Heart Disease in Women

What can women do to reduce their risk of heart disease?

Living a healthy lifestyle can help reduce the risk of heart dis- ease. Try these heart-healthy strategies: Quit smoking. If you don’t smoke, don’t start. Try to avoid exposure to secondhand smoke, which also can damage blood vessels. Exercise regularly. In gen- eral, everybody should do moderate exercise, such as walking at a brisk pace, on most days of the week. Maintain a healthy weight. Ask your doctor what weight is best for you. If you’re overweight, losing even a few pounds can lower blood pressure and reduce the risk of diabetes. Eat a healthy diet. opt for whole grains, a vari- ety of fruits and vegetables, low-fat or fat-free dairy products, and lean meats. Avoid saturated or trans fats, added sugars, and high amounts of salt. Manage your stress. Stress can cause your arteries to tighten, which can increase your risk of heart disease, particu- larly coronary microvascular disease. Limit alcohol. If you have more than one drink a day, cut back. One drink is approximately 12 ounces (360 milliliters) of beer, 5 ounces (150 milliliters) of wine or 1.5 ounces (45 milliliters) of distilled spirits, such as vodka or whiskey.

Follow your treatment plan. Take your medications as prescribed, such as blood pressure medications, blood thinners and aspirin. Manage other health conditions. High blood pressure, high choles- terol and diabetes increase the risk of heart disease.

Introduction

Cardiovascular disease is the worldwide leading cause of death in women. Biological differences between the sexes, a result of ge- netic, epigenetic and sex hormone-mediated factors, are complex and incompletely understood. These differences are compounded by socio-cultural factors and together account for the variation in the prevalence, presentation and natural history of cardiovascular disease between men and women. Although there is growing rec- ognition of sex-specific determinants of outcomes, women remain under-represented in clinical trials, and sex-disaggregated diag- nostic and management strategies are not currently recommended in clinical guidelines. Women remain more likely to experience delays in diagnosis, to be treated less aggressively and to have worse outcomes. As a consequence, cardiovascular disease in women remains understudied, underdiagnosed and undertreated. This review will focus on female-specific characteristics of car- diovascular disease and how these may impact on anesthetic and peri-operative risk assessment and care. We highlight significant differences between the sexes in the natural history of cardiovascu- lar disease, including those disease entities that are more common in women, such as sudden coronary artery dissection or micro- vascular dysfunction. Given the rapidly rising incidence of mater- nal cardiovascular disease and associated complications, special consideration is given to the risk assessment and management of these conditions during pregnancy. Increased awareness of these issues has the potential to improve the effectiveness of the multi- disciplinary heart team and ultimately improve the care provided to women.

Approximately one in three women in the United States has some form of cardiovascular disease, and 90 percent of women have at least one risk factor for heart disease or stroke. This contributes to a sobering fact: heart disease is the leading cause of death among American women. The good news: it is largely preventable.

One of the most important steps you can take to prevent heart dis- ease is to learn more about both the risk factors and symptoms in women.

Risk factors in women

Risk factors are aspects of your medical history, your family’s medical history, and your lifestyle that contribute to heart disease. Risk factors fall into three categories:

Those you cannot control

Those you can help manage, with your doctor’s guidance Those that can contribute to heart disease that you should discuss with your doctor.

Risk factors you cannot control

Age: As women age, their risk increases because of lower estrogen levels and the chances of developing additional health issues that can affect the heart.

Family history: You are at greater risk if an immediate family member had heart disease at an early age-55 for a male relative or younger than 65 for a female relative.

Race: African-American and Hispanic women have a higher risk than Caucasian women.

Gender: Women have a lower risk than men of developing heart disease before menopause, but after menopause, the risk is about equal.

Risk factors you can help manage

Smoking: Smokers are two to four times more likely to have heart disease than non-smokers. When you stop smoking, your body be- gins to heal, and you will experience almost immediate decreases in blood pressure and heart rate.

High blood pressure: Among women of childbearing age, 20 per- cent have high blood pressure even though many do not realize it. The rate increases to 40 percent between ages 45 and 64, and 60 percent for those age 65 and over. High blood pressure puts added strain on the heart.

High cholesterol: About one-third of American women have cho- lesterol levels high enough to pose a serious heart disease risk.

