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Cardiovascular diseases in women: the heart of the matter

It was 4 am one winter night on call when I got paged:

“Youngish diabetic female, mid-thirties, chest pain for a few hours. Unremarkable ECG. Let me send troponins and see. Doesn’t seem cardiac.”

“Doesn’t seem cardiac”

Dismissed, just like that, because she was young, and because she was a woman.

A proper listen to her symptoms revealed that this could indeed, be cardiac. She was admitted, her troponins were raised, a coronary angiography done a few hours later showed an occluded principal obtuse marginal branch which was stented. She was symptom-free the same day.

Fortunately for her, a definitive culprit lesion in her coronaries could be identified, that was amenable to stenting and thus treated. For the majority of women with non-obstructive coronaries, presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA)1 or ischemia with no obstructive coronary arteries (INOCA), investigations would very likely have stopped right there, with that normal coronary angiography. Dismissed.

CVD in women

Cardiovascular disease (CVD) is the number one cause of mortality among women across the globe.2 Despite improved treatment algorithms and the enormous strides made in cardiovascular care, women continue to have worse clinical outcomes than men, partly owing to them being underdiagnosed, understudied and undertreated.

One size does not fit all: A spectrum of differences

The inherent biological differences between men and women, in addition to the socio-cultural attributes of gender, mean that women have very different characteristics of ischemia in terms of symptoms, triggers, and aetiologies.3

Symptoms: While chest pain is the predominant presenting symptom in both men and women in acute coronary syndrome (ACS), historically, women have been known to present with more “atypical” symptoms such as neck pain, fatigue, dyspnea or nausea, often triggered by emotional stress but even this time-honored notion has been challenged by a recent study that found that typical symptoms were more common among women and have greater predictive value in women than in men with myocardial infarction.4

Co-morbidities: Women with ACS are known to be older, with a clustering of risk factors and greater prevalence of co-morbidities.3  Particularly, diabetes, smoking and a family history of ischaemic heart disease have been shown to have a stronger impact on event rates among women.3 Younger women with ACS have been found to have a worse pre-event health status (both physical and mental) in comparison to men.5

The age paradox: Premenopausal women are thought to be relatively protected against CVD compared to similar-aged men, owing to favorable effects of estrogen on cardiovascular function and metabolism. Intriguingly though, recent studies report an increase in hospitalization rates of ACS among young women, despite a decline among younger men. The mechanisms behind these differences remain a fairly understudied area.

Delayed presentation: Women are also known to present later, frequently attributing their symptoms to a non-cardiac-related condition such as acid reflux, stress, or anxiety.2,3 This inaccurate symptom attribution, in addition to a lack of awareness of risk, and barriers to self-care in general, lead to a delay in seeking treatment, contributing to poorer outcomes.

Different etiologies: By virtue of an obstructed coronary artery, my patient got lucky in terms of prompt diagnosis and treatment. In about 10% of all patients, and in about a third of women, such a culprit coronary lesion cannot be identified on angiography.2,3 Furthermore, microvascular angina affects close to a half of patients with non-obstructive coronary arteries.7 This coronary microvascular dysfunction (CMD) is defined as the presence of symptoms and objective evidence of ischemia in absence of obstructive coronary artery disease, with blood flow reserve and/or inducible microvascular spasmAngina with no obstructive coronary arteries is twice as prevalent in women as in men, 7 and might also contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF), which is also more commonly observed in women.9

Women are still under-studied in clinical trials

In the face of such a formidable gender disparity in CVD, women continue to be under-represented in some areas of cardiovascular clinical trials, particularly in ischaemic heart disease and heart failure drug trials, the most common cardiovascular conditions affecting women. In fact, a number of pivotal cardiovascular drug trials of 2019 had less than a quarter of women enroll.12-15 Interestingly, the PARAGON-HF trial, where 51.7% of patients were women, found a heterogeneity in treatment response: women with HFpEF responded better to valsartan-sacubitril, with a 28% reduction (rate ratio 0.73) in the primary endpoint.

