Mohammed Waseem Akhter
Craig S. Smith
This chapter focuses on the common presenting symptoms and conditions of cardiovascular disorders and the differential diagnoses to be considered in the evaluation of the patient. Chest pain, dyspnea, syncope/sudden cardiac death, hypertension, and dyslipidemia are discussed and further subdivided by clinical presentation and diagnostic approach.
Coronary artery disease (CAD) is the most common form of heart disease and is the leading cause of mortality globally accounting for 13% of all deaths per year. In the United States alone, 370,000 people die annually from CAD.
Chest pain is a common presenting symptom for patients with ischemia due to obstructive CAD. Other associated complaints include shortness of breath, heartburn, nausea, light-headedness, and cold sweats. All patients with chest pain require a careful evaluation since the differential diagnosis for this presentation can range from benign musculoskeletal injury to a life-threatening condition such as an acute myocardial infarction (AMI).
The initial goal of clinical assessment (incorporating a thorough history and physical plus ancillary testing) is to differentiate noncardiac chest pain from discomfort from cardiac etiologies.
Noncardiac chest pain can still be associated with significant morbidity and mortality from conditions such as aortic dissection, pulmonary embolism, tension pneumothorax, pericardial tamponade, and mediastinitis. However, the assessment and treatment strategies for these conditions vary drastically from those for cardiac chest pain.
Chest discomfort related to CAD occurs in <2% of outpatient chest pain visits as opposed to 15% of emergency room visits.
When clinical suspicion (based on a patient’s risk profile) is high, the chest pain is likely to be indicative of either myocardial injury or infarction. This is clinically described as an acute coronary syndrome (ACS). At the lower end of the spectrum is unstable angina (UA; chest pain without positive cardiac biomarkers), progressing in severity to a non-ST-segment elevation myocardial infarction (NSTEMI) and then a ST-segment elevation myocardial infarction (STEMI).
The pathogenesis for all forms of ACS is an imbalance between myocardial oxygen supply and demand most commonly from a reduction in coronary artery blood flow (most often due to luminal narrowing from atherosclerosis, vasoconstriction, or coronary embolism).
Cardiac troponins (cTn) I and T are preferentially expressed in the heart and a part of the contractile apparatus of the myocyte. The injury is acute if there is a dynamic rise and/or fall of troponin. It is, however, chronic if there is a persistent elevation only.
Myocardial injury is frequently seen in ACS and is defined by an elevation in cTn value above the 99th percentile upper reference limit (URL).
To establish a diagnosis of an AMI, myocardial necrosis has to be present along with clinical signs and symptoms of ischemia, and electrocardiographic changes. Supportive data from invasive or noninvasive imaging studies and pathology investigations can aid in diagnostic accuracy.
Whether there are ST elevations (STEMI) or no ST elevations (NSTEMI) on the presenting electrocardiogram influences the decision-making
process for both triaging and treatment of patients. There are significant differences in clinical outcomes between the two types since they represent unique mechanisms in terms of the etiologies of myocardial damage.
Cardiac sources of chest pain:
▼ Ischemic/nonatherosclerotic—aortic stenosis, hypertrophic cardiomyopathy (HCM), severe systemic hypertension, right ventricular hypertension, aortic regurgitation, severe anemia, coronary vasospasm, anatomical abnormalities
▼ Inflammatory—pericarditis, infectious and autoimmune vasculitis
▼ Hyperadrenergic states—stress cardiomyopathy, severe hypertension, pheochromocytoma
▼ Chest pain syndromes—mitral valve prolapse, psychosomatic
Noncardiac sources: Gastrointestinal (gastroesophageal reflux disease, esophageal rupture, esophagitis, esophageal motility/achalasia, referred pain—biliary colic, appendicitis), pulmonary (pneumonia, pulmonary embolism, pulmonary hypertension, sarcoidosis, effusion, pneumothorax, pleuritis, serositis), aortic, musculoskeletal, psychosomatic
□ Who Should Be Suspected?
When ischemic heart disease manifests acutely, it is called an ACS. The main cause is varying degrees of coronary occlusion/thrombosis due to superficial plaque erosion or plaque rupture.
The pretest probability of existing CAD influences the likelihood that a chest pain presentation is from an ACS.
Due to the morbidity and mortality associated with this condition, there should be an emphasis on keeping it as a primary working diagnosis, subject to diligent and repeated review clinically and biochemically, until it is decisively ruled out.
UA and NSTEMI are closely related clinical conditions with similar pathophysiology but differing severity. NSTEMI is usually characterized by ischemic chest discomfort at rest, absence of ST-segment elevation on a 12-lead ECG, and positive necrosis biomarkers.
As an elevation of cardiac biomarkers may not be immediately evident, UA and NSTEMI may be initially indistinguishable. However, the distinction is important to make for early acute management. Increasing evidence supports early aggressive anticoagulation and mechanical revascularization as superior to conservative medical therapy for NSTEMI patients.
