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DAPA-CKD: Is SGLT2i the ANSWER? Will the guidelines change?

Over the past years, series of clinical trials prove the beneficial effect of glucose cotransporter 2 (SGLT2) inhibitors in reducing the risk of cardiovascular events in people with type 2 diabetes mellitus. The results from these trials were consistent, significant, and demonstrated a considerable reduction in heart failure hospitalization among patients who used SGLT2 inhibitors, whereas the benefit on atherothrombotic events such as myocardial infarction and stroke was moderate.

Similar findings from The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation trial (CREDENCE) were obtained for patients with type 2 diabetes mellitus and chronic kidney disease who are exceptionally at higher risk for cardiovascular disease. In CREDENCE trial, Canagliflozin reduced the risk of chronic kidney disease, cardiovascular death or hospitalization, myocardial infarction, and stroke. Although diabetes is not the only cause of chronic kidney disease, and people with chronic kidney disease are still at increased risk for cardiovascular disease, regardless if they had a preexisting history of cardiovascular disease or not. Therefore, its essential to implement guidelines that recommend the use of certain therapeutics as routine treatment for primary and secondary prevention of cardiovascular disease in patients with chronic kidney disease, regardless of their diabetes status.

During #AHA20, I enjoyed attending the online session by Dr. John McMurray, where he shared scientific breakthrough results from the Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) Mega-Trial. The session reported the results of the effect of dapagliflozin on prespecified kidney and cardiovascular outcomes in patients with chronic kidney disease with and without diabetes. The DAPA-CKD trial was a randomized, double-blind, placebo-controlled, multicenter trial, where adults with or without type 2 diabetes, with estimated glomerular filtration rate (eGFR) between 25 and 75 ml/min/1.73 m2, and a urinary albumin-to-creatinine ratio (UACR) between 200 and 5000 mg/g were eligible for DAPA-CKD trial. In this trial, patients were randomized to dapagliflozin 10 mg once daily or placebo with follow up at 2 weeks, 2,4, and 8 months and at 4 months intervals thereafter. The primary composite outcome was the time to the first occurrence of any of the following: > 50% decline in eGFR, onset of end-stage renal disease, or death from kidney or cardiovascular disease. Moreover, secondary outcomes were: 1) kidney composite outcome identical to the primary endpoint with the exception of death from cardiovascular death 2)( a cardiovascular composite outcome consisting of hospitalization for heart failure or death from cardiovascular  causes; and 3) death from any cause.

 

Effects of dapagliflozin on prespecified clinical outcomes according to the baseline history of cardiovascular disease.

 The DAPA-CKD trial found that among patients with cardiovascular disease who received dapagliflozin, the primary composite outcome occurred in 11.2% participants, while the primary outcome occurred in 17.2% in participants who were in the placebo group, (HR 0.61; 95% CI, 0.47-0.79) and the corresponding numbers in people without cardiovascular disease were 7.9% and 12.9% respectively, (HR 0.61; 0.48-0.78).

The DAPA-CKD trial also found that for both the primary and secondary prevention patients, the event rates favored dapagliflozin for all components of the primary and secondary outcomes, although reduction in cardiovascular risk was not statistically significant.

DAPA-CKD Figure

Additionally, among patients with cardiovascular disease, cardiovascular death or hospitalization for heart failure occurred in 9.3% of participants in the dapagliflozin group and 12.8% of participants in the placebo group, (HR 0.7; 0.52-0.94) and the corresponding numbers for patients without cardiovascular disease were 1.8% and 2.7% respectively, (HR 0.67; 0.40-1.13). The observed reduction in cardiovascular risk for these two groups was driven by reduction in heart failure hospitalization which occurred in 4.1% of participants in the dapagliflozin group and 7.3% participants in the placebo group with cardiovascular disease and the corresponding numbers for patients without cardiovascular disease were 0.3% and 1.0% (HR, 0.31; 0.10-0.94) respectively. These results show that dapagliflozin reduced the risk of adverse kidney outcomes irrespective of baseline cardiovascular disease status. Moreover, the mortality benefit from dapagliflozin as demonstrated from the DAPA-CKD study supports the findings of the DAPA-HF trial. In summary, dapagliflozin reduced the risk of kidney failure, death from cardiac disease or hospitalization for heart failure, furthermore, it prolonged survival, in people with chronic kidney disease, irrespective of the presence of a concomitant cardiovascular disease.

 

What is next?

The data from DAPA-CKD trial for dapagliflozin effect on patients with cardiovascular disease and chronic kidney disease is clear, but we have so much work to do. Is Dapagliflozin the answer? How would this change the guideline directed medical therapy (GDMT) for the care of patients with an increased heart failure, cardiovascular or chronic kidney disease risk, regardless of their glycemic status?

 

References:

  1. Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease. John J.V. McMurray , David C. Wheeler , Bergur V. Stefánsson , Niels Jongs , Douwe Postmus , Ricardo Correa-Rotter , Glenn M. Chertow , Tom Greene , Claes Held , Fan Fan Hou , Johannes F.E. Mann , Peter Rossing , C. David Sjöström , Robert D. Toto , Anna Maria Langkilde , and Hiddo J.L. Heerspink for the DAPA-CKD Trial Committees and Investigators
  2. Presented by Dr. John J. V. McMurray at the American Heart Association Virtual Scientific Sessions, November 13, 2020.
  3. Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al., on behalf of the DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients With Chronic Kidney Disease.N Engl J Med 2020;383:1436-46.
  4. Presented by Dr. Hiddo J.L. Heerspink at the European Society of Cardiology Virtual Congress, August 30, 2020.
  5. Rationale and protocol:Heerspink HJ, Stefansson BV, Chertow GM, et al., on behalf of the DAPA-CKD Investigators. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant 2020;35:274-82.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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How to make the most #AHA20

The American Heart Association 2020 annual meeting provides an exceptional chance to learn practice changing insights from late-breaking-scientific sessions and share meaningful networking opportunities. It comes as no surprise the excellent organization of the #AHA20 virtual conference and I have personally enjoyed attending most if not all of the online sessions as they were very engaging and enlightening. After attending today’s sessions, I felt empowered, motivated, and excited to continue my journey of training in cardiovascular medicine and research, most importantly I felt rejuvenated as I am now up-to-date with the latest findings of late-breaking trials.

