Classic risk factors for development of ischemic heart disease are relevant for women as well as men as seen in the INTERHEART study, a worldwide case control study of close to 30,000 people in 52 countries. The study estimated that 90 % of the risk of MI is attributable to nine measureable risk factors: smoking, dyslipidemia, diabetes mellitus, hypertension, obesity, psychosocial stress, poor diet, lack of regular exercise, and alcohol consumption. Traditional risk factors are highly prevalent in women. However, certain risk factors place women at greater risk then men. There is a higher prevalence of obesity in women, especially extreme obesity with body mass index (BMI) ≥40 kg/m² [59]. Obesity infers greater risk of diabetes mellitus, hypertension, and is an independent risk factor for CVD, increasing mortality [60]. Women also have a higher prevalence of diabetes, and diabetic women have at least a three-fold greater risk of IHD than non-diabetics [61]. The risk of fatal IHD was shown to be 50 % higher in diabetic women as compared to men, in a meta-analysis of 37 prospective cohort studies [62]. Similarly, hypertensive women have a two to three fold increased risk of coronary events [63]. The metabolic syndrome consisting of the constellation of central obesity, glucose intolerance, hypertension, and dyslipidemia places women at the highest risk of developing IHD, to a greater extent than men with the metabolic syndrome, or either gender without the combination [64]. Female specific risk factors such as preeclampsia of pregnancy, doubles the risk of developing ischemic heart disease later in life [65]. Gestational diabetes and hormonal changes due to ovarian dysfunction [61], or the reductions in female specific hormones such as estrogen and progesterone that occur with menopause all increase a women’s risk of developing cardiovascular disease. Importantly though, hormone therapy such as estrogen replacement is not recommended for primary or secondary prevention of CVD in women based on current guidelines [12].

The management of SIHD requires an intensification of lifestyle changes and risk factor reduction including aggressive lipid lowering directed at secondary prevention of future cardiac events. All cardiovascular risk factors should be modified in SIHD, and are recommended as Class I therapies (benefit outweighs risk) by the ACCF/AHA guidelines for SIHD [12]. Clinicians should aim to modify risk factors for primary and secondary prevention in women according to these guidelines which are described in more detail in the preceding dedicated chapter.

Patient education is key to successful lifestyle changes and risk factor modification. Dietary improvements reduce risk of cardiovascular events by decreasing the prevalence and severity of modifiable risks such as hypertension, dyslipidemia, and hyperglycemia. Smoking is the single most important preventable cause of IHD in women, especially in women younger than 50 years of age [66]. Smoking cessation and avoidance of second hand smoke improves endovascular function and reduces atherogenesis [67]. A retrospective look at patients with IHD comparing those who quit smoking to ongoing users found an estimated 36 % relative risk reduction in overall mortality [68]. Utilizing behavioral and pharmaceutical therapy in addition to the clinician’s constant recommendation to quit smoking can significantly improve chances at success.

A weight loss approach with strong emphasis on limiting caloric intake, along with a diet low in saturated fats and cholesterol while high in fresh fruit, vegetables, and whole grains, should be the cornerstone of the clinician’s dietary advice. The cardio-protective effects offered by daily consumption of fruits or vegetables, moderate consumption of alcohol three or more times per week, and moderate or strenuous physical exercise were stronger comparatively in women then men [69]. Setting patient goals based on weight and waist circumference allow self-monitored indicators that provide ongoing feedback and results, without clinic visits. The ACCF/AHA guidelines recommend reaching a BMI of 18.5–24.9 kg/m², and maintenance of a waist circumference less than 35 in. in women [12]. Many patients have difficulty in making drastic changes to their diet and benefit from a referral to a dietician.

Exercise regimens are an integral part of a successful weight loss and cardiac rehabilitation approach, which not only reduces the risk of future cardiac events but also helps in symptom control. Women tend to see greater benefit in adopting even a modest increase in regular physical activity. Benefits of exercise have been shown to improve female specific risk factors, particularly those associated with microvascular angina. Positive cardiovascular effects of exercise in women with SIHD are associated with beneficial changes in lipid levels, blood pressure, inflammation, endothelial function and autonomic regulation [70–72]. There is likely a dose–response relationship between exercise intensity and duration and the benefits seen in cardiovascular protection. The difficulty for most clinicians is the fact that a majority of women diagnosed with SIHD are older and partake in little to no daily physical activity at baseline.