In a compelling 2018 editorial, doctors Pilote and Raparelli explore the practical reasons for under-enrollment of women in cardiovascular drug trials, notably male-patterned inclusion criteria and gender-related barriers to screening and participation in trials, such as caretaking roles and low socioeconomic status. While proposing interventions to mitigate this issue (childcare and such support for women during time spent as a research participant, inclusion criteria that consider sex differences in pathophysiology, prespecified subgroup analyses, etc.), they warn that such under-representation of women could lead to sex-biased outcome measurements and missed opportunities to transfer results in clinical practice.

The issue, in essence, is not just about researching CVD in women: even within this large cohort, differences in symptoms, presentation and outcomes, heterogeneity related to age, ethnicity and geographic locations exist. Why younger women with ACS tend to have unfavorable prognoses is an as-yet unanswered question, with huge scope for research, as is microvascular dysfunction, known to be more prevalent among women.

What can be done?

With February being national heart month, and the American Heart Association’s #GoRedForWomen campaign soaring at its highest, it seems like a good time to reflect on what can (and should) be done for women with CVD. Because there is plenty left to do.

Raise awareness: It’s vital that both women and men are aware that heart disease is as big a killer in women as in men. The AHA’s signature women’s initiative Go Red for Women (https://www.goredforwomen.org/) and the sub-initiatives of Wear Red Day are great platforms dedicated to increase women’s heart health awareness. The Women’s Heart Alliance (https://www.womensheartalliance.org/) is another organization working to promote gender equity in research, prevention, awareness and treatment.

Enroll more women in clinical trials: it’s important to identify barriers accounting for the low inclusion of women in clinical trials, and actively intervene to overcome them.

Women’s Heart Health Clinic: a number of programs have successfully initiated women’s heart health clinics, exclusively catering to the diagnosis and treatment of this often-underestimated patient group.

Get more women involved: at every level, be it as clinical trialists, advocates, physicians, nurses or other health-care providers.

As physicians, perhaps the best thing we can do for our female patients is to pay more attention. Don’t dismiss a symptom, because nothing should “not seem cardiac” until proven otherwise.

So, yes:

Listen to her.

Diagnose her.

Investigate her.

Study her.

Treat her.

And don’t just #GoRedForWomen in February. #GoRedForWomen throughout the year.

 

References

  1. Pasupathy S, Tavella R, Beltrame JF. Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): The Past, Present, and Future Management. Circulation. 2017;135(16):1490-1493.
  2. Mehta LS, Beckie TM, DeVon HA, Grines CL, Krumholz HM, Johnson Mnet al; American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation. 2016;133(9):916-47.
  3. Haider A, Bengs S, Luu J, Osto E, Siller-Matula JM, Muka T, et al. Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome. European Heart Journal (2019) 0, 1–14.
  4. Ferry AV, Anand A, Strachan FE, Mooney L, Stewart SD, Marshall L, et al. Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex-Specific Criteria. J Am Heart Assoc. 2019 Sep 3;8(17):e012307.
  5. Dreyer RP, Smolderen KG, Strait KM, Beltrame JF, Lichtman JH, Lorenze NP, et al. Gender differences in prevent health status of young patients with acute myocardial infarction: a VIRGO study analysis. Eur Heart J Acute Cardiovasc Care 2016;5:43–54.
  6. Arora S, Stouffer GA, Kucharska-Newton AM, Qamar A, Vaduganathan M, Pandey A, et al. Twenty year trends and sex differences in young adults hospitalized acute myocardial infarction: the ARIC Community Surveillance Study. Circulation. 2019;139:1047–1056.
  7. 037137Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–744.
  8. Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U,et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;250:16–20.
  9. Srivaratharajah K1 Coutinho T, deKemp R, Liu P, Haddad H, Stadnick E, et al. Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction. Circ Heart Fail. 2016;9(7).
  10. Scott PE, Unger EF, Jenkins MR, Southworth MR, McDowell TY, Geller RJ, et al. Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs. J Am Coll Cardiol. 2018;71(18):1960-1969.
  11. Pilote L, Raparelli V. Participation of Women in Clinical Trials: Not Yet Time to Rest Our Laurels. J Am Coll Cardiol. 2018;71(18):1970-1972.
  12. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019;381(21):2032-2042.
  13. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.
  14. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, et al; ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019 ;381(16):1524-1534.
  15. Presented by Dr Judith S. Hochman at the American Heart Association Scientific Sessions (AHA 2019), Philadelphia, PA, November 2019. https://www.ischemiatrial.org/system/files/attachments/ISCHEMIA%20MAIN%2012.03.19%20MASTER.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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Recognizing Congenital Heart Disease (CHD) as an Important Part of #HeartMonth; Important Considerations for Healthcare Providers

