5]. Foam cell formation is important in ho...
Show MoreThe use of high dose melatonin early and aggressively for those infected with COVID-19 was the subject of an international symposium held in December 2020 (1). Dr Richard Neel reported on over 1000 cases that have responded to monotherapy with melatonin.
Why this works, as speculated upon in this article, is open to debate. What is most important is that people can benefit from this treatment modality. Thank you for the opportunity to raise awareness of this underappreciated therapeutic option.
References
(1) https://www.youtube.com/watch?v=p_4JeOj1JLc
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 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 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 MoreThe 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?
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