There are differing guidelines for the amount and intensity of prescribed physical activity for prevention of cardiovascular disease development and reduction of future events. Current ACCF/AHA guidelines recommend 30–60 min of moderate-intensity aerobic activity preferably daily or at least five times a week [12]. The definition of moderate-intensity activity is what requires 3 to <6 MET (metabolic equivalent of task). Brisk walking is considered the minimal strenuous exercise qualifying as moderate-intensity. As walking is the most common leisure exercise among US adults, it is a good starting point, providing the pace is brisk. As a reference, 6 METs is obtained by reaching 5 min on a standard treadmill Bruce protocol, which is 2.5 mph at a 12 % grade. For most women with SIHD, the clinician can reasonably recommend starting an exercise regimen without the need for a medically supervised program.

Some patients, such as those with a history of multiple MI’s, cardiac arrest, known severe functional impairment, or known residual exercise-induced ischemia on treadmill testing are considered to be at high risk of cardiac complications during exercise. This high-risk group should be referred for a medically supervised exercise program for 8–12 weeks to establish the appropriate prescription for a safe exercise regimen [12]. Specific patients who also should be referred for cardiac rehab include: post-MI, post-coronary revascularization either by (PCI) or surgically with coronary artery bypass grafting (CABG), valvular surgery, pacemaker or defibrillator implantation, cardiomyopathy, and compensated congestive heart failure. Cardiac rehab programs have a set protocol that increase intensity and duration of exercise while monitoring heart rate, blood pressure, and symptoms by physical therapists or exercise physiologists. Patients should continue participating in cardiac rehab until they are able to safely perform adequate exercise that is in line with their needs and health goals.

Aspirin is a cyclooxygenase inhibitor, which is indicated for lifelong secondary prevention in all patients with IHD. It provides benefit through prevention of platelet aggregation that leads to coronary thrombosis from plaque rupture. A reduction of 37 % in serious vascular events using aspirin therapy was found by meta-analysis of trials with nearly 3,000 patients with SIHD [73]. The optimal dose to obtain vascular protection and minimize risk of gastrointestinal side effects such as bleeding had been contentious, but was found in the same analysis to be as efficacious using 75–162 mg with less risk of bleeding compared to 325 mg. Providers should make an effort to reduce the dose to minimize risk of bleeding in patients who are using high dose aspirin for cardiovascular prevention. If intolerance or allergy to aspirin exists, substituting a thienopyridine such as clopidogrel which inhibits adenosine diphosphate (ADP) receptors, and provides anti-platelet effect with at least an equal risk reduction in recommended [74]. In patients who undergo PCI with intracoronary stent placement, use of both aspirin and an ADP receptor inhibitor is required for at least 1 month and up to 1 year depending on the type of stent, bare metal requiring less time than drug eluting. The use of dual anti-platelet therapy allows time for the stent to become covered by endothelial cells thereby eliminating direct contact of the metal with blood, and reducing the risk of acute stent thrombosis. At the end of the recommended time for dual anti-platelet therapy, reducing therapy to low dose aspirin alone is acceptable. Using both aspirin and clopidogrel long term for secondary prevention in SIHD was shown by the CHARISMA trial to have no significant benefit over aspirin alone [75]. However post-hoc analysis showed that high-risk groups including patients with recent MI, peripheral vascular disease, and ischemic stroke, did have less cardiovascular events with dual anti-platelet therapy. The use of long-term dual anti-platelet therapy may be beneficial in certain high-risk patients when preventive benefit outweighs the increased bleeding risk [12].

ACE’s and ARB’s are cardioprotective medications that provide positive effects in SIHD as well as anti-hypertensive action, prevention of nephropathy in diabetes, and beneficial effect in treatment of cardiomyopathy. These effects have been shown to significantly reduce cardiovascular events including MI and death in patients with reduced LVEF [76]. Initiation of ACE inhibitor therapy has also been shown to reduce mortality in the immediate post MI period [77]. ACE inhibitors may offer additional benefit in women based on the positive effects on vascular function and additional angina reduction [78]. An improvement in vascular function as measured by invasive coronary reactivity testing in women with MVA was shown in the WISE study after 16 weeks of therapy with the ACE inhibitor quinapril [79]. The response was strongest in women with the greatest baseline vascular dysfunction, and there was a statistical improvement in angina episodes also seen in the ACE inhibitor group compared to placebo. ACE inhibitors as a class are recommended for all patients with SIHD and either hypertension, diabetes mellitus, reduced LV function, or chronic kidney disease, unless contraindicated. ARB therapy has shown similar reductions in cardiovascular events though statistically less than ACE inhibitors making them a suitable replacement in SIHD for patients who are unable to tolerate ACE inhibitors [12]. Importantly, ACE inhibitors and ARB’s are contraindicated during pregnancy. Before initiating these medications, younger pre-menopausal women should be asked about the possibility of being pregnant.