Congenital Heart Disease (CHD) is a diagnosis that often causes confusion, concern, and fear, not only for family and patients but also for healthcare providers who are not exposed to them frequently. February is Heart Month; it is important that we take time to recognize the youngest of our heart patients, as well as those who are now adults living with Congenital Heart Disease.

CHD is the most common congenital malformation in newborns and there are great than 1 million adults now with CHD in the United States,1 which makes it important for every health care provider to know about; it requires understanding of sometimes complex physiology, a high index of suspicion, and most importantly a multidisciplinary approach to care with the patient and often parent at the center. For a review on CHD you can click here3, but below are some important things to consider:

  • CHD does not always present at birth and can be missed on routine prenatal obstetric ultrasound, fetal echocardiogram, and the neonatal pulse ox screening. Fortunately, not all CHD requires surgery or intervention at all.
    • General OB ultrasounds and fetal echo will likely catch major congenital heart disease, but there are some smaller lesions that are difficult to diagnose due to normal fetal circulation, which is abnormal after birth.
    • The pulse ox screen was initiated in 2011 to improve detection and outcomes in critical congenital heart disease that could cause hypoxemia and a higher risk of death early on; these lesions are typically prostaglandin dependent and outcomes can be improved if addressed early on.2
    • CHD is often associated with extreme clinical situations, but many infants with CHD will not present this way and may not require surgery at all. They still require follow up with a pediatric cardiologist.
  • CHD is not always “cured” but often palliated, and these patients can have different hemodynamics to consider as a result.
    • While many patients receive surgery to create a “normal” heart, many infants born with complex congenital heart disease will require multiple surgeries, termed palliation, that create a new way of circulation (such as the Fontan Procedure4). Altered hemodynamics(blood flow) are important to understand and it is important to know what surgeries have been performed.
    • Some surgeries, while restoring normal or near-normal can still put patients at risk for long term issues that need to be followed closely such as heart failure, hypertension, valvar issues or arrhythmias.
  • There are now more adults living with CHD than children.
    • Thanks to advances in medicine and surgery, adults now represent the largest population of patients with CHD. While many of these patients are healthy and can live normal lives, they still need lifelong care with providers who specialize in CHD.
    • It is important to encourage adolescents with CHD to learn about their diagnosis early on and take their health into their own hands. The transition to an adult congenital heart disease (ACHD) provider is something that needs to be encouraged not only by pediatric cardiologists but primary care physicians and adult cardiologists
    • Most CHD patients can, and should be encouraged to, participate in a healthy lifestyle including exercise; however, this should be in discussion with a CHD provider to help provide guidance.
    • Click here5 to find an ACHD specialist near you.
  • CHD parents and patients are great resources of knowledge and want to be heard.
    • CHD parents and patients are their best advocates and are often the most knowledgeable about their heart and what they have been through. It is important to take their complaints and concerns seriously. Do not be afraid to ask them questions and learn their history.
  • CHD requires a multidisciplinary approach; CHD providers are willing to answer a call and collaborate.
    • CHD patients may be at higher risk for psychological issues such as depression and anxiety related to living with chronic disease.6 They are also not free from other cardiovascular problems that are not necessarily congenital, such as coronary artery disease and stroke1, which is why collaboration amongst specialties is crucial.
    • If you have a question, concern or need more help; never hesitate to reach out to your hospital or patient’s CHD specialist. We are here to help, educate and provide the best care for our patients.

CHD represent a population of heart patients that is consistently growing with continued advances in medical care. Everyone in healthcare is likely to be exposed to these patients during their career, therefore a multidisciplinary, patient-centered approach is important to continued success in the field.