In this blog a share with you tips on how to make the most of the AHA20 conference:\

Organize your session schedule

As with any conference, you need to organize your schedule. It would be beneficial to overview the #AHA20 online planner and have an idea about the sessions that are presented during the day with the corresponding time for these sessions. Taking a close look at the conference schedule allows you to prioritize the sessions you want to attend live. It might be useful to set a reminder or even block your calendar for sessions that you want to be sure to watch live.   One of the great features of the AHA20 is that sessions are available on-demand after the conference until January 4th, providing attendees more flexibility and a great opportunity to attend as many sessions as possible.

Familiarize yourself with the conference page tools

It is intuitive to test the platform and familiarize yourself with the features of the conference website, also, to test your audio and WiFi connection before attending one of the live zoom sessions. Laptops or desktop computers work better than viewing sessions on a smartphone, however, the #AHA20 platform is generally compatible with mobile devices.

Dedicate some time for learning

One of the tips I decided to adopt this year for #AHA20 conference is to set some time after the conference to go over the notes I’ve taken during the sessions and learn the findings from the late-breaking- scientific sessions as many of what has been discussed today in these trials could have an impact on clinical practice and improving patients health outcome.

Lastly, make sure to have fun.

One of the ways of having fun this year is to engage with the Early Career Bloggers on Twitter, make sure you follow them and interact with their posts. Reading twitter threads and discussions are also very interesting and a fun way to socialize during the AHA conference.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

 

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The Role of Intestinal Microbiota and Cardiovascular Disease

In recent years, the role of intestinal microbiome and host health has gained wide interest due to many findings suggesting gut microbiota may play a role in the development and maintenance of cardiovascular disease (CVD) and metabolic disorders, such as hypertension, obesity, diabetes mellitus, and metabolic syndromes. Hypertension, one of the important risk factors for CVD, plays a significant role in intestinal dysbiosis. Dysbiosis is a change in the gut microbiota that imbalance the ratio of Firmicutes (F) to Bacteroidetes (B) (F/B) and is considered as a biomarker for gut dysbiosis. When environmental factors, dietary habits, medications such as antibiotics, intestinal infections or other factors alter the species and balance of the intestinal microorganism ecosystem in the adult gut, dysbiosis can take place, causing inflammation and metabolic disorders, thus promoting the development of CVD.

The recently discovered contribution of intestinal microbiota and its contribution to the development of CVDs and its risk factors has significantly increased attention to the important connection between the heart and the gut. The intestinal microbiota function as a filter of our largest environmental exposure, that is what we eat. What we eat provides nutrients for intestinal microbial metabolism. Several intestinal microbial metabolites are biologically active and could possibly affect the host phenotype and health outcomes.

The gut microbiota resembles a large virtual endocrine organ that is capable of responding and reacting to circulating signaling molecules within the host. Intestinal microbiota- host interaction occurs through many pathways, including trimethylamine-N-oxide (TMAO) and short chain fatty acids (SCFA). This interaction has been shown to affect the host phenotypes relevant to cardiovascular disease, ranging from inflammation, obesity, and insulin resistance, to more direct process like atherosclerosis and susceptibility to hypercoagulability. Furthermore, multiple animal and human clinical studies revealed striking association between either gut microbiota composition, or their derived metabolites, and both the presence and incident development of CVD.

The healthy gut microbiome

 The composition of the healthy gut microbiome can vary significantly across individuals. However, this composition is relatively stable over time. The gut microbiome is primarily composed of species within the Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria and Cerrucomicrobia phylae. The precise composition of species varies among individuals due to variety of genetic and environmental factors, including diet and medications used such as antibiotics. It is not surprising that microbial metabolite profiles are strongly associated with enterotypes. For instance, Bacteroidetes bacteria predominantly metabolize proteins, whereas, Prevotella species are saccharolytic bacteria that primarily metabolize carbohydrates. The gut microbiota has evolved to play a symbiotic role in extracting calories from indigestible macromolecules. Indigestible carbs and proteins are fermented by the colonic bacteria to form short chain fatty acid (SCFA) such as acetate, propionate and butyrate which play a significant role in weight loss and provide various health benefits. Microorganisms that are incapable of catabolism of indigestible macromolecules, use the SCFA produced by other microbiota as fuel in a process called cross-feeding. In addition to its role as an important energy source for both host and microbiota, the SCFA is important in regulation of the inflammatory response. Furthermore, commensal gut bacteria are necessary for dampening the immune response to non-pathogenic bacteria, hence they protect the host from the harms of sterile inflammation and they are also responsible for establishing an intact gut epithelial barrier, thus preserving the digestive and absorptive functions of the intestine and protecting from the invasion of pathogens and toxic metabolites into the circulation.

 The Intestinal Microbiota and CVD:

 The unique link between the gut microbiota and cardiovascular diseases has been described recently with the discovery of the link of Trimethylamine-N-Oxide (TMAO) to atherosclerosis. TMAO is produced by the breakdown of Phosphatidylcholine and other trimethylamine containing compounds by the intestinal bacteria. In a recent human experiment that consisted of ingestion of two hard boiled eggs (high in phosphatidylcholine) and deuterium [d9]-labeled phosphatidylcholine before and after suppression of intestinal microbiota with oral broad-spectrum antibiotics, it was found that circulating TMAO and its d9 isotopologue (both molecules are derived from the metabolism of phosphatidylcholine) was remarkably elevated after the phosphatidylcholine challenge.  However, plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. In a large independent clinical cohort (n=4,007), patients in the highest quartile of plasma TMAO levels had a 2.5-folds higher risk of major adverse cardiovascular event than patients in the lowest quartile. Furthermore, higher fasting plasma levels were found to correlate with the risk of incident major adverse cardiovascular events independent of the classic cardiovascular risk factors. In mouse models, studies confirmed that dietary supplementation of Choline or TMAO increased TMAO levels, macrophage foam cell formation and inflammation, and atherosclerosis development. Moreover, TMAO has also been shown to enhance platelet hyperactivity and thrombosis risk. In a human cohort study, there was a dose-dependent association between plasma TMAO levels and platelets aggregation. This association explains the increased risk of cardiovascular events with high TMAO levels.

Ahmadmehrabi S, Tang WHW. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol. 2017;32(6):761-766. doi:10.1097/HCO.0000000000000445

Dysbiosis has been linked to increased CVD risk. A lower ratio of Bacteroidetes to Firmicutes has been associated with significantly increased risk to hypertension, diabetes mellitus, obesity and atherosclerosis. When there is decreased intestinal microbiota diversity (decreased Bacteroidetes to Firmicutes ratio) there will be an increase in the plasma TMAO levels and reduced SCFA level which is important for increasing insulin sensitivity, secretion of the satiety hormone GLP1, lower BMI and increase HDL levels. Higher levels of TMAO and lower levels of SCFA has been associated with increased risk for Type 2 Diabetes (T2DM) and metabolic syndrome. Hypertension has also shown to be associated with gut dysbiosis; however, the exact mechanism is still unknown.