UA presents as three scenarios: ischemic discomfort at rest (approximately 20 minutes’ duration), new-onset discomfort at mild exercise threshold in the last 6 weeks, or progression of previously stable angina to easily evoked with ordinary physical activity or increased in severity (Canadian Cardiovascular Society Class III).
UA should be differentiated from stable angina pectoris. While similar in character, stable angina pectoris represents short-lived chest discomfort elicited from states of higher cardiac demand that is relieved with rest and is without a crescendo pattern as described above.
Because of a lack of objective data for diagnosis, UA is the most subjective of the ACS diagnoses. Nevertheless, history/exam, ECG, and cardiac biomarkers on presentation can be utilized to formulate a likelihood of an ACS diagnosis.
Elderly, diabetic, and female patients are more likely to present with ACS symptoms that do not include chest pain. Rather, symptoms may include dyspnea, diaphoresis, emesis, or hypotension.
Many biomarkers have emerged and are used as diagnostic tools in ACS. These include CK, CK-MB, troponins I and T and high-sensitivity (hs) cTn, LDH, and myoglobin. To varying extents, these are all elevated in ACS. Troponin, due to its high specificity, is the preferred gold standard to test for myocardial injury. After the onset of symptoms, it is elevated at 3-6 hours and can stay high up to 10 days. It has the added advantage of providing prognostic information especially for mortality.
It is for this reason that the American College of Cardiology and American Heart Association guidelines endorse using troponin as the preferred biomarker to differentiate between UA and an AMI (STEMI/NSTEMI).
The initial therapy for ACS includes the use of potent antiplatelet agents, intravenous anticoagulants, and statin drugs. Dual antiplatelet therapy is superior to monotherapy in the setting of an AMI.
The effectiveness of an antiplatelet drug can be determined with assays that measure platelet reactivity to adenosine diphosphate (ADP) ontreatment. High platelet reactivity to ADP is associated with increased ischemic events, while lower reactivity can result in increased bleeding. Routine testing for platelet function with the intent of adjusting drug dosing in patients with ACS has not been endorsed by results from randomized controlled trials. This practice can therefore not be supported based on available data.
□ Who Should Be Suspected?
An AMI is diagnosed clinically in the presence of an abnormal cardiac biomarker along with at least one of the following signs or symptoms of myocardial ischemia:
▼ Symptoms of acute myocardial ischemia
▼ ECG changes indicative of new ischemia (new ST-T changes or left bundle branch block [LBBB])
▼ Development of pathologic Q waves on ECG
▼ Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
▼ Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy
In 2018, the Expert Consensus Document on the Fourth Universal Definition of Myocardial Infarction was updated with regard to the criteria
for the diagnosis of the different types of myocardial infarction (MI). The details involving abnormal cTn reference ranges as they pertain to the different criteria are listed later in the diagnostics section. The six types of MI are
▼ Type 1—Infarction due to coronary atherothrombosis
▼ Type 2—Infarction due to supply-demand mismatch not from acute atherothrombosis
▼ Type 3—Infarction resulting in sudden death without confirmation from biomarkers or ECG changes
▼ Type 4—Infarction related to a percutaneous coronary intervention (PCI)
Type 4a is an MI related to the index PCI (≤48 hours) from procedural complications such as coronary dissection, main vessel or side branch occlusion, coronary thrombosis, distal embolization, compromise of collateral flow, or no-reflow phenomenon.
Type 4b is an MI due to a stent/scaffold thrombosis documented either during angiography or during a postmortem autopsy. In relation to the timing of the procedure, events occurring even after 1 year after stent placement are counted.
Type 4c is a procedure-related MI due to focal or diffuse restenotic disease.
▼ Type 5—Infarction related to coronary artery bypass graft (CABG) ≤48 hours from the index procedure
The physical examination of patients with uncomplicated ACS is usually normal but has the goal of evaluating for precipitating factors (uncontrolled hypertension, anemia, thyrotoxicosis, sepsis), assessing hemodynamic consequences of ACS (congestive heart failure [CHF], third heart sound, new mitral regurgitant murmur, shock), revealing comorbid conditions that impact treatment decisions (malignancy), and ruling out other chest pain etiologies. A targeted initial examination should evaluate for unequal extremity pulses and aortic regurgitation (aortic dissection), a pericardial rub (pericarditis), pulsus paradoxus (tamponade), or reproducible chest pain with palpation (musculoskeletal) (Figure 5-1).
The ECG should be performed first and within 10 minutes of first medical contact and reviewed for ischemic findings as ECG changes have both diagnostic and prognostic implications.
▼ ST-segment deviation (depression or elevation) is the most specific sign of ischemia. T-wave changes are the most sensitive.
▼ ST-segment elevation of >1 mm in two contiguous precordial or two adjacent limb leads that is persistent and accompanied by symptoms consistent with ACS (>30 minutes) should be considered for immediate mechanical or pharmacologic reperfusion due to the poor short-term prognosis of STEMI. This category also includes ECG changes of hyperacute T waves, new LBBB, or posterior MI (may require posterior leads for diagnosis).