 

  1. Wang, Tingting, et al. “Congenital Heart Disease and Risk of Cardiovascular Disease: A Meta‐Analysis of Cohort Studies.” Journal of the American Heart Association, 9 May 2019, ahajournals.org/doi/10.1161/JAHA.119.012030.
  2. Engel, Melissa S, and Lazaros K Kochilas. “Pulse Oximetry Screening: a Review of Diagnosing Critical Congenital Heart Disease in Newborns.” Medical Devices (Auckland, N.Z.), Dove Medical Press, 11 July 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4946827/. Puri, Kriti, et al. “Congenital Heart Disease.” American Academy of Pediatrics, American Academy of Pediatrics, 1 Oct. 2017, pedsinreview.aappublications.org/content/38/10/471.
  3. Puri, Kriti, et al. “Congenital Heart Disease.” American Academy of Pediatrics, American Academy of Pediatrics, 1 Oct. 2017, pedsinreview.aappublications.org/content/38/10/471.
  4. “The Royal Children’s Hospital Melbourne.” The Royal Children’s Hospital Melbourne, rch.org.au/cardiology/parent_info/Information_for_patients_and_parents_about_the_Fontan_Operation/.
  5. “Adult Congenital Heart Association – Home.” ACHA, achaheart.org/.
  6. Areias, Maria Emília Guimarães, et al. “Long Term Psychosocial Outcomes of Congenital Heart Disease (CHD) in Adolescents and Young Adults.” Translational Pediatrics, AME Publishing Company, July 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC4728933/.

“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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#HeartMonth and Healthy choices

See what’s on Netflix or go for a run? We’re more than half-way through #HeartMonth and I’m still picking the next episode of Netflix nine times out of ten. That said, with the Heart Month hashtags flooding my twitter feed I have been inspired to start “prescribing” exercise to patients who are having trouble making healthy exercise choices. Thanks to #cardiotwitter I also have a couple of interesting studies to show patients on the benefits of running.

One observational study at the London Marathon found an approximately 4-year reduction in vascular age associated with training for and completing the race among first-time runners. Most of these people ran 6 to 13 miles per week for the 4-5 months leading up to the race. [1] A separate, outcomes-focused meta-analysis published in 2019 analyzed data from 14 studies and found a 27% risk reduction of all-cause mortality associated with running. The authors concluded that mortality risk reduction was seen with running even just once per week. [2]

Heart disease is the nation’s leading cause of death, but it doesn’t have to be. February is American #HeartMonth to reminds us that we can fight back by making healthy choices: being active, eating healthier, and going for that occasional run.

My son and I after his first Turkey Trot last year

References:

  1. Bhuva A, D’Silva A, Torlasco C, et al. Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening. J Am Coll Cardiol. 2020 Jan 7;75(1):60-71. doi: 10.1016/j.jacc.2019.10.045.(https://www.ncbi.nlm.nih.gov/pubmed/31918835)
  2. Pedisic Z, Shrestha N, Kovalchik S, et al. Is running associated with a lower risk of all-cause, cardiovascular and cancer mortality, and is the more the better? A systematic review and meta-analysis. Br J Sports Med 2019; 0:1-9. doi:10.1136/bjsports-2018-100493 (https://www.ncbi.nlm.nih.gov/pubmed/31685526)

 

“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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Surviving A Deadly Heart Attack

With cardiovascular disease (CVD) being the leading cause of mortality and morbidity among the western population, it is not a long shot for one to think almost everyone knows someone that has encountered heart disease or the symptoms thereof. Not surprising that I had the opportunity to meet these people whom I am now writing.

