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?
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.
DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
The authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Fu...
DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
The authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Furthermore, cancer has been associated with statin treatment in several cohort and case–control studies as well (2), and also in several animal experiments (2).
There is a massive documentation to support the claim that low LDL-C predisposes to infectious diseases (3). In a meta-analysis of 19 cohort studies that included 68,406 deaths, Jacobs et al. found an inverse association between cholesterol and mortality from respiratory and gastrointestinal diseases, most of which are due to infections (3). It is unlikely that these diseases caused low cholesterol because these associations persisted after the exclusion of deaths occurring during the first 5 years.
Additional support comes from a 15-year follow-up study of more than 120,000 individuals by Iribarren et al. They found a strong inverse association between cholesterol as determined initially, and the subsequent risk of being admitted to hospital due to an infectious disease (3). Obviously, a disease they had not yet achieved could not have caused their low cholesterol.
DiNicolantonio and McCarty believe that the most conclusive evidence disputing a causal relationship between low LDL-C and cancer is provided by Mendelian randomisation, according to which none of the genotypes linked to lower LDL-C are associated with higher cancer risk. But association does not mean causation. Other genes in the same individual may have opposite effects, and as pointed out by Burgess et al: ”Power, linkage disequilibrium, pleiotropy, canalization and population stratification have all been recognized as potential flaws in the Mendelian randomization approach”.5
They also suggest that a high plasma level of interleukin-6 (IL-6) lowers LDL-C and that high IL-6 is the real cause of increased mortality because it is associated with higher rates global mortality in the elderly. However, it is also associated with various infections as well,6,7 which could be another explanation. What is little known, although it has been documented again and again by at least a dozen research groups, is that LDL partakes in the immune system by adhering to and inactivating almost all kinds of microorganisms and their toxic products.8,9 It is therefore more likely that the low LDL-C is the culprit, rather than an elevated IL-6. Why low LDL-C causes cancer remains to be elucidated.
References
1. DiNicolantonio JJ, McCarty MF. Is interleukin-6 the link between low LDL cholesterol and increased noncardiovascular mortality in the elderly?. Open Heart 2018;5:e000789. doi:10.1136/openhrt-2018-00078
2. Ravnskov U. Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383-8.
3. Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM 2003;96:927-34.
4. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90.
5. Burgess S, Timpson NJ, Ebrahim S, Davey Smith G. Mendelian randomization: where are we now and where are we going? Int J Epidemiol 2015;44:379-88. 27.
6. Martinez AN, Mehra S, Kaushal D. Role of interleukin 6 in innate immunity to Mycobacterium tuberculosis infection. J Infect Dis 2013;207:1253-61. doi: 10.1093/infdis/jit037.
7. Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989;169:333-8. 26.
8. 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.
9. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-4.
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opi...
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opioid use disorders, providing sterile injecting equipment (e.g. needles, syringes, water, cleaning swabs, cookers, and ascorbic acid), and counselling patients on safer injecting practices to reduce risks of infection (9–15).
Hospital admissions for IDU-associated IE represent an opportunity for clinicians to reach patients who are less likely to seek medical attention, and for many patients may provide new motivation to engage in treatment for substance use disorders (16–23). Treatment of acute opioid withdrawal at the time of admission, managing the substance use disorder, and establishing a therapeutic alliance can help to improve adherence to medical management of IE and avoid unplanned discharges against medical advice that often result from active, untreated substance use disorders (10,13,16,18,19,24–31).
Unfortunately, inpatient treatment for IDU-associated IE often focuses on the infection and the medical sequelae without addressing the underlying substance use disorder (9,28,32–35). For example, in a recent study of patients treated for IDU-associated IE at a Boston hospital, only 8% had a plan for opioid agonist therapy at the time of discharge (32).