Figure 5-1. Algorithm for the diagnosis of chest pain. *This algorithm is intended to direct the workup in patients with chest pain of unclear etiology. †Many of these patients will be discovered to have musculoskeletal syndromes that are diagnosed through a detailed history and physical examination. Musculoskeletal diagnoses to specifically consider include overuse syndromes, costochondritis, pectoral girdle syndrome, and xiphodynia. CT, computed tomography; ECG, electrocardiogram; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; UGI, upper gastrointestinal series; US, ultrasound.
▼ If STEMI (or equivalent) is excluded, the presence of ST-segment depressions and T-wave abnormalities should be assessed.
▼ Horizontal or downsloping depressions of ≥0.05 mV are important indicators of ongoing ischemia.
▼ T-wave inversions or “pseudonormalizations” may aid diagnosis, particularly with symptoms, but are less sensitive for ischemia.
▼ As ACS is highly dynamic, serial ECGs (every 20-30 minutes) and clinical reassessment should be performed if the initial ECG is nondiagnostic and the patient remains symptomatic.
▼ Continuous ECG monitoring should be performed in all UA/NSTEMI patients admitted to the hospital for surveillance of arrhythmias and ongoing ischemia.
Cardiac biomarkers, along with the ECG, remain a cornerstone for the diagnosis of MI. cTn T and I are preferred markers given the myocardial specificity. CK-MB is the next favored biomarker and is released more rapidly with ischemia than troponin, although it lacks the former’s absolute tissue specificity.
▼ Most NSTEMI patients have troponin elevation within 3-6 hours after symptom onset. Initially, negative biomarkers should be remeasured within 8-12 hours after symptom onset.
▼ New “high-sensitivity” troponin assays increase sensitivity with an associated loss of specificity, particularly in low-risk patients, and must be interpreted in the clinical context.
▼ Even without ACS as an etiology, however, an elevation in troponin >99th percentile portends a worse prognosis when compared to patients without elevation.
Cardiac imaging is emphasized in the definition of AMI and can aid in clinically indeterminate cases. Because of its widespread availability and mobility, echocardiography is often used to differentiate myocardial ischemia from nonischemic etiologies of chest pain. Regional wall motion abnormalities can help distinguish ischemia from perimyocarditis, valvular heart disease, cardiomyopathy, pulmonary embolism, or ascending aortic dissection. Wall thickness (or lack thereof) may aid in determining if MI is acute or subacute/old. While MRI is validated for these purposes as well, its availability, cost, and time make it less efficient for acute chest pain evaluation.
Low-risk patients (age <70, no rest pain, pain <2 weeks without prolonged episodes, normal ECG, no prior CAD, or diabetes mellitus) with negative biomarkers may be discharged home and additional evaluation performed as an outpatient. Appointment should be made within 72 hours for evaluation.
Intermediate-risk patients without high-risk features require in-hospital triage with provocative noninvasive imaging. The sensitivity and specificity of stress testing can be combined with pretest risk to give a prognosis of coronary heart disease.
Exercise treadmill testing is simple to perform and can help with risk stratification of intermediate-risk patients. It has limited utility in the presence of LBBB on baseline ECG, ventricular paced rhythms, left ventricular hypertrophy (LVH), and significant conduction abnormalities.
The advantage of echocardiography over SPECT (single photon emission computed tomography) is lack of radiation exposure but carries higher
false-negative results at submaximal heart rates. SPECT has higher positive-negative predictive values over treadmill testing alone.
Cardiac MRI has excellent spatial resolution without radiation, similar to SPECT, and may assess myocardial viability. Stress MRI can be performed with dobutamine or adenosine. It is however difficult to image the heart in patients with irregular heart rhythms. Those with metal implants cannot be safely imaged, and alternative modalities need to be selected.
Cardiac CT (64 slice) has excellent negative predictive value (>90%), but slightly diminished positive predictive value (80%). Rapid acquisition is possible and requires lower heart rates for accurate image analysis. There is a tendency to overestimate disease severity, and the test only provides anatomic, not functional, information.
□ Laboratory and Diagnostic Findings
Troponin T and I molecules have amino acid sequences specific to cardiac cells. These proteins control the interaction between actin and myosin mediated by calcium.
Biomarkers for hemodynamic stress (similar to brain-type natriuretic peptide [BNP]) have been shown to have some utility in predicting cardiovascular death and heart failure episodes in patients with NSTEMI. Some of the biomarkers studied include C-terminal provasopressin (copeptin), midregional proadrenomedullin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP). The application of these markers in clinical decision-making is still uncertain.
It is important to note that the Fourth Universal Definition of an MI incorporates both clinical and biochemical derangements due to myocardial necrosis. The clinical criteria of MI classification are described previously.
▼ Type 1 (from coronary atherothrombosis)—Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL.
▼ Type 2 (from supply-demand mismatch)—Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL.
▼ Type 3 (sudden death without confirmation from biomarkers)—Classified in the absence of measured biomarkers.