 

Therapeutic Interventions:

The recent discovery of the TMAO and SCFA pathways and evidence for links between gut dysbiosis and several risk factors for cardiovascular disease now provides new opportunities for therapeutic interventions. Now knowing that alteration in the gut microbiota community is associated with much pathology, therapeutic interventions aimed at restoring microbial composition balance present an auspicious therapeutic approach. A fiber rich diet has been reported to increase SCFA- producing microbiota and lower blood pressure in patients with end-stage-renal disease. Dietary supplements of prebiotics, which are typically food indigestible molecules have a favorable impact on intestinal microbiota composition and can be beneficial. Similarly, probiotics, which are compilation of live bacteria administered to promote gut microbiome health have shown to have beneficial effects on the gut microbial environment and to be associated with cardioprotective effects. While prebiotics and probiotics focus on eliciting the growth of healthy gut bacteria, antibiotics treatment is focused on reducing the harmful bacteria content. However, the lack of specificity of broad-spectrum antibiotics makes them a less favorable approach.

With the recent discovery of the unique pathways between the gut microbiome and the heart and their association with CVD, we are presented with a new and a promising opportunity for CVD treatment and prevention. The most up-to-date discoveries and use of a structural analog of choline,3,3-dimethyl-1-butanol (DMB), was shown to inhibit TMA production and reduce circulating plasma TMAO levels and to reduce macrophage foam cell formation and risk of atherosclerosis, more importantly, this small-molecule inhibitor shown not be lethal to the gut microbiota ecosystem.

References:

  1. Ahmadmehrabi S, Tang WHW. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol. 2017;32(6):761-766. doi:10.1097/HCO.0000000000000445
  2. Yang T, Richards EM, Pepine CJ, Raizada MK. The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Nat Rev Nephrol. 2018;14(7):442-456. doi:10.1038/s41581-018-0018-2
  3. Jin M, Qian Z, Yin J, Xu W, Zhou X. The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med. 2019;23(4):2343-2350. doi:10.1111/jcmm.14195
  4. Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal Microbiota in Cardiovascular Health and Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(16):2089-2105. doi:10.1016/j.jacc.2019.03.024
  5. Yoshida N, Yamashita T, Hirata KI. Gut Microbiome and Cardiovascular Diseases. Diseases. 2018;6(3):56. Published 2018 Jun 29. doi:10.3390/diseases6030056

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Battling the Pandemic of misinformation

The Myth

 The global disruption caused by the coronavirus disease (COVID-19) has resulted in conspiracy theories and misinformation about the scale of the pandemic and the origin, diagnosis, treatment, and prognosis of the disease. Falsified information including international disinformation has been spread through various social media platforms such as Twitter, Instagram, Youtube, and WhatsApp. In some countries such as India, Bangladesh, Ethiopia, journalists have been arrested for allegedly spreading fake news about the pandemic.

Misinformation has been propagated by prominent public figures, celebrities, and politicians, while, several religious groups have claimed that their faith will protect them from the virus. Some claim that the virus is a bio-weapon, accidentally or purposely leaked from laboratories, a population control stratagem, the result of a spy operation, or linked to 5G network.

On Jan 30th, several news channels reported about the increasing spread in the conspiracy theories and false health advice in relation to COVID-19. Notable examples at the time include:

“ Bill Gates is behind the COVID-19 pandemic”

“ COVID-19 can be cured by ingesting Clorox”

“ Coronavirus can be prevented by anti-corona sprays”

“ Gargle with an antiseptic and warm water such as vinegar, salt, or lemon for every day to clear your airways”.

On February 2nd, the World Health Organization (WHO) described a “massive infodemic” of incorrect information about the virus, which makes the work of public health practitioners even more difficult and poses risk to global health.

 Misinformation is among the most critical issues confronting our frontline heroes. The issue of fake medicines and treatment has become all of the more pervasive in the age of COVID-19. This urges the governments to recognize this serious issue and calls for the development of a unified national and international response and action plan that include comprehensive legal framework, robust reporting systems, and strong national regulatory mechanisms linked to the global regulatory network as well as greater pharmacovigilance capacity

Busting the Myth

The pandemic has created ideal situations for criminals to exploit people’s fears of contracting the disease by advertising falsified information regarding treatments and vaccines, promoting fake tests, and spreading dangerous rumors about potential cures. In some countries, several people have died from drinking toxic alcohol after coronavirus cure rumor. The World Health Organization (WHO) and the US Food & Drug Administration  (FDA), has warned against other mythical cures for COVID-19 and confirmed that, to date,  there is no specific treatment recommended to treat the SARS-CoV-2 viral infection.

Several countries around the world are struggling with infectious disease and fragile health systems, and the increased spread of false information on fake cures could put these systems under huge pressures and make the situation for physicians and public health practitioners a lot harder than what it already is.

“ COVID-19 is on the rise in Africa, and we are already facing shortages of critical protective equipment and plethora of misinformation,” says Thembeka Gwagwa, ICN’s second Vice-President, and a nurse from South Africa. : Lack of access to care will mean many people will seek cheap, fake medicines which will have devastating consequences”.

Our role as citizens and healthcare professionals

 Researchers at Massachusetts Institute of Technology have shown that videos and posts that trigger an emotional response are shared more and are most likely to influence the public.

As citizens, we have the most important role in curbing misinformation. Social media platforms are a source of immense power that can influence the public and promote awareness about fake cures and false news. Since out-of-context images are a major source of misinformation, citizens can learn to use reverse search image tools such as RevEye and TinEye to locate their origin and verify the truthfulness of these images. Videos can sometimes be misleading and present an even higher level of complexity, however, tools like InVid have begun to make a difference. In general, we should always be vigilant and verify the accuracy of information by looking up a reliable source before we spread the information.

As healthcare professionals, our role is to educate the public on safety concerns related to the use of fake medical products and dispel false rumors about potential cures. Our role is to promote health literacy to support properly informed preventative measures and discourage self-diagnosis and self-prescribing. Although healthcare professionals are under severe pressure during this pandemic, however, the work of educating and informing patients and their families should not be seen as an additional burden but rather as part of safeguarding the health of the community and the public.