Weight: Excess weight can also put added strain on your heart, raising your blood pressure, cholesterol, and glucose (sugar) lev- els. Another way to assess weight-related risk is to measure your waistline. For women, a waist measurement of 35” or more indi- cates an increased risk.

Inactivity: Inactivity can weaken the heart, and it also makes it easier to gain weight, increasing your chances of developing other health issues, such as high blood pressure and high cholesterol.

Other risk factors to consider

Diabetes: Women with diabetes are at greater risk than men with diabetes. Over time, high blood sugar (glucose) levels can damage the body’s blood vessels and increase the chances that fatty depos- its will build up in the arteries.

Chemotherapy and radiation treatment: Radiation therapy as well as some drugs used to treat cancer, particularly breast cancer, can increase your risk of heart disease. If you have had a cancer diagnosis, talk with your doctor about seeing a cardio-oncologist, a specialist in cancer treatments and its effects on the heart.

Pregnancy complications: Women who develop high blood pres- sure or diabetes during pregnancy are at higher risk for develop- ing heart disease later in life. It is particularly important for these women to see their doctor regularly for checkups each year and to pay attention to important lifestyle issues, such as exercise and healthy eating.

Stress and depression: Both chronic stress and the sudden onset of stress seem to affect women’s hearts more than men’s hearts. And people with consistently high levels of stress double their risk of heart disease—equal to the risk of high cholesterol and high blood pressure. A Sudden stressful experience, such as a loved one’s death or a bad accident, has been linked to stress-induced cardiomyopathy (broken-heart syndrome), particularly in wom- en. And both stress and depression tend to affect a woman’s heart more than a man.

Sleep apnea: A serious condition in which breathing sudden- ly stops during the night, sleep apnea may be underdiagnosed in women. During an apnea episode, the brain triggers the body to awaken to resume breathing. This frequent, rapid awakening (which you may not even be aware of) can increase blood pressure and put added strain on your heart.

Autoimmune disease: Some of these diseases, such as lupus and rheumatoid arthritis—both more common in women than men— tend to negatively affect the heart, possibly due to the inflamma- tion they cause.

Womens symptoms of heart disease

While women can experience the crushing chest pain that men of- ten describe, women’s symptoms of a heart attack and heart dis- ease overall are likely to be more subtle. Here are the ABCs of women’s heart disease warning signs:

Angina (chest pain): Angina may feel like traditional pain, but it may also feel like a tightness or pressure in the chest or throat that radiates down the jaw or left shoulder or arm.

Breathlessness: Having shortness of breath or waking up breath-less at night can be a warning sigh.

Chronic fatigue: Overwhelming or out-of-character fatigue may be a symptom. Severe fatigue that lasts several days can also be a heart attack symptom.

Dizziness: Feeling light-headed or dizzy can indicate heart valve disease or arrhythmia (an irregular heart rhythm).

Edema: Swelling, particularly in the lower legs and ankles, should be assessed by a doctor.

Fluttering or rapid heartbeats: These experiences may cause pain or difficulty breathing.

Gastric upset: Talk with your doctor about nausea or vomiting unrelated to diet.

Heartburn: Some women use “heartburn” or “indigestion” to de- scribe heart-related pain. These symptoms do not necessarily mean that you have heart dis- ease. But you should listen to your heart and your body. Talk with your doctor about these symptoms, what triggers them, and how long they last.

Method Section

This case-series of cardiovascular diseases presenting in pregnant females explored the medical approach to acute cardiovascular presentations in pregnant females. The cases were reviewed retro- spectively through an in-depth exploration of the medical records. Individual patients were contacted by telephone and asked if their case could be published if anonymity was maintained. All living patients agreed. The deceased patient’s mother agreed.

The case reviews allowed for highlighting of the clinical presen- tations, physical examination findings, imaging features and treat- ment approaches to patients with spontaneous coronary artery dis- section versus paradoxical embolism to the coronary tree, stress induced cardiomyopathy, pulmonary embolism versus amniotic fluid embolism, primary pulmonary embolism, peripartum cardio- myopathy, ventricular arrhythmias, dilated cardiomyopathy, and bicuspid aortic valve associated aortopathy. Cardiovascular Ur- gencies and Emergencies in Pregnancy: A Case Based Review of Some Cardiovascular Diseases Affecting Pregnant Females.