▼ Type 4 (PCI-related MI)—Arbitrarily defined by an elevation of cTn values more than five times the 99th percentile URL in patients with normal baseline values. In patients with elevated preprocedure cTn in whom the cTn levels are stable (≤20% variation) or falling, the postprocedure cTn must rise by >20%. However, the absolute postprocedural value must still be at least five times the 99th percentile URL.
▼ Type 5 (CABG-related MI)—Arbitrarily defined as elevation of cTn values >10 times the 99th percentile URL in patients with normal baseline cTn values. In patients with elevated preprocedure cTn in whom cTn levels are stable (≤20% variation) or falling, the postprocedure cTn
must rise by >20%. However, the absolute postprocedural value still must be >10 times the 99th percentile URL.
High-sensitivity cTn assays can measure cTn fivefold to a hundredfold lower than a conventional assay.
▼ In 2017, the FDA approved the clearance of the first hscTn assay in the United States.
▼ The use of a more sensitive assay in clinical practice will result in the frequency of UA decreasing with an 18-30% increase in the diagnosis of NSTEMIs.
▼ To be classified as a high-sensitivity assay, the test should have a coefficient of variance <10% at the 99th percentile value, and a concentration below the 99th percentile should be detectable above the assay’s limit of detection for >50% of healthy individuals in the population of interest.
▼ The increased sensitivity of the assay now allows for the detection of first low-level elevations measurable within 90-180 minutes of an indexed cardiac event.
▼ False negatives are rare and due to anti-cTn antibodies. hscTn test values are also lowered by hemolysis.
▼ False-positive elevations can be due to heterophile antibodies and/or macrokinases.
▼ Rapid screening protocols have been proposed to rule out or rule in AMIs.
▼ With hscTn serial measurements made at 0 and 2 hours can most often rule out an AMI.
Values less than or equal to the sex-specific 99th percentile (10 ng/L for women and 15 ng/L for men)
The absence of a delta of 4 ng/L or greater when integrated with the ECG, patient’s history, and validated risk scores (Figure 5-2)
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 130(25):e344-e426.
Anderson JL, Morrow DA. Acute myocardial infarction. N Engl J Med. 2017;376:2053-2064.
Brush JE, Kaul S, Krumholz HM. A brief review of troponin testing for clinicians—expert analysis. 2017. Available from www.acc.org/latest-in-cardiology/articles/2017/08/07/07/46/a-brief-review-of-troponin-testing-for-clinicians. September 29, 2018.
Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying Cause of Death 1999-2016 on CDC WONDER Online Database, released December, 2017. Data are from the Multiple Cause of Death Files, 1999-2016, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Available from wonder.cdc.gov/ucd-icd10.html. September 23, 2018.
Eisen A, Giugliano RP, Braunwald E. Updates on acute coronary syndrome: a review. JAMA Cardiol. 2016;1(6):718-730.
Robson J, Ayerbe L, Mathur R, et al. Clinical value of chest pain presentation and prodromes on the assessment of cardiovascular disease: a cohort study. BMJ Open. 2015;5(4):e007251.
Thygesen K, Alpert JS, Jaffe AS, et al.; ESC Scientific Document Group. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2019;40(3):237-269. doi: 10.1093/eurheartj/ehy462.
CHEST PAIN: NONATHEROSCLEROTIC ISCHEMIA
Approximately 5% of patients with AMI do not have atherosclerotic coronary disease, increasing to 20% in patients under the age of 35. Necropsy studies in these individuals often demonstrate luminal narrowing, leading to ischemia via several mechanisms: internal narrowing by obstructions or encroachment by adjacent structures.
Ischemia may also result from dynamic changes in an otherwise normal arterial wall (spasm and anomalous arteries) or an imbalance in oxygen supply and demand (type 2 MI).
Over 50% of fatal MIs without coronary disease likely represent coronary vasospasm.
□ Who Should Be Suspected?
Diagnosis is often made by exclusion via cardiac imaging due to overlap of symptom presentation with ACS.
Young age (<35 years) and lack of coronary risk factors raise the suspicion of congenital coronary anomalies or congenital coronary aneurysm. A careful history to exclude cocaine use (supported by tox screen if needed) is mandatory in STEMI patients without significant atherosclerotic risk factors, as is rheumatic history.
Coronary spasm has also been described with patients receiving chemotherapeutic drugs such as 5-fluorouracil and those taking herbal medicines. A careful medical reconciliation should be performed on all chest pain patients and review of “vasospastic potential” performed, and this includes use of estrogen replacement therapy (coronary dissection).
Hypercoagulable/malignancy history should be reviewed, and subtherapeutic INR for patients on Coumadin should be assessed for the possibility of coronary embolism.
Congenital Coronary Anomalies
Present in 1-2% of the general population but 4% of autopsies for MI. When coronary arteries arise from the contralateral sinus of Valsalva, the anomalous artery may course between the great vessels. States of increased cardiac output may cause either compression or torsion of the proximal coronary artery resulting in ischemia, infarct, or sudden cardiac death.