Furthermore, there are several campaigns that aim to raise the awareness of fake medicines where victims get to voice their own stories with fake medicines. These campaigns are now a warning of an ever-growing “infodemic” alongside the SARS-CoV-2 pandemic.

Lastly, our fight against COVID-19, future pandemics, and falsified medical information emphasis the urgent need to strengthen the health system, promote health literacy and citizens’ sense of awareness and responsibility, educate healthcare professionals, and better support the ones we have. If we are to be prepared for the next health crisis, and without any doubts, there will be one, we need to better support and invest in our public health and health workforce sector.

References:

  1. https://news.harvard.edu/gazette/story/2020/05/social-media-used-to-spread-create-covid-19-falsehoods/
  2. Rochwerg, Bram MD1,2; Parke, Rachael PhD3,4; Murthy, Srinivas MD5; Fernando, Shannon M. MD6; Leigh, Jeanna Parsons PhD7; Marshall, John MD8; Adhikari, Neill K. J. MD8,9; Fiest, Kirsten PhD10–12; Fowler, Rob MD8,9; Lamontagne, François MD13,14; Sevransky, Jonathan E. MD15Misinformation During the Coronavirus Disease 2019 Outbreak: How Knowledge Emerges From Noise, Critical Care Explorations: April 2020 – Volume 2 – Issue 4 – p e0098 doi: 10.1097/CCE.0000000000000098
  3. Cuan-Baltazar, J. Y., Muñoz-Perez, M. J., Robledo-Vega, C., Pérez-Zepeda, M. F., & Soto-Vega, E. (2020). Misinformation of COVID-19 on the Internet: Infodemiology Study. JMIR public health and surveillance6(2), e18444. https://doi.org/10.2196/18444
  4. Li HO, Bailey A, Huynh D, et al. YouTube as a source of information on COVID-19: a pandemic of misinformation?.BMJ Global Health 2020;5:e002604
  5. Citizens’ use of social media in government, perceived transparency, and trust in government. Public Perform Manag Rev.2016; 39: 430-453
  6. Nicole M. Krause, Isabelle Freiling, Becca Beets & Dominique Brossard(2020) Fact-checking as risk communication: the multi-layered risk of misinformation in times of COVID-19, Journal of Risk Research, DOI: 1080/13669877.2020.1756385

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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The complex dilemma of COVID-19 and ACEI/ARB therapies: to use or not to use?

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) is the virus responsible for COVID-19 pandemic with its origin in Wuhan, China, in December 2019. As of today April 22nd 2020, the total number of deaths from COVID-19 infection is 176,860. Epidemiological data from research studies show an uneven-handed impact on the population, with and exponential increase in disease severity and mortality in those beyond the sixth decade of life and with multiple comorbidities 1. According to a large study published by the Chinese Center for Disease Control and Prevention, as of end of Feb 11 2020, a total of 44 672 tested positive for COVID-19 infection, and among these patients several comorbidities such as cardiovascular disease, diabetes mellitus seem to be involved in COVID-19 patients with severe course. 2 In this study, 10.5% of the fatal cases occurred in patients with cardiovascular disease, 7.3% in patients with diabetes mellitus, 6% in patients with arterial hypertension, 6.3% in patients with chronic respiratory disease and 5.6% in patients with cancer.2

 Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin II receptors blockers (ARB) are indicated as first line treatment for patients with cardiovascular diseases and diabetes mellitus.3 The ACE inhibitors initially inhibits ACE leading to decreased angiotensin I levels, causing a possible negative feedback loop which ultimately upregulates more expression of ACE2 receptors to be able to interact with the reduced levels of the available angiotensin I.4 Researchers believe that ACE2 receptors, located on the alveolar epithelial cells, serve as a high affinity receptor and co-transporter for SARS-Cov-2 to enter the lungs. Given that ACE2 receptors are upregulated in patients who are on ACEI and ARB therapies, it was hypothesized that this increase in ACE2 expression could play a role in the severe course of COVID-19 infection in this population. This has caused significant controversy regarding the approach for patients taking ACEI/ARB amid the pandemic, with some advocating for discontinuation of these medications, while expert opinions are recommending continuation of ACEI/ARB medications, given the lack of strong clinical evidence. 1,2

 First, to unravel this complex controversy, one must recognize the scarcity of data on the topic, particularly in humans. However, because of the urgency of the situation it becomes important to use inductive reasoning to make a decision toward protecting our patients. Although it is well established now that ACE2 is targeted by SARS-Cov-2 to gain entrance into cells, but, one must acknowledge that it plays a critical anti-inflammatory role in the renin-angiotensin-system (RAS), through signaling the conversion of angiotensin II, which carry pro-inflammatory effects and causes vasocontraction and hence increase in blood pressure, to Angiotensin 1-7, which carries anti-inflammatory and cardio-protective properties that can protect for subsequent lethal lung injury 1.

“What was missing in the discussion in the aforementioned dilemma is the age associated decline in ACE2 expression as observed in the lungs of the rats, which is in line with a constellation of major pro-inflammatory changes perpetrated by an age-associated increase in RAS signaling throughout the body. Exaggerated forms of this pro-inflammatory profile are also salient pathophysiologic features of hypertension and diabetes, which are highly prevalent at older ages”, says Dr. Majd Alghatrif, from the National Institute of Aging/ National Institute of Health (NIA/NIH).1

Dr. Alghatrif also explained that the upregulation of ACE2, which happens in diabetic and hypertensive patients who are treated with ACEI/ARB medications, in a way, plays a major restorative of the cardio-physiological function.  Because of these paradoxical findings: given ACE2 itself is the gateway of SARS-Cov-2 into body cells, how can the reduction of ACE2 in older population predispose this population to greater COVID-19 infection? To understand this paradox clearly, we must distinguish the role ACE2 as a gateway for SARS-Cov-2 from its anti-inflammatory function in the RAS signaling pathway that is compromised in individuals with COVID-19 infection, contributing to the severity of its course in this population. It is because of the decrease of ACE2 expression and subsequent upregulation of angiotensin II expression in older individuals especially those with diabetes and hypertension, that contributes to pro-inflammatory events in this sub-population and potential cause of lethal lung injury that requires mechanical intervention. The use of ACEI/ARB medications specifically in this sub-populations increases the expression of ACE2 which plays a corrective role to these changes that occur with advance in age. These findings are consistent with the role of the RAS system and support continuing therapy with ACEI/ARB.1,2,3

 Finally, given this complex dilemma, rapidly evolving nature of the disease, and the mass hysteria of social media, several cardiology associations (ACC/AHA, HFSA and ESC Hypertension Council) released an official statement regarding the continuation of ACEI/ARB for COVID-19 patients.5 The well-studied reduction in mortality conferred by ACE/ARB use and the beneficial outcomes with patients with cardiovascular disease, diabetes, chronic kidney disease and proteinuria outweigh the theoretical risk. As the COVID-19 pandemic rapidly evolves and affect more patients with cardiovascular comorbidities, further trials treating patients with severe COVID-19 with RAS interventions to examine the role of these interventions in preventing lethal lung injuries are warranted1,5,6.