Results

Cardiovascular Urgencies and Emergencies

Case 1

Cardiology was consulted on a 32-year-old female for severe shortness of breath (SOB), chest pressure, and labile hemodynam- ics during delivery. She had two prior normal deliveries.

Post-delivery she required intubation and had a blood pressure (BP) of 190/100 mm Hg and heart rate (HR) of 130 beats per min- ute (bpm). The ECG revealed sinus tachycardia, low voltage QRS and poor R wave progression with diffuse, non-specific ST chang- es (Figure 1).

Figure 1: Sinus tachycardia with loss of R waves across the precordium and non-specific ST changes

Treatment with a diuretic, beta-blocker, and intravenous nitroprus- side resulted in a BP = 150/90 and HR = 95 bpm. Oxygenation was adequate with assisted ventilation. Urgent echocardiography revealed left ventricular (LV) systolic function was depressed with an ejection fraction of 20%, dilated right ventricle (RV) with se- vere reduction of RV systolic function, severe tricuspid regurgita- tion (TR) and elevated right heart pressure (Figure 2). Incidentally, an atrial septal defect (ASD) was identified.

Figure 2: TR envelope: blue arrow to 3.5 m/sec. The RV-RA gradient is approximately 50 mmHg.

Urgent cardiac tomography (CT) scan was negative for pulmonary embolism (PE) and aortic dissection. Magnetic resonance (MR) imaging revealed the left ventricular ejection fraction (LVEF) was 22% and the RV was enlarged. The differential diagnosis generat- ed was a stress-induced cardiomyopathy, paradoxical embolism to the coronary tree, and spontaneous coronary artery dissection. The patient became hemodynamically stable with medical therapy and was extubated with normal oxygen saturations. Follow up evalua- tion of the ASD with a trans-esophageal echocardiography (TEE) revealed a thin, dyskinetic distal anterior septum and apex, a sinus venous ASD, and normal LV and RV systolic function. Right heart pressure was normal. The patient was feeling well without symp- toms and baby was doing well. Review of the case raised a ques- tion of an apical myocardial infarction due to SCAD versus em- bolism to the coronary tree. This led to review of the prior ECGs. The ECG analysis supported the notion of an anterior infarct, as the initial ECG was normal (Figure 3).

                                    Figure 3: Normal ECG prior to delivery

The ECG post-delivery revealed loss of R waves across the pre- cordium (Figure 1). This retrospectively raised a strong suspicion that the initial insult was an unrecognized coronary artery dissec- tion versus a paradoxical embolism across the ASD to the coro- nary circulation. The interventional team felt the angiogram was supportive of a dissection. This infarct was supported on MRI and TEE imaging. Surgery was consulted for evaluation of the si- nus venous ASD in the setting of enlarged right heart chambers by echocardiography and MRI. The review of the MRI revealed normal venous connections. Because of the apical infarct, surgery requested a cardiac catheterization. The catheterization revealed an occluded left anterior descending coronary artery (Figure 4). This occluded vessel retrospectively identified the etiology of the post-delivery hemodynamic instability. The patient was feeling well and elected not to pursue surgery for the ASD or coronary disease.

                Figure 4: Coronary angiography reveals an occluded LAD (Blue arrow).

Pregnancy and Spontaneous Coronary Artery Dissection (P-Scad)

P-SCAD is a rare condition with an incidence of (0.1%) for all pa- tients referred for coronary angiography [1]. The mean age at pre- sentation is 35-40 years, and greater than 70% of SCAD cases are female [2]. Typically, patients with spontaneous coronary artery dissection are divided into four etiologic groups: peripartum, ath- erosclerotic, idiopathic, and vasculitic in patients with connective tissue disease [2]. This classification does not cover all potential etiologies of SCAD.

Approximately (33%) of P-SCAD cases occur in the peripartum period, with 1/3 late in pregnancy and 2/3 in the early puerperal period [2]. The peak incidence is two weeks after delivery. The role of the peripartum period in the pathogenesis is an enigma. Theories include hormonal changes, such as high estrogen lev- els, resulting in subtle changes in arterial wall architecture with ensuing susceptibility to spontaneous dissections. These changes include hypertrophy of the smooth muscle cells, loosening of the intracellular matrix due to increase in acid mucopolysaccharides, and decreased collagen production in the media [3,4]. Additional- ly, increased total blood volume, high cardiac output, and strain- ing and shearing forces during labor may result in increased wall stress. Thus, hemodynamic and hormonal changes are thought to increase the risk of intimal tears. Patients in the pregnancy subset with underlying connective tissue disorders, such as Marfan syn- drome, Ehler-Danlos type 4 and systemic lupus erythematous with vasculitis, may be at even higher risk for P-SCAD [5,6].