Diagnosis is made by imaging based on ACS risk profile of presentation. Cardiac catheterization (high-risk patients) demonstrates interarterial course of anomalous vessel. Direct visualization with cardiac CT or MRI is an advantage when considering these modalities for stress testing in younger populations but must be balanced by cost consideration. Surgical bypass for high-risk anatomy is the preferred treatment.
Myocardial Bridges (“Tunneled” Epicardial Arteries)
Congenital in origin: The course of the epicardial coronary artery dives below the myocardium and is compressed in systole. As the majority of coronary blood flow occurs in diastole, tachycardia with resulting shortened diastolic filling period is often required to produce ischemia. Length of the tunneled arterial segment may not play a significant role in risk.
Diagnosis made by direct visualization by angiography or CT/MRI. The presence of a myocardial bridge does not necessarily imply ischemia is present.
Congenital (more common in the right coronary artery) or acquired (infection/inflammation): Turbulent flow in the aneurysm may predispose to thrombus formation and ACS. Acquired aneurysm may be the result of atherosclerosis (50%) or syphilis, mycotic emboli, Kawasaki disease, or lupus. Appropriate serologies should be sent when aneurysm is identified by imaging (see Chapter 4, Autoimmune Diseases, and Chapter 13, Infectious Diseases).
Coronary artery emboli should be considered in any patient presenting with ACS (usually STEMI) in the setting of atrial fibrillation (AF), active infective
endocarditis, prosthetic heart valve, known LV thrombus, or left-sided cardiac tumor (right-sided tumors require a right-to-left shunt to be present). Initial triage is performed as dictated by ACS algorithm, and diagnosis is often made angiographically. Coronary embolism most often involves the left anterior descending artery (LAD) and may resolve spontaneously with anticoagulation.
Embolism or spasm should be considered for angiographically normal arteries in the setting of MI.
Spontaneous Coronary Artery Dissection
Occurs from vessel wall hematoma between media and adventitia in the absence of trauma or iatrogenic causes. Most diagnosed with autopsy and occur in LAD or left main artery.
Described in young women with risk factors among whom 25-30% are pregnant or in the postpartum period. Likely etiologies include hormonal impairment of collagen synthesis. Oral contraceptive use is also associated with dissection. Thrombolytic therapy should not be given in postpartum patients with STEMI due to increased chance of propagation of hematoma.
Men are more likely to be older and have right coronary involvement with coronary risk factors. Systemic hypertension is not a risk factor for dissection.
Other associated conditions include cocaine or cyclosporine use, HCM, Marfan or Ehlers-Danlos syndrome, and immune-mediated diseases such as rheumatic arteritis, autoimmune thyroiditis, hepatitis C infection, sarcoidosis, systemic lupus erythematosus (SLE), Kawasaki arteritis, and eosinophilic coronary arteritis.
Coronary Artery Spam
Spasm that occurs within epicardial coronary arteries usually occurs at sites with non-flow-limiting luminal narrowing by atherosclerotic plaque. An abundance of smooth muscle cells is usually present in necropsy studies at the known sites of spasm.
Hyperadrenergic conditions associated with spasm include pheochromocytoma and cocaine, amphetamine, and ecstasy use. This includes dobutamine infusion for stress testing. Epicardial spasm can be seen in inflammatory conditions of thyrotoxicosis, allergic angina, as well as administration of fluorouracil, capecitabine, sumatriptan, and bromocriptine.
Diagnosis of spasm is usually made with angiography. Provocative challenge during catheterization with ergotamine is no longer performed due to risk of MI/death from refractory spasm. Potential offending medications or behaviors should be stopped immediately.
Epicardial spasm should be differentiated from syndrome X, or microvascular spasm. This syndrome carries a benign prognosis but presents with
angina-like pain. Stress testing often reveals signs of ischemia with normal epicardial arteries on invasive testing (coronary flow reserve—which can be assessed invasively and is often abnormal). Pain is likely due to either microvascular spasm or abnormal pain perception (sympathetic predominance).
Hypertrophic Obstructive Cardiomyopathy
See Dyspnea/Congestive Heart Failure section.
Angelini P, Trivellato M, Doris J, et al. Myocardial bridges: a review. Prog Cardiovasc Dis. 1983;26:75-88.
Chetlin MD, Virami R. Myocardial infarction in the absence of coronary atherosclerotic disease. In: Virmani R, Forman MB, eds. Nonatherosclerotic Ischemic Heart Disease. New York, NY: Raven Press; 1989:1-30.
Kawsara A, Núñez Gil IJ, Alqahtani F, et al. Management of coronary artery aneurysms. JACC Cardiovasc Interv. 2018;11(13):1211-1223.
Picard F, Sayah N, Spagnoli V, et al. Vasospastic angina: a literature review of current evidence. Arch Cardiovasc Dis. 2019;112(1):44-55.