References:

  1. AlGhatrif M, Cingolani O, Lakatta EG. The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease: Insights From Cardiovascular Aging Science. JAMA Cardiol.Published online April 03, 2020. doi:10.1001/jamacardio.2020.1329
  2. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team . The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID‐19)—China, 2020. China CDC Wkly. 2020; 2:113–122.
  3. Khalil H, Zeltser R. Antihypertensive Medications. [Updated 2020 Apr 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554579/
  4. Rico-Mesa, J.S., White, A. & Anderson, A.S. Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep22, 31 (2020). https://doi.org/10.1007/s11886-020-01291-4
  5. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. 2020; 395
  6. Guan W.J. Ni Z.Y. Hu Y. et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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How Coronavirus (COVID-19) can affect your heart health?

The rapid spread of the coronavirus (now known as COVID-19) has sparked a global alarm. The World Health Organization (WHO) has declared a state of public health emergency of international concern (PHEIC), as many countries are grappling with a rise in the number of confirmed cases. As of March 5th 2020, data from WHO have shown that more than 95,499 confirmed cases have been identified in 84 countries/territories with more than > 99% of the cases emerging from China1. In the United States, the Centers for Disease Control and Prevention (CDC) have increased the risk from Coronavirus spread to level 3 and advised against non-essential travels to China, Iran, Italy, and South Korea. “It is not so much a questions of if this will happen anymore, but rather more a question of exactly when this will happen and how many people in this country will have severe illness” said Dr. Nancy Messonier, director of the National Center for Immunization and Respiratory Disease at the Center for Disease Control and Prevention in the United States.

What is coronavirus?

Coronavirus (CoV) are a large family of viruses that causes illness ranging from the common cold to more severe diseases such as the Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-Cov). A novel coronavirus (nCov) is a new strain that has not been previously identified in humans. Coronavirus are zoonotic, meaning they can transmit between animals (such as bats, cats, camel, and cattle) and human.

What is the clinical profile of COVID-19 infection?

 Coronavirus infection is spread from human-to-human via droplets or direct contact. The infection is estimated to have a mean incubation period of 6.4 days (0-27 days), and a basic reproduction number of 2.24-3.58. Fever was the most common clinical feature followed by cough, shortness of breath, body ache, headache, and sore throat. There have been reports of gastrointestinal symptoms (nausea, vomiting, or diarrhea) before respiratory symptoms occur, but this is largely a respiratory virus. Those who have the virus may not have obvious symptoms (asymptomatic), or may have symptoms ranging from mild to severe. In some cases, the virus could be life-threatening. Older adults are less likely to present with fever, thus close assessment of these group of patients with other symptoms such as cough and shortness of breath is critical.

What are the cardiac Implications of COVID-19?

Early reports show that 50% of hospitalized COVID-19 patients had an underlying chronic medical illness, 80% of which are cardiovascular and cerebrovascular disease. The American College of Cardiology (ACC) issued a bulletin recently to warn patients with heart disease about their potential risk for complications if they contracted the disease. This does not mean that patients with cardiovascular disease or with cerebrovascular disease are at increased risk of getting coronavirus. However, they should practice additional precautions, since they are at great risk for complications. Nearly 20% of people developed Acute Respiratory Distress Syndrome (ARDS) according to a case report of Wuhan hospitalized patients. In addition, 7.2% of patients developed acute cardiac injury, 8.7% shock, 3.6% developed acute kidney injury, and 16.7% developed arrhythmia. Several unpublished first-hand reports suggest at least some patients develop myocarditis. Therefore, it would be reasonable to triage patients with COVID-19 infection according to the presence of underlying cardiovascular disease, renal disease, respiratory and other chronic diseases for prioritized treatment.

Several experts suggested rigorous use of guideline-directed plaque stabilizers (such as ACE-inhibitors, Statin, Beta-blockers, Aspirin) as it could protect cardiovascular patients during wide-spread outbreak of the virus. Furthermore, it is important for patients with cardiovascular disease to remain up to date with vaccination, including pneumococcal vaccine given the risk of secondary bacterial infection. It would be also crucial to receive the influenza vaccine to prevent any other sources of fever which could be initially confused with coronavirus infection.

The outbreak of COVID-19 has become a global clinical and public health threat. Knowledge about this novel virus remains limited. What we can do now is aggressively implement infection control measures to prevent the spread of COVID-19 via human- to- human transmission.

References:

  1. World Health Organization declares Global Emergency: A review of the 2019 Novel Coronavirus (COVID-19), International Journal of Surgery, (March 2020)
  2. Travel Health Notices: https://wwwnc.cdc.gov/travel/notices#travel-notice-definitions
  3. Chen H, Zhou M, Dong X, et al. Epidemiological and Clinical Characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; published online January 29. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930211-7
  4. Wang D, Hu B, Hu C, et al.Clinical Characteristics of 138 Hospitalized Patients with2019 Novel Coronavirus- Infected Pneumonia in Wuhan, China. JAMA. Published online February 07, 2020. doi:10.1001/jama.2020.1585
  5. Cardiac Implications of Novel Coronavirus (COVID-19): https://www.acc.org/~/media/665AFA1E710B4B3293138D14BE8D1213.pdf

 

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Can artificial intelligence save our lives?

The role of artificial intelligence (AI) in our life is advancing rapidly and is making strides in the early detection of diseases. The consumer market is composed of wearable health devices that enables continuous ambulatory monitoring of vital signs during daily life (at rest or physical activity), or in a clinical environment with the advantage of minimizing interference with normal human activities1. These devices can record a wide spectrum of vital signs, including: heart rate and rhythm, blood pressure, respiratory rate, blood oxygen saturation, blood glucose, skin perspiration, body temperature, in addition to motion evaluation. However, there is a lot of controversies whether these health devices are reliable and secure tools for early detection of arrhythmia in the general population2.