P-SCAD is thought to be the consequence of an intramural hema- toma of the coronary artery, resulting in a false lumen compressing the true lumen, resulting in myocardial ischemia [7]. The clinical presentation ranges from unstable angina to sudden cardiac death. Young woman with angina and ECG changes should lead to a high suspicion for SCAD and urgent evaluation and angiography should be considered. In young women the left anterior descending coro- nary artery is the most common location [2]. When angiography is performed the approach ranges from mostly conservative to rarely revascularization with stenting depending on the angiographic and clinical circumstances.

Take home messages for P-SCAD

• Awareness and recognition of P-SCAD is critical to the diag- nosis. Acute myocardial infarction (AMI) in pregnancy should be treated similarly to AMI in the general population [8].

• A multidisciplinary approach between cardiology and obstet- rics is mandatory as data is lacking regarding the safety of guideline directed medical therapy (GDMT) in pregnancy. Expert opinion is that low dose aspirin (ASA), beta-blocker (BB) therapy and short-term heparin during percutaneous in- tervention (PCI) are reasonable therapies [8].

• The most experienced operators, due to the risk associated with PCI, should undertake revascularization. Generally, cor- onary intervention should be limited to cases that are unstable. The approach to P-SCAD must be determined on a case-by- case basis by the multidisciplinary team [8].

Case 2

29-year-old female was in her sixth month of pregnancy. She had no prior personal or family history of cardiovascular disease. She had experienced a prior miscarriage. The miscarriage was emo- tionally draining and resulted in depression. Psychology consulta- tion resulted in treatment for anxiety and depression.

Resting at home, she developed chest pain, nausea, and loss of consciousness. Emergency medical services were summoned and the paramedics performed an ECG revealing ST elevation infero- laterally (Figure 5). Upon arrival to the emergency room, she de- veloped ventricular fibrillation requiring cardiac defibrillation to restore sinus rhythm.

                 Figure 5: ECG revealing ST elevation inferiorly and laterally.

In the intensive care unit, the patient was hemodynamically sta- ble with an infusion of intravenous dobutamine. She was alert and cognitively intact. Urgent echocardiography revealed an akinetic apex with hypercontractile basal segments. LVEF was estimated to be 35%. There was no associated outflow tract obstruction. There was mild mitral regurgitation. Urgent angiography revealed nor- mal coronary arteries. Laboratory results revealed a mildly elevat- ed troponin and normal electrolytes. The patient was treated with a beta-blockers and diuretic. She clinically recovered without chest pain, shortness of breath, or further rhythm disturbance. Troponin levels normalized and the ECG evolved from ST elevation to in- verted t waves inferolaterally. Repeat echocardiography on day 7 revealed normalization of the apical hypokinesis. LVEF = 60%. The patient was discharged home and at nine months gave birth via caesarian section to a healthy baby without newborn cardio- vascular deformity.

Takotsubo cardiomyopathy in pregnancy (P-TC)

This case represents a rare form of P-TC with a malignant, life-threatening rhythm disturbance. There is no available evi- dence that pregnancy predisposes to a stress-induced cardiomy- opathy. The majority of stress induced cardiomyopathies recover to normal LV function. In patients where LV dysfunction persists, GDMT is the standard of care and the criteria for implantation of an implantable cardio-defibrillator are determined on a case-by- case basis [9,10].

Takotsubo cardiomyopathy (TC) is a unique form of transient non-ischemic cardiomyopathy that typically occurs in a setting provoked by a stressor - physical, emotional, or both - and hence, is also given the nickname of stress-induced cardiomyopathy. The syndrome occurs most commonly in post-menopausal females. The characteristic clinical syndrome of TC involves acute LV dysfunction with distinctive echocardiographic feature of apical to mid ventricular hypo- to akinesis and sparing of the basal myo- cardium in the absence of significant obstructive coronary artery disease (CAD).