Rogers IS, Tremmel JA, Schnittger I. Myocardial bridges: overview of diagnosis and management. Congenit Heart Dis. 2017;12(5):619-623.
CHEST PAIN: INFLAMMATORY
Chest pain may occur due to an inflammatory response to immune-mediated or infectious triggers without necessarily predisposing to ischemic insult. Pericardium, myocardium, or direct coronary artery involvement may occur. Ischemia may occur when coronary arteries are involved as a direct result of the inflammatory process (necrosis and aneurysm formation) or via wall thickening and luminal narrowing, rupture of the vessel wall, or thrombosis due to hypercoagulable state or accelerated atherosclerosis.
Vasculitis describes a heterogeneous group of disorders that are characterized by leukocyte migration in the vessel wall resulting in damage of blood vessels, which leads to tissue ischemia and necrosis.
Epicardial coronary vasculitis is relatively rare but can be life threatening. Coronary arteries are involved through either direct extension or hematogenous spread.
Cardiac manifestations are rarely predominant in vasculitis and are just as likely to occur as a result of other organ involvement or treatment side effects of this systemic process.
Heart failure due to direct myocardial involvement, ischemic cardiomyopathy, or valvular involvement in vasculitis is more common than ACSlike presentation.
Size and shape of both arteries and veins are affected due to a primary process or secondary to an underlying pathology.
□ Classification by
Primary: polyarteritis nodosa, Wegener granulomatosis, giant cell arteritis, and hypersensitivity vasculitis (see Chapter 2, Autoimmune Diseases)
▼ Infections: bacteria (e.g., septicemia caused by gonococcal organisms or Staphylococcus), mycobacteria, viruses (e.g., CMV, hepatitis B), Rickettsia (e.g., Rocky Mountain spotted fever), and spirochetes (e.g., syphilis, Lyme disease)
▼ Associated with malignancy (e.g., multiple myeloma, lymphomas)
▼ Connective tissue diseases (e.g., RA, SLE, Sjögren syndrome)
▼ Diseases that may simulate vasculitis (e.g., ergotamine toxicity, cholesterol embolization, atrial myxoma)
Size of Involved Vessel (Noninfectious Vasculitis)
Large vessel: dissection of the aorta (dissecting aneurysm), Takayasu arteritis, giant cell (temporal) arteritis
Medium-sized vessel: polyarteritis nodosa (or small), Kawasaki disease, primary granulomatous CNS vasculitis
Small vessel: ANCA-associated vasculitis (Wegener granulomatosis, Churg-Strauss syndrome, drug-induced, microscopic polyangiitis), immune complex-type vasculitis (Henoch-Schönlein purpura, cryoglobulinemia, rheumatoid vasculitis [or medium], SLE, Sjögren syndrome, Goodpasture syndrome, Behçet syndrome, drug-induced serum sickness), paraneoplastic vasculitis (lymphoproliferative, myeloproliferative, carcinoma), inflammatory bowel disease
Any size vessel (pseudovasculitis): antiphospholipid syndrome, emboli (e.g., myxomas, cholesterol emboli, bacterial or nonbacterial endocarditis), drugs (e.g., amphetamines)
□ Who Should Be Suspected?
Patients may present with fatigue, weakness, fever, myalgias, arthralgia, headache, abdominal pain, hypertension, nosebleeds, palpable purpura, and/or mononeuritis.
Coronary artery imaging (angiography, MRI, CT) that reveals a “stringof-pearls” sign of sequential proximal coronary aneurysms is suggestive of a vasculitic process. A focused rheumatic history should be performed in all patients with this angiographic finding.
□ Laboratory Findings
The gold standard in the diagnosis of most vasculitides is based on pathologic findings in a biopsy of the involved tissue:
Hematology: ESR is increased in 90% of cases, often to very high levels; C-reactive protein (CRP) correlates with disease activity even better than ESR. Normochromic anemia of chronic disease, thrombocytosis, and mild leukocytosis occur in 30-40% of patients; eosinophilia may occur but is not a feature. Leukopenia or thrombocytopenia occurs only during cytotoxic therapy.
Urinalysis: hematuria, proteinuria, and azotemia.
Core laboratory: serum globulins (IgG and IgA) are increased in ≤50% of cases. Serum C3 and C4 complement levels may be increased. Rheumatoid factor may be present in low titer and ANA positive in vasculitis secondary to connective tissue disorders. ANCA determination provides valuable information and is highly specific for the diagnosis of small vessel vasculitides, particularly Wegener granulomatosis.
Imaging studies: arteriogram, MRI, and ultrasound.
Considerations: cANCA (antiproteinase 3; coarse diffuse cytoplasmic pattern) is highly specific (>90%) for active Wegener granulomatosis. Sensitivity is >90% in systemic vasculitic phase, approximately 65% in predominantly granulomatous disease of respiratory tract and approximately 30% during complete remission.
▼ ELISA titer does not correlate with disease activity; a high titer may persist during remission for years. cANCA is also occasionally found in other vasculitides (polyarteritis nodosa, microscopic polyangiitis [e.g., lung, idiopathic crescentic and pauci-immune GN], Churg-Strauss vasculitis).