Atrial fibrillation (afib) is the most common arrhythmia currently affecting over 5 million individuals in the US and it’s expected to reach almost 15 million people by 2050. Afib is associated with an increased risk of stroke, heart failure, mortality, and represents a growing economic burden3. Afib represents a diagnostic challenge, it is often asymptomatic and is often diagnosed when a stroke occurs. Afib represents also a long term challenge and often involves hospitalization for cardioversion, cardiac ablation, trans-esophageal echo, anti-arrhythmic treatment, and permanent pacemaker placement. However, if afib is detected, the risk of stroke can be reduced by 75% with proper medical management and treatment3.

Physicians need fast and accurate technologies to detect cardiac events and assess the efficacy of treatment. A reliable, convenient and cost-effective tool for non-invasive afib detection is desirable. Several studies assessed the efficacy and feasibility of wearable technologies in detecting arrhythmias. The Cleveland Clinic conducted a clinical research where 50 healthy volunteers were enrolled. They tested 5 different wearable heart rate monitors including: (Apple Watch, Garmin Forerunner, TomTom Spark Cardio, and a chest monitor) across different types and intensities of exercises (treadmill, stationary bike and elliptical). The study found that the chest strap monitor was the most accurate in tracking the heart rate across different types and intensities of exercises4.

Apple and Stanford’s Apple Heart Study enrolled more than 419,297 Apple Watch and iPhone owners. Among these users, 2,161 (roughly 0.5%) received a notification of an irregular pulse. Of those who received the notifications, only about 450 participants scheduled a telemedicine consultation and returned a BioTelemetry ECG monitoring patch. When the Apple Watch notification and ECG patch were compared simultaneously, researchers found 71% positive predictive value, and about 84% of the cases were experiencing Afib at the time of the alert. Additionally, 34% of participants whose initial notification prompted an ECG patch delivery were later diagnosed with Afib. This finding shows that Apple watch detected afib in about one-third of the cases which is “good” for a screening tool considering the “intermittent nature of afib and that it may not occur for a whole week” says Dr. Christopher Granger, a professor of medicine at Duke University who participated on the steering committee for the Apple Heart study5.

These studies are observational studies and are not outcome-driven. They are not randomized and are not placebo-controlled. There are potentials for false negatives, where the Apple watch fails to detect the afib and false-positive where it detects arrhythmia that does not exist. Unfortunately, patients who are false negative don’t consult the physician about their symptoms of palpitations and shortness of breath since it provides false security. While patients with false-positive are sent unnecessarily to the clinic that could lead to further unnecessary tests and anxiety for the patient.

Is the Apple Watch ready to be used as a default screening tool to monitor the heart rate and rhythm in the general population and by physicians with patients with or at high risk for Afib is still unclear and warrant further studies. In conclusion, physicians should be cautious when using data from consumer devices to treat and diagnose patients.

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.

References:

  1. Cheung, Christopher C., Krahn, Andrew D., Andrade, Jason G. The Emerging Role of Wearable Technologies in Detection of Arrhythmia. Canadian Journal of Cardiology. 2018;34(8):1083-1087. doi:10.1016/j.cjca.2018.05.003
  2. Dias D, Paulo Silva Cunha J. Wearable Health Devices-Vital Sign Monitoring, Systems and Technologies. Sensors (Basel). 2018;18(8):2414. Published 2018 Jul 25. doi:10.3390/s18082414
  3. Chugh, S., Sumeet, Havmoeller, J., Rasmus, Narayanan, F., Kumar, et al. Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-847. doi:10.1161/CIRCULATIONAHA.113.005119
  4. Wrist-Worn Heart Rate Monitors Less Accurate Than Standard Chest Strap. Medical Design Technology. http://search.proquest.com/docview/1875621494/. Published March 9, 2017.
  5. Turakhia, Mintu P., Desai, Manisha, Hedlin, Haley, et al. Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American Heart Journal. 2019;207:66-75. doi:10.1016/j.ahj.2018.09.002

 

 

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Can artificial intelligence save our lives?

The role of artificial intelligence (AI) in our life is advancing rapidly and is making strides in early detection of diseases. The consumer market is composed of wearable health devices that enables continuous ambulatory monitoring of vital signs during daily life (at rest or physical activity), or in a clinical environment with the advantage of minimizing interference with normal human activities1. These devices can record a wide spectrum of vital signs including: heart rate and rhythm, blood pressure, respiratory rate, blood oxygen saturation, blood glucose, skin perspiration, body temperature, in addition to motion evaluation. However, there is a lot of controversy whether these health devices are reliable and secure tools for early detection of arrhythmia in the general population2.

Atrial fibrillation (afib) is the most common arrhythmia currently affecting over 5 million individuals in the US and it’s expected to reach almost 15 million people by 2050. Afib is associated with an increased risk of stroke, heart failure, mortality and represents a growing economic burden3. Afib represents a diagnostic challenge, it is often asymptomatic and is often diagnosed when a stroke occurs. Afib represents also a long term challenge and often involves hospitalization for cardioversion, cardiac ablation, trans-esophageal echo, anti-arrhythmic treatment, and permanent pacemaker placement. However, if afib is detected, the risk of stroke can be reduced by 75% with proper medical management and treatment3.

Physicians need fast and accurate technologies to detect cardiac events and assess the efficacy of treatment. A reliable, convenient and cost-effective tool for non-invasive afib detection is desirable. Several studies assessed the efficacy and feasibility of wearable technologies in detecting arrhythmias. The Cleveland clinic conducted a clinical research where 50 healthy volunteers were enrolled. They tested 5 different wearable heart rate monitors including: (Apple Watch, Garmin Forerunner, TomTom Spark Cardio, and a chest monitor) across different types and intensities of exercises (treadmill, stationary bike and elliptical). The study found that chest strap monitor was the most accurate in tracking the heart rate across different types and intensities of exercises4.

The Apple and Stanford’s apple Heart Study enrolled more than 419,297 Apple Watch and iPhone owners. Among these users 2,161 (roughly 0.5%) received a notification of an irregular pulse. Of those who received the notifications, only about 450 participants scheduled a telemedicine consultation and returned a BioTelemetry ECG monitoring patch. When the Apple Watch notification and ECG patch were compared simultaneously, researchers found 71% positive predictive value and about 84% of the cases were experiencing Afib at the time of the alert. Additionally, in 34% of participants whose initial notification prompted an ECG patch delivery were later diagnosed with Afib. This finding shows that Apple watch detected afib in about one third of the cases which is “good” for a screening tool considering the “intermittent nature of afib and that it may not occur for a whole week” says Dr. Christopher Granger, a professor of medicine at Duke University who participated on the steering committee for the Apple Heart study5.