Alternatively, patients may exhibit reverse TC with basal hypoki- nesis and hyperkinesia of the apical and mid segments of the left ventricle [11]. Even though the apical ballooning phenotype is the most common and typical presentation, much confusion has result- ed from various nomenclatures being used for different presenta- tions of this syndrome. A well-recognized syndrome now, it is also being reported in populations other than postmenopausal women. The occurrence in premenopausal women is rare, and a literature search reveals there are few cases reported in pregnancy [11].

Patients usually present with typical chest pain (70-90%) and dys- pnea (20%); other less common presentations include syncope, pulmonary edema and cardiac arrest [10]. Dynamic electrocardio- graphic changes and elevated cardiac biomarkers (reflecting acute myocardial injury) are usually present [11]. Coronary angiogra- phy, however, typically does not reveal any evidence of epicardial coronary obstruction. However, patients with CAD can experience stress-induced cardiomyopathy. Symptoms can be severe and lead to death in 2% of patients [12]. Song and colleagues reported 32% (n = 16) of their patients with TC (n = 50) presented with cardio- genic shock as the initial presentation [1].

The most common electrocardiographic changes reported in TC are ST-segment elevations in precordial leads on admission (range, 46-100% of patients). Subsequent deep symmetrical T-wave in- version in multiple leads and Q-wave formation (range, 6-31% of patients) are frequently found [9,10]. Also, QT interval prolonga- tion (range, 450-501 ms) can be present [8,13]. The combination of clinical symptoms and electrocardiographic changes at patient’s initial presentation makes differentiation of TC from ACS very challenging. Most TTC patients present with elevated cardiac bio- markers and have a modest peak in levels within 24 hours, but levels are markedly lower than would be anticipated on the basis of the extent of wall motion abnormalities and electrocardiogram findings [14-17].

Management focuses on supportive care in the acute phase, while avoiding vasopressor medications because hyperdynamic basal LV can result in outflow tract obstruction. Mortality is low if patients survive the initial critical period and, by definition, they go on to have a full recovery. Recurrence has been reported but recurrences are rare. TC follow-up revealed the rate of major adverse cardiac and cerebrovascular events were 9.9% per patient year, and the rate of death was 5.6% per patient year [17].

Take Home Messages For P-Tc

• P-TC is very rare

• P-TC ventricular arrhythmias are rare

• Patients with P-TC presenting with an acute coronary syn- drome (ACS) should be managed according to guidelines for the general population including revascularization techniques [8].

• P-TC patients presenting with heart failure (HF) should be treated according to HF guidelines. Management goals are similar to non-pregnant HF therapy, while avoiding medi- cations toxic to the fetus including angiotensin converting enzyme (ACE) inhibitors, angiotensin 11 receptor blockers (ARBs), angiotensin - nephrilysin inhibitors (ARNI), aldo- sterone receptor antagonists (MRA) and atenolol. HF with congestion should be treated with loop diuretics, but avoided if feasible due to potential reduction in placental blood flow. Hydralazine and nitrates are safe in pregnancy, although less effective than ACE inhibitors, and should only be used in the presence of hypertension and LV dysfunction with or without congestion. Beta-blockers should be up- titrated starting at low dose to desired effect [8].

• Management of electrical disturbances in P-TC can include: cardioversion, as it is presumed safe in all stages of pregnancy as it does not compromise fetal blood flow. The risk of fetal arrhythmias or initiation of pre-term labor is low [8].

Case 3

25-year-old female presented to the emergency room with severe shortness of breath and hypoxia. She had delivered a full-term baby girl via caesarian section and was discharged five days pre- viously. She was short of breath post-delivery and upon discharge. She became progressively shorter of breath. Her chest X-ray re- vealed diffuse alveolar infiltrates suggesting pulmonary edema.

Cardiology was consulted. She was hemodynamically stable with a blood pressure of 160/90 and heart rate of 95 bpm. Respiratory rate was elevated at 20 per minute. Her jugular venous pressure (JVP) was elevated and she had a 2/4-holosystolic-murmur at right 4th intercostal space. There was no leg edema.