▼ p-ANCA (against various proteins [e.g., myeloperoxidase, elastase, lysozyme; perinuclear pattern]) occurs only with fixation in alcohol, not formalin. A positive result should be confirmed by ELISA. The test has poor specificity and 20-60% sensitivity in a variety of autoimmune diseases (microscopic polyangiitis, Churg-Strauss vasculitis, SLE, inflammatory bowel disease, Goodpasture syndrome, Sjögren syndrome, idiopathic GN, chronic infection). However, pulmonary small vessel vasculitis is strongly linked to myeloperoxidase antibodies.
▼ Both p-ANCA and cANCA may be found in non-immune-mediated polyarteritis and other vasculitides.
▼ Atypical pattern (neither cANCA nor p-ANCA; unknown target antigens) has poor specificity and unknown sensitivity in various conditions (e.g., HIV infection, endocarditis, CF, Felty syndrome, Kawasaki disease, ulcerative colitis, Crohn disease).
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
See Chapter 11, Hematologic Disorders.
Henoch-Schönlein purpura is a self-limited hypersensitivity systemic vasculitis of the small vessels. It involves the skin and to variable degrees joints, kidneys, and GI tract. The small vessel and renal involvement is caused by IgA deposition.
□ Who Should Be Suspected?
This condition is seen more commonly in children (90% of cases) but it may affect adults as well.
In adults, renal disease is common. The renal picture may vary, with minimal urinary abnormalities occurring for years. Patients may present with palpable purpura without thrombocytopenia or a coagulopathy and acute abdominal pain, or with purpura and joint symptoms.
□ Laboratory Findings
Diagnosis is made clinically; there are no pathognomonic laboratory findings.
Histology: renal or skin biopsy supports the diagnosis; it shows focal segmental necrotizing GN that becomes more diffuse and crescentic with IgA and C3 deposition.
Urinalysis: RBCs, casts, and slight protein in 25-50% of patients. The renal picture varies from minimal urinary abnormalities for years to endstage renal disease within months. Gross hematuria and proteinuria are uncommon.
Hematology: coagulation tests are normal.
Core laboratory: Blood urea nitrogen (BUN) and creatinine may be increased.
KAWASAKI SYNDROME (MUCOCUTANEOUS LYMPH NODE SYNDROME)
Kawasaki syndrome is a variant of childhood polyarteritis of unknown etiology, with a high incidence of coronary artery complications.
□ Laboratory Findings
Histology: diagnosis is confirmed by histologic examination of the coronary artery (same as for polyarteritis nodosa).
Hematology: anemia (approximately 50% of patients). Leukocytosis (20,000-30,000/µL) with shift to the left occurs during the 1st week; lymphocytosis appears thereafter, peaking at the end of the 2nd week, and is a hallmark of this illness. Increased ESR.
CSF findings: increased mononuclear cells with normal protein and sugar.
Urinalysis: increased mononuclear cells; dipstick negative.
Joint fluid findings: increased white blood cell (WBC) count (predominantly PMNs) in patients with arthritis.
TAKAYASU SYNDROME (ARTERITIS)
Takayasu syndrome is the term for granulomatous arteritis of the aorta. Temporal arteritis and rheumatic disease may also be associated with aortitis.
Greater incidence in young to middle-aged Asian females. Coronary involvement occurs in 15-25% of cases. Involvement is usually in segments and rarely diffuse.
Average age of onset is 24 years, and the diagnosis should be considered in individuals of <40 years with AMI.
Diagnosis is established by characteristic arteriographic narrowing or occlusion or histologic examination. Laboratory tests are not useful for diagnosis or to guide management.
□ Laboratory Findings
Findings are due to involvement of coronary or renal vessels.
Hematology: increased ESR is found in approximately 75% of cases during active disease but is normal in only 50% of cases during remission. WBC count is usually normal.
Core laboratory: serum proteins are abnormal, with increased γ-globulins (mostly composed of IgM). Female patients have a continuous high level of urinary total estrogens (rather than the usual rise during the luteal phase after a low excretion during the follicular phase).
THROMBOANGIITIS OBLITERANS (BUERGER DISEASE)
Thromboangiitis obliterans is very rare and is the vascular inflammation and occlusion of medium and small arteries and veins of limbs; it is related to smoking and occurs mostly in males. Histology shows characteristic inflammatory and proliferative lesions. Coronary involvement is uncommon. Laboratory tests are usually normal.
INFECTIOUS (SECONDARY) VASCULITIS
Various microorganisms may cause vasculitis of any size vessel by either hematogenous spread or direct extension of cardiac structures involved (pericardium, valves).
Most important infections of the coronary arteries are syphilis, tuberculosis, and syphilitic arteritis.
□ Who Should Be Suspected?
Tuberculosis coronary arteritis occurs mainly in patients with preexisting pericardial or myocardial tuberculosis.