There are multiple reasons for this implementation gap (28,35). Most physicians do not feel competent in addictions care (36,37). Jurisdictions have different limitations on methadone or buprenorphine prescribing, and institutions may not have clear pathways to identify community-based clinicians to continue prescribing opioid agonist therapy following hospital discharge (38,39). In our institutions (which do not yet have multidisciplinary IE care teams), patients with IE may be admitted or discharged through internal medicine, cardiology, cardiac surgery, or critical care, with ad hoc coordination between those services along with infectious diseases or medical microbiology. Each service may feel that the substance use disorder underlying the IE, and the associated increased risks of recurrence and mortality, are not within their scope of practice and are not the responsibility of their particular discipline (34). Clearly reducing these risks is in the best interests of our patients and our communities – so whose responsibility will it be?
While the European and American endocarditis guidelines do not specify how addiction medicine could fit into multidisciplinary IE care teams, recommendations from the British Heart Valve Society specify that all patients with IE who inject drugs should be offered addictions care (40). National and international IE guidelines should consider injection drug use as an important co-morbidity to address as part of patient-centred IE care.
A coordinated, multidisciplinary care team responsible for all inpatients with IE represents an indispensable opportunity to integrate addiction medicine expertise and offer care for substance use disorders to every patient with IE who injects drugs. An IE team should help facilitate initiation of opioid agonist therapy and promote other harm reduction strategies during hospital admissions in order to reduce the heightened risks of early hospital discharges against medical advice, recurrent infective endocarditis, and mortality. This approach could prolong life and reduce suffering for our patients with IE who inject drugs.
References
1. Kaura A, Byrne J, Fife A, Deshpande R, Baghai M, Gunning M, et al. Inception of the “endocarditis team” is associated with improved survival in patients with infective endocarditis who are managed medically: findings from a before-and-after study. Open Heart. 2017 Dec 1;4(2):e000699.
2. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta J-P, Del Zotti F, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075–128.
3. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017 Jun 20;135(25):e1159–95.
4. Wurcel AG, Anderson JE, Chui KKH, Skinner S, Knox TA, Snydman DR, et al. Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs. Open Forum Infect Dis. 2016 Jul 26;3(3).
5. Shrestha NK, Jue J, Hussain ST, Jerry JM, Pettersson GB, Menon V, et al. Injection Drug Use and Outcomes After Surgical Intervention for Infective Endocarditis. Ann Thorac Surg. 2015 Sep 1;100(3):875–82.
6. Ronan MV, Herzig SJ. Hospitalizations Related To Opioid Abuse/Dependence And Associated Serious Infections Increased Sharply, 2002–12. Health Aff (Millwood). 2016 May 1;35(5):832–7.
7. Fleischauer AT. Hospitalizations for Endocarditis and Associated Health Care Costs Among Persons with Diagnosed Drug Dependence — North Carolina, 2010–2015. MMWR Morb Mortal Wkly Rep. 2017;66(22);569–573.
8. Hartman L, Barnes E, Bachmann L, Schafer K, Lovato J, Files DC. Opiate Injection-associated Infective Endocarditis in the Southeastern United States. Am J Med Sci. 2016 Dec 1;352(6):603–8.
9. Serota DP, Kraft CS, Weimer MB. Treating the Symptom but Not the Underlying Disease in Infective Endocarditis: A Teachable Moment. JAMA Intern Med. 2017 Jul 1;177(7):1026-1027.
10. Donroe JH, Holt SR, Tetrault JM. Caring for patients with opioid use disorder in the hospital. CMAJ. 2016 Dec;188(17-18):1232–9.
11. Haber PS, Demirkol A, Lange K, Murnion B. Management of injecting drug users admitted to hospital. The Lancet. 2009;374(9697):1284–93.
12. Schuckit MA. Treatment of Opioid-Use Disorders. Longo DL, editor. N Engl J Med. 2016 Jul 28;375(4):357–68.
13. Sharma M, Lamba W, Cauderella A, Guimond TH, Bayoumi AM. Harm reduction in hospitals. Harm Reduct J. 2017 Jun 5;14:32.
14. Thakarar K, Weinstein ZM, Walley AY. Optimising health and safety of people who inject drugs during transition from acute to outpatient care: narrative review with clinical checklist. Postgrad Med J. 2016 Jun 1;92(1088):356–63.