An urgent echocardiogram revealed an enlarged RV with de- creased systolic function with severe tricuspid regurgitation (TR) and estimated pulmonary artery systolic pressure (PASP) was 55 mm Hg (Figure 6). LV systolic function was normal. Treatment included a beta-blocker, diuretic, and low dose angiotensinogen converting enzyme inhibitor. An urgent CT pulmonary angiogram was negative for pulmonary embolism. The working exclusionary diagnosis became amniotic fluid embolism (AFE).

Figure 6: TR envelope is 3.35 m/sec. The RV - RA gradient + RAP (10 mmHg) ~ 55 mmHg

She stabilized clinically with improved hemodynamics and respi- ratory status. She was discharged on medical therapy. In 6 weeks, she had a repeat echocardiogram revealing normal LV systolic function, decreased RV size, and mild TR with an estimated PASP = 25 mm Hg. The patient and the baby were both doing well. Pul- monary embolism versus Amniotic Fluid Embolism in Pregnancy (P- PE/AFE) Pregnancy and the puerperium are well-established risk factors for venous thromboembolism and anaphylactic syn- drome of pregnancy related amniotic fluid embolism. Both pulmo- nary embolism (PE) and amniotic fluid embolism (AFE) should be considered in a pregnant or post-partum patient with hypotension, hypoxia, hypertension, and right heart failure [18].

There are no clinical symptoms or signs that are specific for pul- monary embolism (PE). There is an overlap between symptoms of PE and normal physiologic changes of pregnancy [18]. Thus, iden- tifying a clinically important PE during pregnancy, or post-partum, is challenging. It is essential that clinicians understand the poten- tial for over diagnosing and under diagnosing PE during pregnan- cy. PE is a common cause of death in the hospital and should al- ways be considered when pregnant patients have tachycardia and shortness of breath.

Diagnostic considerations include D-dimer levels, leg ultrasound imaging, and CT pulmonary angiography (CTPA). CTPA has high sensitivity and specify (100%, 89%) for detecting pulmonary em- boli [19,20]. Rapid diagnosis leads to appropriate anticoagulation therapy and improved survival of the infant and mother. Undiag- nosed PE has a mortality rate approaching 30%, which is reduced to approximately 2-8% when diagnosed and treated appropriately [21,22].

When the CTPA is negative for a pulmonary embolism there should be thoughtful consideration for AFE. AFE is a rare and potential fatal obstetric emergency. AFE may occur during pregnancy, but is more commonly identified during labor and early post-partum. Risk factors for AFE include fetal distress, maternal age, placental abnormalities, eclampsia, polyhydramnios, cervical lacerations, and cesarean section, and rapid delivery. AFE is an allergic like reaction to amniotic fluid entering the mother’s circulation. Man- agement is monitoring and treating the respiratory, cardiovascular, and hematological perturbations that arise. AFE is not preventable, but it is essential to recognize it and treat it expectantly [23].

Take Home Message For P- Pe/Afe

• Pulmonary emboli (PE) and deep venous thrombosis (DVT) are known etiologies of pregnancy related morbidity and mor- tality. The risk of venous thromboembolism (VTE) is para- mount in the immediate post-partum period and does not re- turn to normal risks until 6 weeks post-delivery. A high index of suspicion and low threshold for investigation is imperative in pregnant patients [8].

• The optimum diagnostic approach for pregnant females is undefined. A Wells score in combination with D-dimer (low specificity in pregnant patients) testing is a strategy attempting to determine when imaging is needed. A negative D-dimer is helpful, but low D-dimer concentrations have been observed in normal pregnancies [8].

• If VTE suspicion is high, then compression ultrasonography should be performed and if negative, but suspicion remains high, then further testing with low-dose CT scanning should be performed [8].

• When the suspicion is high and testing is underway, the pa- tient should be treated with low molecular weight heparin (LMWH). LMWH is the drug of choice for treatment of VTE in pregnancy and the puerperium [8].

• When CTPE is negative, AFE is the diagnosis of exclusion and careful monitoring is necessary with treatment of organ system complications [23]. 