Syphilitic arteritis can involve the first 3-4 mm of the left and right coronary arteries with an obliterative arteritis.
When a nonviral infectious angiitis occurs, it is almost always accompanied by myocarditis with abscesses and pericarditis.
□ Laboratory Findings
Core lab blood work, cultures, and PCR analysis should be dictated by systemic clues to the underlying infectious process.
Thrombophlebitis is vascular inflammation due to a blood clot.
□ Laboratory Findings
Findings are due to associated septicemia, complications (e.g., septic pulmonary infarction), and underlying disease.
Hematology: increased WBC count (often >20,000/µL), with marked shift to the left and toxic changes in neutrophils. DIC may be present.
Core laboratory: azotemia.
Culture: positive blood culture (Staphylococcus aureus is the most frequent organism; others are Klebsiella, Pseudomonas aeruginosa, enterococci, Candida).
Hetland LE, Susrud KS, Lindahl KH, et al. Henoch-Schönlein Purpura: a literature review. Acta Derm Venereol. 2017;97(10):1160-1166.
Keser G, Aksu K. Diagnosis and differential diagnosis of large-vessel vasculitides. Rheumatol Int. 2019;39(2):169-185. doi: 10.1007/s00296-018-4157-3.
Son MBF, Newburger JW. Kawasaki disease. Pediatr Rev. 2018;39(2):78-90.
PERICARDITIS (ACUTE) AND PERICARDIAL EFFUSION
The pericardium is a double-walled sac that surrounds the heart. The inner visceral pericardium is normally separated from the outer, fibrous parietal pericardium by a small volume (15-50 mL) of fluid, a plasma ultrafiltrate. Inflammation of the pericardium results in pericarditis, with or without an associated pericardial effusion.
Common causes of pericardial inflammation include infection, uremia, trauma, malignancy, hypersensitivity, and autoimmune diseases. Viral infections (coxsackie- and echovirus) are by far the most common and are usually self-limited.
Cardiac tamponade is more likely to present as dyspnea in its mild form with additional precordial discomfort and hypotension/shock more likely with severe tamponade.
When presenting as chest pain, myocarditis is often due to concomitant pericarditis. Myocardial involvement alone more often presents as dyspnea and dilated cardiomyopathy (DCM; see Dyspnea section), although younger patients are more likely to present.
□ Who Should Be Suspected?
Any recent trauma victim in shock, post-MI patients, patients with comorbid conditions predisposed to effusion (neoplasm, chronic inflammatory disease), and patients with chest pain after a viral prodrome.
Typical signs and symptoms of acute pericarditis include chest pain (often pleuritic and worse with inspiration and supine position), pericardial
friction rub (pathognomonic), ECG changes (e.g., ST elevation, PR depression), and pericardial effusion.
Not all patients will manifest all of these features; the presence or absence of an effusion does not exclude the diagnosis.
□ Laboratory and Diagnostic Findings
Echocardiography: Most useful imaging technique for the evaluation of acute pericarditis and is critical for patients if tamponade is suspected. Small pericardial effusions, undetectable by routine examinations, may be detected, providing support for the diagnosis of pericardial disease. Typically >1 cm of effusion is required for safe performance of pericardiocentesis. Doppler-derived flow-velocity measures of mitral and tricuspid flow may assist in diagnosing tamponade, but it is ultimately a clinical diagnosis based on inspiratory decline in systolic arterial pressure exceeding 10 mm Hg (pulsus paradoxus), which can be also seen in chronic obstructive pulmonary disease (COPD) and pulmonary embolism. The absence of any chamber collapse on echocardiography has a high negative predictive value for tamponade (92%), although the positive predictive value is low (58%). Abnormalities of right heart venous return (expiratory diastolic reversal) are more predictive but cannot be obtained in one third of patients.
Electrocardiography: ECG abnormalities may support a diagnosis or suggest alternative diagnoses, such as MI or early repolarization abnormalities. There are several important distinguishing characters of pericarditis ECGs from that of STEMI patients. There is upward concavity of ST elevations (compared with downward for ischemic) that rarely exceeds 5 mm with PR-segment depression (not in aVR) that is not present with repolarization abnormalities. T-wave inversions may persist with tuberculous, uremic, or neoplastic pericarditis. Electrical alternans suggests large effusion.
Chest x-ray: Generally normal but may detect specific abnormalities, like increased cardiac silhouette with effusions (water-bottle heart), pleural effusion, or evidence of underlying etiology (TB, fungal disease, pneumonia, neoplasm).
Chest CT and MRI detect effusions with high sensitivity and specificity and may provide useful information pertinent to performing pericardiocentesis (hematocrit of effusion, loculations, pericardial thickening). Often, concern of tamponade makes echocardiography the imaging modality of choice for clinically tenuous patients due to its mobility.
Tuberculin skin test or interferon-gamma release assay: Evaluation to rule out TB is recommended for all patients. Additional diagnostic testing for TB, like AFB cultures, should be performed on patients at increased risk on the basis of epidemiologic and clinical factors.
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