The use of HMG-CoA reductase inhibitor statin therapy in primary and secondary prevention of cardiovascular disease is well described and detailed in an earlier chapter of the book. In women with SIHD, data has shown lower is better even when compared to men. The data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombosis in Myocardial Infarction (PROVE IT-TIMI 22) trial found high dose statin therapy further reduced cardiovascular endpoints over standard dose therapy [80]. The reduction was enhanced more in women then men with established CVD. A low density lipoprotein (LDL) goal of <70 mg/dL was reached in 65 % percent of the women in the high dose group who obtained even greater risk reduction than men. The study found high dose statin therapy offered an additional 25 % relative risk reduction compared to standard dose therapy. Updated AHA guidelines recommend treatment of women with SIHD to a goal LDL cholesterol <100 mg/dL, and intensive LDL reduction in high-risk women preferably to <70 mg/dL [81]. It should be the primary lipid goal for clinicians to prevent progression of cardiovascular disease in women. There is also evidence proving statin therapy in addition to reducing atherosclerosis, improves vascular function by reducing vasoconstriction and increasing vasodilation through an endothelial mediated effect [82]. These endothelial, or pleiotropic effects may improve symptoms of angina mediated by inflammation and vascular dysfunction. Though more research is needed specifically in women, intensive statin therapy may have a larger role in prevention of cardiovascular events and in treatment of MVA.

Niacin, nicotinic acid, or vitamin B3 is a broad-spectrum lipid-regulating agent that has been used for decades prior to the statin era to reduce cardiovascular events. Niacin exerts its effects on both cholesterol metabolism and non-lipid mediated vascular protective effects [83]. The data for reduction in cardiovascular endpoints has been mixed with old pre-statin randomized controlled trials showing benefit in secondary prevention compared to placebo [84]. The AIM-HIGH trial randomized 3,414 patients, 14.8 % female with known CAD and on intensive statin therapy to extended release high dose niacin or placebo [85]. The trial concluded early after 3 years follow up when no significant difference was found in cardiovascular events, though HDL was increased and triglycerides lowered significantly. Though the data remains mixed, current guidelines for SIHD recommend use of high dose niacin alone if intolerant to statins, or in combination with a statin to reach established lipid goals.

Based on ACCF/AHA guidelines for SIHD, beta-blockers are recommended as first line therapy for treatment of angina for both men and women [12]. They act through multiple mechanisms that reduce myocardial oxygen consumption. Reduction in heart rate (chronotropy) allows increased diastolic time, when filling of the myocardial vasculature occurs. A decrease in myocardial contraction (inotropy) and arterial afterload additionally lowers the workload imposed on the heart. In addition to angina relief, post-MI or ACS patients have a mortality benefit with use of beta blocking agents. Beta blockers should be utilized even in absence of angina for at least 3 years if left ventricular function is preserved, and indefinitely if LV function is 40 % or less [86]. Additional benefits have been noted in newer generation of beta-blockers. These effects can offer additional angina relief for individual patients. Carvedilol has vasodilatory effects and additional sympathetic alpha blockade that increases symptom relief in women with MVA [87]. Nebivolol has been shown to additionally improve endothelial function through antioxidant properties that reduce markers of inflammation [88]. A reasonable approach for the clinician managing angina symptoms is trialing alternate beta-blockers particularly in women with non-obstructive coronary artery disease who continue to have symptoms on recommended doses of initial beta-blocker choice.