Case 4

21-year-old primigravida female presented to the emergency room at 32 weeks of gestation. She had a 7-week history of progres- sive shortness of breath associated with central chest pressure and tachycardia. She had not sought prior medical care. She was un-aware of any health issues. On physical examination she had tachy- cardia at 110 bpm and tachypnea with a respiratory rate of 22 per minute. Blood pressure was 100/60. Jugular venous pressure was elevated to the angle of the jaw while sitting up. She had a right parasternal heave and lower extremity-pitting edema. Her second heart sound was accentuated. She had a pan-systolic murmur at the right sternal border. The electrocardiogram revealed P pulmonale, RAD, and RV strain pattern. The chest X-ray revealed prominent RV silhouette and dilated pulmonary arteries. The echocardiogram revealed severe RV dilation and hypertrophy (RVH), moderate RV systolic dysfunction, a large right atrium (RA), severe PR, severe TR, plethoric IVC with a calculated right ventricular systolic pres- sure (RVSP) of 80 mm Hg (Figure 7) and the plethoric inferior vena cava (IVC) revealed systolic flow reversal in the hepatic vein (HV). The mitral inflow Doppler and tissue Doppler were normal.

Discussion

Heart disease is the leading cause of death for women. Women often experience heart disease differently than men. For exam- ple, men have more heart attacks than women, but women have a higher heart attack death rate. Women experience higher bleeding rates during percutaneous coronary interventions (PCI) performed through femoral arterial access. Women are also more susceptible to drug-induced cardiac arrhythmias.

FDA’s Office of Women’s Health (OWH) supports research to provide valuable insight into sex differences in the diagnosis and treatment of cardiovascular disease. OWH has worked across sev- eral FDA Centers to support studies on issues ranging from sex differences in cardiac interventions to the cardiotoxicity of breast cancer drugs. Since 1994, OWH has funded 69 studies (14 ongo- ing and 55 completed). The results of the completed studies have led to a better understanding of cardiovascular disease in women and contributed to the development of guidance documents for drug and device development for men and women.

Current OWH-funded Research on Heart Disease. Completed OWH-funded Research on Heart Disease. Research on the Effects of Drugs on Women’s Heart Health. QT Prolongation: Research on the Effects of Drugs on Women’s Hearth Health. The FDA Of- fice of Women’s Health has been a leader in supporting research to better understand and predict drug-induced heart arrhythmias in women. Heart rate is controlled by electrical signals that pass through the heart each time it contracts and relaxes. These signals make up the heart’s electrical cycle – which is commonly mea- sured by the waves on an electrocardiogram (ECG).

When the heart’s electrical cycle is abnormal, this can cause irreg- ular heart rhythms (arrhythmias). A type of arrhythmia more com- mon in women than in men is Torsade de Pointes (TdP). TdP events are rare but dangerous and can lead to sudden death. Several drugs have the potential to cause TdP and up to 70% of the drug-induced cases of TdP occur in women. Almost all drugs that cause TdP pro- long the QT-interval on the ECG (which corresponds to the heart’s relaxation phase). Since TdP events are rare, the drug-induced pro- longation of the QT-interval on the ECG is used as an indicator for increased risk of TdP. Since its inception in 1994, the Office of Women’s health has worked with FDA’s other research programs to support studies on drug-induced QT prolongation.

Phase 1: Understanding the Sex Differences

The exact reason for the higher rate of drug-induced TdP in wom- en is unknown. However, a number of factors may play a role in this sex difference including higher drug levels in women due to smaller body size, influence of sex hormones, differences in how drugs are broken down and transported to the heart or greater sen- sitivity to drugs that cause abnormal heart rhythms. OWH fund- ed studies to understand the mechanism of the sex differences in drug-induced QT prolongation. OWH also funded research within the Center for Drug Evaluation and Research (CDER) enabling post-market drug analysis to better recognize drug safety effects in women.

Learn more about current OWH-funded research on QT and other CVD topics. Learn about other FDA CVD research at the National Center for Toxicological Research

Phase 2: Supporting the Development of FDA Guidance

Building on the previous studies, OWH partially funded additional research on metabolic drug-drug interactions that contribute to QT prolongation. This research contributed to FDA guidance on the assessment of the QT prolongation potential of drugs for both men and women. As part of this guidance, FDA recommended that drug sponsors conduct a comprehensive study, called the Thorough-QT (TQT) study when seeking FDA approval of a new drug. The TQT study, implemented in 2005, has been an effective screening tool. Although certain commonly used drugs, such as antihistamines and antibiotics, had to be withdrawn from the US market because of drug-in.

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