16. Velez CM, Nicolaidis C, Korthuis PT, Englander H. “It’s been an Experience, a Life Learning Experience”: A Qualitative Study of Hospitalized Patients with Substance Use Disorders. J Gen Intern Med. 2017 Mar;32(3):296–303.
17. Frank MG. Capsule Commentary on Velez et al., “It’s Been an Experience, a Life Learning Experience”: A Qualitative Study of Hospitalized Patients with Substance Use Disorders. J Gen Intern Med. 2017 Mar;32(3):314–314.
18. McNeil R, Small W, Wood E, Kerr T. Hospitals as a “risk environment”: An ethno-epidemiological study of voluntary and involuntary discharge from hospital against medical advice among people who inject drugs. Soc Sci Med. 2014 Mar;105:59–66.
19. McNeil R, Kerr T, Pauly B, Wood E, Small W. Advancing patient-centered care for structurally vulnerable drug-using populations: a qualitative study of the perspectives of people who use drugs regarding the potential integration of harm reduction interventions into hospitals: Hospital-based harm reduction. Addiction. 2016 Apr;111(4):685–94.
20. Pollini RA, O’Toole TP, Ford D, Bigelow G. Does this patient really want treatment? Factors associated with baseline and evolving readiness for change among hospitalized substance using adults interested in treatment. Addict Behav. 2006 Oct;31(10):1904–18.
21. Shanahan CW, Beers D, Alford DP, Brigandi E, Samet JH. A Transitional Opioid Program to Engage Hospitalized Drug Users. J Gen Intern Med. 2010 Aug;25(8):803–8.
22. O’Toole TP, Pollini RA, Ford D, Bigelow G. Physical health as a motivator for substance abuse treatment among medically ill adults: Is it enough to keep them in treatment? J Subst Abuse Treat. 2006 Sep 1;31(2):143–50.
24. Pauly B (Bernie), McCall J, Browne AJ, Parker J, Mollison A. Toward Cultural Safety: Nurse and Patient Perceptions of Illicit Substance Use in a Hospitalized Setting. Adv Nurs Sci. 2015;38(2):121–35.
25. Merrill JO, Rhodes LA, Deyo RA, Marlatt GA, Bradley KA. Mutual Mistrust in the Medical Care of Drug Users. The Keys to the “Narc” Cabinet. J Gen Intern Med. 2002 May;17(5):327–33.
26. Aszalos R, McDuff DR, Weintraub E, Montoya I, Schwartz R. Engaging hospitalized heroin-dependent patients into substance abuse treatment. J Subst Abuse Treat. 1999 Sep;17(1-2):149–58.
27. Lee CS, Liebschutz JM, Anderson BJ, Stein MD. Hospitalized opioid-dependent patients: Exploring predictors of buprenorphine treatment entry and retention after discharge. Am J Addict. 2017 Oct 1;26(7):667–72.
28. Hassamal S, Goldenberg MD, Ishak W, Haglund M, Miotto K, Danovitch I. Overcoming Barriers to Initiating Medication-assisted Treatment for Heroin Use Disorder in a General Medical Hospital: A Case Report and Narrative Literature Review. J Psychiatr Pract. 2017 May;23(3):221–9.
29. Suzuki J. Medication-assisted treatment for hospitalized patients with intravenous-drug-use related infective endocarditis. Am J Addict. 2016 Apr 1;25(3):191–4.
30. Chan ACH, Palepu A, Guh DP, Sun H, Schechter MT, O’shaughnessy MV, et al. HIV-positive Injection Drug Users Who Leave the Hospital Against Medical Advice: The Mitigating Role of Methadone and Social Support. Jaids J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):56–9.
31. Ti L, Milloy M-J, Buxton J, McNeil R, Dobrer S, Hayashi K, et al. Factors Associated with Leaving Hospital against Medical Advice among People Who Use Illicit Drugs in Vancouver, Canada. PLOS ONE. 2015 Oct 28;10(10):e0141594.