These studies are observational studies and are not outcome driven. They are not randomized and are not placebo controlled. There are potentials for false negatives, where the Apple watch fails to detect the afib and false positive where it detects arrhythmia that does not exist. Unfortunately, patients who are false negative don’t consult the physician about their symptoms of palpitations and shortness of breath since it provides false security. While patients with false positive are sent unnecessarily to the clinic that could lead to further unnecessarily test and anxiety for the patient.

Is the Apple Watch ready to be used as a default screening tool to monitor the heart rate and rhythm in the general population and by physicians with patients with or at high risk for Afib is still unclear and warrant further studies.  In conclusion, physicians should be cautious when using data from consumer devices to treat and diagnose patients.

 

References:

  1. Cheung, Christopher C., Krahn, Andrew D., Andrade, Jason G. The Emerging Role of Wearable Technologies in Detection of Arrhythmia. Canadian Journal of Cardiology. 2018;34(8):1083-1087. doi:10.1016/j.cjca.2018.05.003
  2. Dias D, Paulo Silva Cunha J. Wearable Health Devices-Vital Sign Monitoring, Systems and Technologies. Sensors (Basel). 2018;18(8):2414. Published 2018 Jul 25. doi:10.3390/s18082414
  3. Chugh, S., Sumeet, Havmoeller, J., Rasmus, Narayanan, F., Kumar, et al. Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-847. doi:10.1161/CIRCULATIONAHA.113.005119
  4. Wrist-Worn Heart Rate Monitors Less Accurate Than Standard Chest Strap. Medical Design Technology. http://search.proquest.com/docview/1875621494/. Published March 9, 2017.
  5. Turakhia, Mintu P., Desai, Manisha, Hedlin, Haley, et al. Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American Heart Journal. 2019;207:66-75. doi:10.1016/j.ahj.2018.09.002

 

 

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.

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The 21-year-old man who survived an acute myocardial infarction

One of the most important things we can do as health-care providers, parents, teachers, caregivers and peers is to successfully recognize and improve the health issues and health outcomes of the teens and young adults. In this blog I’ll share the story of a young man who was seen by my husband in the ED and sparked my interest as a scientist to study the prevalence and clinical profile of myocardial infarction (MI) in young adults in my community.

I encourage you to share this blog with the young adults in your life, as well as parents and caregivers who have teenagers:

Three nights ago as my husband was preparing to sign off his shift in the ED, a 21 years-old man was brought in by the ambulance with a 30-minute history of severe central, crushing pain radiating down to his left arm. The pain was associated with nausea, vomiting, sweating and breathlessness. It was his first time to ever experience a central crushing pain. The man had a history of membranoproliferative glomerulonephritis and was on immunosuppressive therapy. He was also diagnosed with secondary hypertension and was on enalapril and nifedipine. Thankfully, he was in safe hands, the ED team were able to recognize his symptoms and a diagnosis of acute myocardial infarction was made. But, can you imagine how emotionally and physically upsetting this was to himself and his family.

Overview

Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Myocardial Infarction (MI) is a lethal manifestation of CAD and can present as sudden death. Although it mainly occurs in patients older than 45 years, young men and women can suffer from myocardial infarction1. Unfortunately, when it happens to young adults, the disease can carry significant psychological impact, financial constraints and morbidity to the patients and their family. The protection being offered by young age is gradually being taken away with the high prevalence of CAD risk factors in these young adults such as obesity, lack of physical activity and smoking. Several studies have described the clinical profile and outcome of young patients with MI and its incidence ranged between 2%-10%. Overall, young patients are more likely to be male, with a history of smoking and hyperlipidemia, however, they were less likely to have other comorbidities and less extensive CAD on coronary angiogram2.

Causes of myocardial infarction in young adults

The causes of myocardial infarction in young adults can be broadly divided into two groups, those with angiographically normal coronary arteries and those with coronary artery disease of varying etiology.

Angiographically “normal” coronary arteries

  • Hypercoagulable state:
    • Nephrotic Syndrome
      • Proteinuria associated with the nephrotic syndrome results in the loss of low molecular weight proteins which alters the concentration and activity of coagulation factors. As a result, factors IX, XI and XII are decreased due to urinary excretion. While the liver tries to compensate for the hypoalbuminaemic state, there is an increased synthesis of factor II, VII, VIII, X, XIII and fibrinogen resulting in raised blood levels3.
    • Antiphospholipid syndrome (Hughes syndrome)
      • Arterial and venous thrombosis is a prominent feature of this syndrome together with antiphospholipid antibodies and miscarriage in pregnancy. The mechanism of thrombosis with this syndrome is complex and not well understood. However, it is plausible that anti-phospholipid antibodies predispose to premature atherosclerosis which increases the risk of infarction with his syndrome4.
    • Coronary artery spasm
      • Coronary artery spasm (CAS) is probably the predominant mechanism for myocardial infarction with the use of cocaine. Cocaine has been associated with angina, myocardial infarction, tachyarrhythmia’s and bradyarrhythmias, sudden cardiac death and myocardial contraction bands, which can possibly act as a substrate for arrhythmias. The cardiac effects of cocaine are mediated through four main pathways
        1. Endothelial dysfunction which predisposes to vasoconstriction and thrombosis.
        2. Promotion of atherosclerosis
        3. Increased myocardial oxygen demand due to an acute rise in systemic blood pressure and heart rate.
        4. Coronary vasoconstriction caused by its α1- adrenergic properties and calcium dependent direct vasoconstriction5.
    • Coronary embolization
      • Coronary artery embolism is a rare cause of acute myocardial infarction (AMI) and the precise diagnosis remains challenging for the interventional cardiologist. The true prevalence of this nonatherosclerotic entity remains vague because of its difficult diagnosis in the acute setting.
    • Myocardial bridging
      • This is a congenital anomaly in which the coronary artery is embedded within the subepicardial myocardium or has a band of myocardium overlying it. This can impede blood flow during systole that can persist during diastole resulting in myocardial ischemia3.