 

Heart month heart image

There was a cardiologist at a well-known and respected institution that suggested, her patient, a 60 year old man with two occluded arteries and only a functioning aorta (widow maker) had on average 10 years to live. The patient had one silent heart attack and one where he sought medical treatment. During that time the cardiologist attempted to place a stent to reopen the artery, but had no success due to the “amount of scarring.” Which is why the patient was left with two arteries occluded. I am left to wonder, with all the research that is being conducted to extend life and improve cardiac health including but not limited to pharmaceuticals and the surgical techniques, why is there nothing that can be done other than sending this patient home with a bleak outlook on the next several years of his life. That patient is still alive and doing well, thanks for asking. That is not an isolated case of patients being sent home hopeless. I came across a story on Facebook (2014) about a 58 year old lady that was on hospice for the last four years. She presented to the hospital in full cardiac arrest. The emergency medical team was performing compressions until she arrived at the hospital; thankfully they were able to revive her. She previously suffered 3 heart attacks resulting in 2 triple bypass surgeries, but after that 4rd heart attack in August 2010 the doctors said there was nothing they could do to improve her [cardiac] health. Before you are alarmed, she had multiple chronic illnesses by this time: 3 myocardial infarction (MI), congestive heart failure, diabetes, breast cancer (resulting in double mastectomy), hypertension, and renal failure. Since she was not a good candidate for dialysis, she had a poor prognosis. She was taken off all her medications (from a cocktail of 19 pills to 4, which were for CVD symptoms and a morphine tablet for pain) and the end of life care team made worked diligently to make her comfortable until she passed.  The medical providers alerted the family that she could pass on at any time. That was in 2010, it is now 2018 and she is STILL alive and well! Both patients are.  So, what allowed this Facebooker to live so long with no major arteries? How is this even possible? Is it a case of faith/a miracle alone (which is what the Facebook post suggest) or something that can be medically/scientifically explained? What about the man from the former story? Is 10 years the best he could hope for or is the case with the latter possible in his case? Is there anything we can do pharmaceutically to drive the system toward the former?

the vascular endothelial growth factor graphic

In a 2018 study by Manavski et al, it was suggested that angiogenesis after ischemia is due to clonal expansion of endothelial cells. Indicating there is, indeed, a scientific rationale for the revascularization of the aforementioned hearts. After an MI there is significant scar tissue leading to the inability for the heart to provide the necessary oxygen and nutrients to other organ systems, known as ischemia. The newly ischemic environment potentiates the growth of new vessels to compensate for the loss of cardiac output due to the MI. These vessels are said to be generated through a mechanism known as angiogenic sprouting; in excess this pathological growth that can promote tumor formation. The signaling molecule vascular endothelial growth factor (VEGF) is hallmark in the formation of new vessels, but it is also highly expressed in cancers. Before we get off track, let’s think about the mechanisms in play in an MI. monocytes are attracted to an insult in the vessel, they differentiate into macrophages, those macrophages take up oxidized low density lipoproteins, and since they cannot process them, they die (undergo apoptosis). In ischemia macrophages promote the development of collateral vessels, but in tumors macrophages (M2) produce proangiogenic factors while educating the macrophage as what phenotype to take on – Tumor or cardiac. There are signals in the body that include VEGF and Ang1 that keep endothelial cells inactive to promote vessel stabilization. Furthermore, an oxygen sensor helps the endothelial cells to normalize and readapt to oxygen supply to the organ tissues. There are a battery of enzymes that play a role in vessel maturation which is too exhaustive for this blog, but mainly sprouting is impaired by inhibition of VEGF and S1P receptor signaling is the stabilizer for the vasculature.

In conclusion, having a heart attack is not necessarily a death sentence. Even when all the arteries to the heart of occluded. It is not the norm, but the human body is an overwhelmingly amazing in compensating for the loss of some pathways. Our bodies have system in place with mechanism to support life even when the answers evade medicine and science. With the passion to conduct research, we are finding ways to make our heart health better daily. As we explore mechanistic pathways to reduce oxidative stress, inflammation, and other underlying pathways, it is up to each individual to maintain a healthy heart by following the guidelines set in place by the American Heart Association. As for the patients above, they are working with their medical teams to maintain a healthy life. May I suggest you all continue to seek your physicians’ advice on how to improve/maintain your heart health?


Anberitha Matthews, PhD is a Postdoctoral Fellow at the University of Tennessee Health Science Center in Memphis TN. She is living a dream by researching vascular injury as it pertains to oxidative stress, volunteers with the Mississippi State University Alumni Association, serves as Chapter President and does consulting work with regard to scientific editing.