32. Rosenthal ES, Karchmer AW, Theisen-Toupal J, Castillo RA, Rowley CF. Suboptimal Addiction Interventions for Patients Hospitalized with Injection Drug Use-Associated Infective Endocarditis. Am J Med. 2016 May;129(5):481–5.
33. Liebschutz JM, Crooks D, Herman D, Anderson B, Tsui J, Meshesha LZ, et al. Buprenorphine Treatment for Hospitalized, Opioid-Dependent Patients: A Randomized Clinical Trial. JAMA Intern Med. 2014 Aug 1;174(8):1369.
34. Fanucchi L, Lofwall MR. Putting Parity into Practice — Integrating Opioid-Use Disorder Treatment into the Hospital Setting. N Engl J Med. 2016 Sep;375(9):811–3.
35. Winetsky D, Weinrieb RM, Perrone J. Expanding Treatment Opportunities for Hospitalized Patients with Opioid Use Disorders. J Hosp Med. 2017 Oct 18;E1–3.
36. Wakeman SE, Pham-Kanter G, Donelan K. Attitudes, practices, and preparedness to care for patients with substance use disorder: Results from a survey of general internists. Subst Abuse. 2016 Oct 1;37(4):635–41.
37. Wakeman SE, Baggett MV, Pham-Kanter G, Campbell EG. Internal medicine residents’ training in substance use disorders: a survey of the quality of instruction and residents’ self-perceived preparedness to diagnose and treat addiction. Subst Abuse. 2013;34(4):363–70.
38. Caldiero RM, Parran TV, Adelman CL, Piche B. Inpatient Initiation of Buprenorphine Maintenance vs. Detoxification: Can Retention of Opioid-Dependent Patients in Outpatient Counseling Be Improved? Am J Addict. 2006 Jan 2;15(1):1–7.
39. Noska A, Mohan A, Wakeman S, Rich J, Boutwell A. Managing Opioid Use Disorder During and After Acute Hospitalization: A Case-Based Review Clarifying Methadone Regulation for Acute Care Settings. J Addict Behav Ther Rehabil. 2015;4(2).
40. Chambers J, Sandoe J, Ray S, Prendergast B, Taggart D, Westaby S, et al. The infective endocarditis team: recommendations from an international working group. Heart. 2014 Apr 1;100(7):524–7.
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
The citizenry of India are especially sensitive to excessive linoleic
acid intake as noted by S. L. Malhotra in a research paper published back
in 1967. Excerpt: "Much evidence indicates that consumption of even small
quantities of unsaturated fatty acids decreases the liability to ischaemic
heart disease (Bronte-Stewart et al., 1956; Kinsell et al., 1952). This
hypothesis, too, does not find support in our data. The South...
The citizenry of India are especially sensitive to excessive linoleic
acid intake as noted by S. L. Malhotra in a research paper published back
in 1967. Excerpt: "Much evidence indicates that consumption of even small
quantities of unsaturated fatty acids decreases the liability to ischaemic
heart disease (Bronte-Stewart et al., 1956; Kinsell et al., 1952). This
hypothesis, too, does not find support in our data. The South Indians eat
largely seed oils containing as much as 45 per cent poly-unsaturated fatty
acids, whereas ghee and other milk fats eaten by the Punjabis contain only
2 per cent polyunsaturated fatty acids...A survey of the incidence of
acute myocardial infarction and the dietary behaviour in railway
populations in India showed that the disease was 7 times more common among
South Indians as compared with the Punjabis in the North, even though the
fat intake of Punjabis was 8-19 times more than that of South Indians, and
was chiefly of animal origin."[1]
In line with Malhotra's findings, here is an excerpt from a May 1,
2016 article published in the Times of India: "Clarified butter remained
India's culinary star for centuries till it was sidelined in the 1980s by
vegetable oils because of its high saturated fat. The new oils were
aggressively marketed as superior and heart-healthy. Of late, research has
shown that saturated fats have no link to obesity, heart disease or early
death."[2]
It's been noted that "No country has successfully reduced obesity
rates in 33 years."[3] Perhaps the time has come to develop a new health
paradigm. Obviously, the anti-saturated fat campaign has not been
particularly helpful.[4]
I beg to differ from the authors about the etiology of CVD and
hypertension related to sugar and salt. Both high carbohydrate diets
(sugar) and salt (1-5) activates the sympathetic nervous system as well
stress, ageing, air pollution, salt, smoke, hypertension, diabetes,
etc...;
The sympathetic activation may represent the true cause of coronary artery
disease according our acidity theory of atherosclerosis developed in...