Nitrates are an effective therapy for occasional and chronic angina symptom relief. Short and long-acting formulations of nitroglycerin rapidly cause direct vasodilatory effect on the epicardial arteries increasing oxygen delivery to the myocardium. Through decreasing preload, myocardial wall tension is lowered, in turn reducing ischemia and lowering blood pressure. The blood pressure lowering effect of nitrates can be dose limiting. Nitrate therapy has been shown to be effective in SIHD from both obstructive CAD and in women with microvascular angina. No clinical trial has directly evaluated the use of nitrates in patients with MVA, though an observational study of 99 patients with cardiac syndrome X found effective angina relief in 50 % of the patients [50]. Multiple formulations exist including sublingual dissolving tablets, mucosal sprays, topical pastes, and long-acting oral formulations of nitroglycerin such as isosorbide dinitrate and isosorbide mononitrate. Important caveats for the clinician using nitrate therapy include using the lowest dose that provides symptom control and educating patients to maintain nitrate free intervals of 10–14 h daily to prevent tolerance to the long-acting formulations. Long-acting preparations of nitrates do not cause tolerance to sublingual nitroglycerin, which should be also prescribed for immediate angina relief. The increasing need for quick acting nitroglycerin tablets or spray should key the clinician to worsening symptoms and the need for re-evaluation of the patients IHD. Directions should be given to all patients to present for immediate evaluation in an emergency room setting for angina symptoms not relieved after using 2–3 doses of short acting nitroglycerin. Patients should be reminded that sublingual nitroglycerin tablets lose potency within 6–12 months of opening the bottle and must be stored in the manufacturers container at all time.

Calcium channel blockers (CCBs), including the dihydropyridines: nifedipine and amlodipine, or the non-dihydropyridines: such as verapamil and diltiazem are the last major class of proven anti-anginal medications [89–91]. The effect of calcium channel blockade is a reduction in coronary vascular resistance with increased myocardial perfusion, coupled with decreased systemic arterial pressure. Negative inotropic and chronotropic response of the myocardium reduces oxygen demand and provides exertional angina relief [92]. Caution must be used with existing conduction defects due to sinus node depression and slowing of atrioventricular node conduction that can lead to bradycardia and heart block. This effect is more pronounced with the non-dihydropyridines diltiazem and verapamil and is augmented when used in combination with any beta-blocker. Use of the dihydropyridines amlodipine or nifedipine are least likely to cause excessive heart rate reductions or heart block, but can be limited by their strong effects on lowering blood pressure. Additionally in patients with reduced left ventricular ejection fraction and heart failure symptoms, calcium channel blockers should generally not be used due to worsening of cardiac contractility [93]. CCBs can be equally efficacious in treating angina in patients with intolerance to beta-blocker therapy, and is the recommended substitute. In select patients without conduction defects, combining calcium channel blockers with beta-blockers can provide additional symptom relief. In women with vaso-spastic angina, CCBs are the preferred therapy due to their direct coronary vasodilatory effects [87]. The drug interactions of calcium channel blockers (by utilizing cytochrome P450 metabolism) include amiodarone, digoxin, simvastatin, lithium, cyclosporine, and carbamazepine. Elderly women are more prone to drug interactions in general and clinicians should be aware of the possibilities and monitor them more carefully.

Ranolazine is among the new antianginal drugs approved by the FDA in 2006 that work in an alternate manner compared to the standard therapy classes. Acting through inhibition of the late inward sodium current and decreasing the sodium dependent calcium current during ischemia, it reduces ventricular diastolic tension and myocardial oxygen consumption. Importantly, there is little to no effect on heart rate or blood pressure [12]. As shown in the CARISA and MERLIN TIMI-36 trials, ranolazine reduced the use of sublingual nitroglycerin and angina attacks in men and women [94, 95]. Women with MVA experienced a 29 % further decrease in angina symptoms as compared to men, and ranolazine may be particularly useful in treating women with SIHD without obstructive coronary artery disease [87]. Ranolazine has QTC prolonging effects that have not shown to be pro-arrhythmic alone, but should be used cautiously in combination with other QTC prolonging therapies including anti-arrhythmic drugs [12]. Ranolazine should not be used as initial therapy for angina, but can be useful as an adjunct to first line beta-blockers, CCBs, or both for the control of symptoms in women with SIHD from obstructive CAD, or microvascular disease.

A few drugs worth mentioning are currently not available in the USA, but approved and used in Europe and elsewhere for angina relief in both men and women. Ivabradine is an inhibitor of the “funny channel” (If) that is highly expressed in the sinoatrial node. Through inhibition of this mixed Na-K channel, Ivabradine lowers heart rate and offers similar negative chronotropic effects as beta blockers [87]. Nicorandil is a dual vasodilator with effect on both venous and arterial tone. It is a combined K-channel opener and a nitric oxide donor. The net effect is an increase in myocardial oxygen delivery and reduced demand [96]. Trimetazidine is a drug with antianginal properties not completely understood but thought to be secondary to inhibition of fatty acid oxidation. By altering the substrate for myocardial metabolism, it shifts energy production to glucose, which is more efficient in an environment with low oxygen delivery such as exercise-induced ischemia [97].