Angiographically abnormal coronary arteries

We know that even angiographically “normal” looking coronary arteries can still have significant atherosclerotic plaque, and not surprisingly, can still result in myocardial infarction. Therefore, the definition of normality is arbitrary and not definite.

  • Accelerated atherosclerosis
    • The true prevalence of advanced coronary atheroma in young adults is not well studies. An autopsy study of 760 victims of accidents, suicide and homicides aged 15-34 years found advanced coronary atheroma in 2% of males aged 15-19 years and none in women. This reveals that being male solemnly is a risk factor for atherosclerosis. Additionally, in the 30-34 age group, about 20% of men and 8% of women had advanced coronary atheroma. It is known that genetic mutation in the low density lipoprotein receptor produces familial hypercholesterolemia, an autosomal dominant disorder characterized by premature atherosclerosis and high serum cholesterol. Various other lipid fractions and hyperhomocysteinaemia are implicated in premature atherosclerosis and MI3.
  • Aneurysm and anomalous origin of arteries dissection
    • Coronary artery aneurysm are congenital or acquired secondary to Kawasaki’s disease in childhood. They have been linked to myocardial infarction in young adults, although the actual mechanism is not well understood.
  • Spontaneous dissection
    • Spontaneous dissection is a condition with great prevalence in women, especially in the peripartum or early postpartum period. However, it is a rare cause of MI6.

 

REFERENCES:

  1. Wong CP, Loh SY, Loh KK, Ong PJ, Foo D, Ho HH. Acute myocardial infarction: Clinical features and outcomes in young adults in Singapore. World J Cardiol. 2012;4(6):206–210. doi:10.4330/wjc.v4.i6.206
  2. Sinha SK, Krishna V, Thakur R, et al. Acute myocardial infarction in very young adults: A clinical presentation, risk factors, hospital outcome index, and their angiographic characteristics in North India-AMIYA Study. ARYA Atheroscler. 2017;13(2):79–87.
  3. Osula S, Bell GM, Hornung RS. Acute myocardial infarction in young adults: causes and management. Postgrad Med J. 2002;78(915):27–30. doi:10.1136/pmj.78.915.27
  4. Turrent-Carriles A, Herrera-Félix JP, Amigo MC. Renal Involvement in Antiphospholipid Syndrome. Front Immunol. 2018;9:1008. Published 2018 May 17. doi:10.3389/fimmu.2018.01008
  5. Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. Int J Med Sci. 2014;11(11):1161–1171. Published 2014 Aug 28. doi:10.7150/ijms.9623
  6. Adlam D, Alfonso F, Maas A, Vrints C; Writing Committee. European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J. 2018;39(36):3353–3368. doi:10.1093/eurheartj/ehy080

 

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.

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Late Breaking Science DAPA-HF: SGLT-2 inhibitors might influence Cardiovascular outcomes—- Benefits extend above and beyond HbA1c.

The DAPA-HF trial was definitely the highlight of the scientific sessions at the AHA19 conference. I’m fascinated by the interesting outcomes and keen to learn more about the effect of SGLT-2 inhibitors on heart failure (HF) patients with preserved ejection fraction (HFpEF). In the next few lines, I’m going to briefly discuss the significant findings of DAPA-HF that were presented at AHA19, and will sooner nor later change the guidelines for management of patients with HFrEF.

Sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor) are relatively new class of drugs that act on inhibiting glucose reabsorption from proximal tubules, and thus decrease serum blood glucose concentrations.1 They are commonly prescribed to treat T2DM patients who have poor glycemic control. However, new data are emerging in large support of the beneficial effects of SGLT-2 inhibitors not just on diabetics but also on non-diabetic HF patients. The data is big and clear as presented by Dr. John McMurray at AHA19 and it is expected to list SGLT-2 inhibitors such as dapagliflozin (Farxiga) as guideline directed medical therapeutics (GDMT) in 2021 for HF patients.

In the DAPA-HF, McMurray and colleagues enrolled 4,744 patients with heart failure characterized by reduced ejection fraction (defined as left ventricle ejection fraction of 40% or less) from 20 different countries. There were 2,139 patients diagnosed with diabetes who were more likely to have HF etiology of ischemia when compared to non-diabetic patients with HF. The study population consisted of high risk middle aged patients with a mean LV ejection fraction of 31%. The primary end point was a composite outcome consisted of cardiovascular death, HF hospitalization and urgent HF hospital visits over an average of 18 months. As for diabetics in the DAPA-HF trial there was a 25% reduction of CV events (HR 0.75, 95% CI 0.63-0.90) when comparing dapagliflozin against placebo. While, there was a 27% reduction among those who did not have diabetes (HR 0.73, 95% CI 0.59-0.91).2

“The relative and absolute risk reduction in death and hospitalization were substantial, clinically important and consistent across the age spectrum and baseline health status in both patients with or without diabetes”, McMurray noted.

The mechanism by which dapagliflozin provides the cardiovascular benefits that has been documented in the DAPA- HF trial remains to be unclear. It is plausible that SGLT-2 inhibition modifies many CV risk factors such as BP, visceral adiposity, arterial stiffness, hyperinsulinemia, albuminuria, circulating uric acid levels and oxidative stress. These factors are involved in several pathways related to the cardiorenal outcome, where SGLT-2 inhibitors regulate the glucose and sodium excretion and therefore modify the factors in these pathways.

Below is an illustration that explains the proposed pathways involved in cardioprotective role of SGLT-2 inhibitors3

dapahf

In conclusion, dapagliflozin offers new approaches to the treatment of HF with reduced ejection fraction (HFrEF) in patients with or without diabetes. Data from the DAPA-HF trail provides robust support for the initiation of SGLT-2 inhibitors in patients who either have an established CVD or at risk of developing CVD, and HF in particular, or at risk for renal decline and progression into chronic kidney disease (CKD).

 

References:

  1. Mcmurray, John J. V., Demets, David L., Inzucchi, Silvio E., et al. A trial to evaluate the effect of the sodium–glucose co‐transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA‐HF. European Journal of Heart Failure. 2019;21(5):665-675. doi:10.1002/ejhf.1432
  2. Packer, Milton. Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion. Cardiovascular diabetology. 2019;18(1):129. doi:10.1186/s12933-019-0938-6
  3. Ali, Amar, Bain, Steve, Hicks, Debbie, et al. SGLT2 Inhibitors: Cardiovascular Benefits Beyond HbA1c-Translating Evidence into Practice. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2019;10(5):1595-1622. doi:10.1007/s13300-019-0657-8

 

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.