I beg to differ from the authors about the etiology of CVD and
hypertension related to sugar and salt. Both high carbohydrate diets
(sugar) and salt (1-5) activates the sympathetic nervous system as well
stress, ageing, air pollution, salt, smoke, hypertension, diabetes,
etc...;
The sympathetic activation may represent the true cause of coronary artery
disease according our acidity theory of atherosclerosis developed in 2006.
For more information please see the Powerpoint slides (6) presented by us
in November 2012 at the Fourth International Conference of Advanced
Cardiac Sciences - "The King of Organs Conference, 2012", held in Saudi
Arabia Kingdom.
I'm the author of the book "Acidity Theory of Atherosclerosis - New
Evidences", 2012 available at Amazon.com and other bookstores.
1. 'Volume-expanded' hypertension: the effect of fluid overload and the
role of the sympathetic nervous system in salt-dependent
hypertension,Journal of Hypertension, V30; N1: January 2012
doi:10.1097/HJH.0b013e32834f6de1
2. de Champlain J, Farley L, Cousineau D, van Ameringen MR. Circulating
catecholamine levels in human and experimental hypertension. Circ Res
1976; 38:109-114.
3. 6. Louis WJ, Doyle AE, Anavekar S. Plasma norepinephrine levels in
essential hypertension. N Engl J Med 1973; 288:599-601.
4. Sever PS, Osikowska B, Birch M, Tunbridge RD. Plasma noradrenaline in
essential hypertension. Lancet 1977; 1:1078-1081.
5. Lake CR, Kopin IJ, Ziegler MG, Coleman MD. Plasma catecholamines and
neurogenic hypertension. N Engl J Med 1977; 297:53-54.
6. Powerpoint presentation at
http://www.infarctcombat.org/AcidityTheory.pptx
Dietary advice that reducing fat and saturated fat consumption will
reduce the risk of coronary heart disease was introduced in the UK in
1983. The authors of this systematic review and meta-analysis conclude
that evidence from randomised controlled trials, available at the time,
did not support that advice.
It is important to highlight that the review looks at the results of
just six relatively short-term ra...
Dietary advice that reducing fat and saturated fat consumption will
reduce the risk of coronary heart disease was introduced in the UK in
1983. The authors of this systematic review and meta-analysis conclude
that evidence from randomised controlled trials, available at the time,
did not support that advice.
It is important to highlight that the review looks at the results of
just six relatively short-term randomised controlled trials (RCTs), whose
limitations are acknowledged by the authors. In 1983, there was already
good evidence that saturated fats in the diet raise blood cholesterol and
that blood cholesterol was a modifiable risk factor for coronary heart
disease.
More evidence for the effects of saturated fat has accumulated since
1983. Government advice to limit saturated fat intake to no more than 11%
of total food energy in order to reduce the risk of cardiovascular disease
is based on long standing advice from the Committee on Medical Aspects of
Food Policy (COMA) and is endorsed by the Scientific Advisory Committee on
Nutrition (2008), which now provides the UK with independent advice on
nutrition. The advice is supported by a wealth of evidence and is in line
with more recent assessments made by the Institute of Medicine (2005),
World Health Organization (2008) and the European Food Safety Authority
(2010).
There is good evidence from randomised controlled trials (RCTs) to
demonstrate that saturated fat consumption influences cholesterol levels
and increases the risk of cardiovascular disease. For example, the RISCK
study, a 6 month trial that analysed results from 548 men and women, found
that total cholesterol and LDL cholesterol concentrations were
significantly lower after consumption of diets lower in saturated fat
compared to the control group (Jebb et al. 2010). Skeaff and Miller (2009)
conducted a meta-analysis of 16 trials modifying the amount of saturated
fat in the diet and found that, in studies which significantly lowered
serum cholesterol by replacing saturated fat with polyunsaturated fat,
both heart attacks and deaths from heart disease were significantly
reduced. More recently a Cochrane Collaboration systematic review (Hooper
et al. 2012) concluded that reducing saturated fat by reducing and/or
modifying dietary fat intakes lowered the risk of cardiovascular events by
14%.
The combined results of 14 RCTs investigating statins also found that
a reduction in LDL-cholesterol of 1mmol/L, sustained over a period of 5
years, reduced major vascular events by 23% (Cholesterol Treatment
Trialists' Collaborators, 2005). Chan et al (2011) conducted a meta-
analysis of seven trials investigating the effect of intensive lipid
lowering using statins. The intensive lipid lowering arm had reduced LDL
levels and significantly lower risks for stroke, coronary events, and CVD
and CHD deaths.
The UK National Diet and Nutrition Survey (NDNS) rolling programme
2008/2009 - 2011/2012 shows that people in all age/sex groups are still,
on average, consuming saturated fat above recommendations (12.6% of food
energy for adults aged 19-64 years). The headlines in the press about the
review by Harcombe et al, are likely to have had the damaging effect of
confusing the public about how to choose a healthy diet. Based on the
totality of the evidence, Public Health England will continue to advise
people to consume a diet that is low in saturated fat and support the
Department of Health's Responsibility Deal incentives to reduce saturated
fat in foods.
In addition to focusing on reducing saturated fats, Public Health
England continues to advise that we need to eat fewer calories, less salt
and sugar and more dietary fibre, fruit and vegetables and oily fish.
Chan DK, O'Rourke F, Shen Q, Mak JC, Hung WT. (2011) Meta-analysis of
the cardiovascular benefits of intensive lipid lowering with statins. Acta
Neurol Scand. 124(3):188-95.
Cholesterol Treatment Trialists' Collaborators. Efficacy and safety
of cholesterol-lowering treatment: prospective meta-analysis of data from
90 056 participants in 14 randomised trials of statins. Lancet 2005;
366:1267-78.
Department of Health. 46 Nutritional aspects of cardiovascular
disease. Report on Health and Social Subjects. 1994. London: TSO.
EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA);
Scientific Opinion on Dietary Reference Values for fats, including
saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty
acids, trans fatty acids, and cholesterol. EFSA Journal 2010; 8(3):1461.
Hooper L, Summerbell CD, Thompson R, Sills D, Roberts FG, Moore HJ,
Davey Smith G. Reduced or modified dietary fat for preventing
cardiovascular disease. Cochrane Database Syst Rev 2012 May 16;5:CD002137.
doi: 10.1002/14651858.CD002137.pub3.
IOM (Institute of Medicine). 2005. Dietary Reference Intakes for
Energy, Carbohydrate,
Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids
(Macronutrients). National Academies of Science, Washington DC.
Jebb SA, Lovegrove JA, Griffin BA, Frost GS, Moore CS, Chatfield MD,
Bluck LJ, Williams CM, Sanders TA; RISCK Study Group. Effect of changing
the amount and type of fat and carbohydrate on insulin sensitivity and
cardiovascular risk: the RISCK (Reading, Imperial, Surrey, Cambridge, and
Kings) trial. Am J Clin Nutr. 2010 Oct;92(4):748-58.
National Diet and Nutrition Survey: Results from Years 1-4
(combined) of the Rolling Programme (2008/2009 - 2011/12)
www.gov.uk/government/uploads/system/uploads/attachment_data/file/310997/NDNS_Y1_to_4_UK_report_Executive_summary.pdf
Scientific Advisory Committee on Nutrition, 24th meeting, 12 June
2008, agenda item 4.
Skeaff CM & Miller J. Dietary fat and coronary heart disease:
summary of evidence from prospective cohort and randomised controlled
trials. Ann Nutr & Metab 2009;55:173-201.
WHO. 2008. Fats and fatty acids in human nutrition. Joint FAO/WHO
Expert Consultation. Food and nutrition paper 91, WHO, Geneva.
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 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.
This was so helpful and easy! Do you have any aricelts on rehab?
DiNicolantonio and McCarty suggest that the inverse association between low cholesterol and mortality in elderly people reflects reverse causality; meaning that the low cholesterol is caused by the disorder being treated.1 One of their arguments is that those whose cholesterol decreases with increasing age die more frequently from cancer and other diseases, compared to those with low cholesterol prior to treatment. However, many studies have shown that low cholesterol may predispose to cancer2 as well as infectious diseases.3 In a previous paper2 we identified nine cohort studies including more than 140,000 individuals, in which cancer was inversely associated with cholesterol measured 10–30 years earlier, and where the association persisted after exclusion of cancer cases appearing during the first 4 years.
Show MoreThe authors claim that statin treatment does not increase the risk of cancer based on a meta-analysis of 27 randomised trials published by the Cholesterol Treatment Trialists’ (CTT) Collaborators. But very few statin trials have continued for more than five years, and most carcinogenic chemicals need more time to create cancer. In spite of that cancer appeared significantly more often in three statin trials (2). In two other trials, non-melanoma skin cancer appeared more often and with statistical significance if the figures from the two trials were calculated together (2). Since then the number of non-melanoma skin cancers has not been reported in any trial. Fu...
We read with great interest Kaura and colleagues’ evaluation of a multidisciplinary care team for hospital inpatients with infective endocarditis (IE) (1). The study provides further evidence for the effectiveness of a team-based approach to IE care – a model endorsed by both European (2) and American (3) guidelines. Despite limitations inherent in a before-and-after study design, it is clear that the IE team provides patients rapid access to cardiology, microbiology, and surgical care with coordination between services.
Notably absent from this multidisciplinary approach, however, is care for substance use disorders. We wish to draw readers’ attention to the 10% of study participants for whom injection drug use (IDU) was identified as a predisposing factor in their IE. We believe a coordinated IE team offers enormous potential to provide addictions care and harm reduction services for patients with IE who inject drugs.
Compared with people who do not inject drugs, people who inject drugs are far more likely to have recurrences and repeat hospitalizations for IE, and face increased mortality risk after a first episode of IE (4,5). Rates of hospitalization for IDU-associated IE also appear to be increasing (4,6–8).
Evidence-based interventions can be provided in-hospital to reduce both rates of injecting and harms associated with ongoing injection. These interventions include initiating opioid agonist therapies (e.g. methadone or buprenorphine) for opi...
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 MoreThe citizenry of India are especially sensitive to excessive linoleic acid intake as noted by S. L. Malhotra in a research paper published back in 1967. Excerpt: "Much evidence indicates that consumption of even small quantities of unsaturated fatty acids decreases the liability to ischaemic heart disease (Bronte-Stewart et al., 1956; Kinsell et al., 1952). This hypothesis, too, does not find support in our data. The South...
I beg to differ from the authors about the etiology of CVD and hypertension related to sugar and salt. Both high carbohydrate diets (sugar) and salt (1-5) activates the sympathetic nervous system as well stress, ageing, air pollution, salt, smoke, hypertension, diabetes, etc...; The sympathetic activation may represent the true cause of coronary artery disease according our acidity theory of atherosclerosis developed in...
Dietary advice that reducing fat and saturated fat consumption will reduce the risk of coronary heart disease was introduced in the UK in 1983. The authors of this systematic review and meta-analysis conclude that evidence from randomised controlled trials, available at the time, did not support that advice.
It is important to highlight that the review looks at the results of just six relatively short-term ra...
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