Are Zebras Simply Striped Horses?
Information about a real patient is presented in stages (boldface type) to experts (Drs Olson, Michelena, and Gersh) who respond to the information, sharing their reasoning with the reader (regular type). A discussion by the authors follows.
Patient presentation: A 46-year-old man was transferred from an outside facility to our inpatient pulmonary service with alveolar hemorrhage, transfusion-requiring anemia, and incidentally found obstructive hypertrophic cardiomyopathy (HCM).
Two weeks earlier, he presented to a regional hospital with persistent cough, progressive dyspnea, orthostasis, and new low-volume hemoptysis. On admission to the outside hospital, the patient was hypoxic and urgently intubated after he failed to respond to noninvasive positive pressure ventilation. A bronchoscopy demonstrated blood within the airways. Bronchoalveolar lavage (BAL) revealed a bloody return containing a large percentage of hemosiderin-laden macrophages. Cytology and cultures of the BAL were negative for infection or malignancy. He was extubated but continued to have intermittent bouts of dyspnea, hypoxia, and bilateral alveolar infiltrates on chest imaging. Therefore, a right lung lower-lobe wedge biopsy was performed. The biopsy specimen was not immediately available for review at the time of transfer but was interpreted elsewhere as demonstrating hemosiderosis without capillaritis. A systolic murmur prompted a transthoracic echocardiogram (TTE), which reported obstructive HCM.
Dr Olson (pulmonary consultant): The constellation of hemoptysis, anemia, diffuse pulmonary parenchymal opacities on chest imaging, and bloody BAL with increased hemosiderin-laden macrophages suggested diffuse alveolar hemorrhage (DAH) as the cause of the patient’s hypoxic respiratory failure. DAH refers to bleeding into the alveolar spaces as a result of disruption of the conjoined alveolar-capillary basement membrane.1 DAH may be a result of a wide variety of diseases that are usually grouped into immune-mediated and non–immune-mediated conditions (Table 1).2 The immune-mediated conditions include anti-neutrophilic cytoplasmic antibody–associated vasculitides, connective tissue diseases, anti-glomerular basement membrane disease, and drugs (prescription or illicit), whereas the non–immune-mediated conditions include coagulopathies/bleeding disorders, causes of acute respiratory distress syndrome (especially infection), conditions producing increased left ventricular end-diastolic pressure, radiation exposure, idiopathic pulmonary hemosiderosis, and miscellaneous conditions (ie, pulmonary veno-occlusive disease, pulmonary vein stenosis).
Incorporation of clinical, radiological, laboratory, and pathology information is required to work through the many potential causes of DAH. The clinical presentation of DAH is variable, ranging from asymptomatic radiographic abnormalities to catastrophic respiratory failure. Patients typically, but not uniformly, have hemoptysis, which may be accompanied by dyspnea, fever, and symptoms/signs related to the underlying condition responsible for the DAH. Anemia is common. High-resolution chest computed tomography is obtained to further define the typical but nonspecific diffuse opacities on chest x-ray and usually reveals widespread, bilateral ground-glass or consolidative opacities. In addition, there may be changes related to the underlying disorder such as cavitary lesions in granulomatosis with polyangiitis (Wegener granulomatosis). Initial laboratory testing is conducted to hone the usually nonspecific clinicoradiological data and may include complete blood count with differential; erythrocyte sedimentation rate; blood urea nitrogen and creatinine; urinalysis with urinary sediment; anti-neutrophilic cytoplasmic antibody testing; anti-glomerular basement membrane antibodies; anti-nuclear antibody; rheumatoid factor or anti-cyclic citrullinated antibodies; anti-cardiolipin antibodies or lupus anticoagulant; creatinine kinase; complement levels; and brain natriuretic peptide. Bronchoscopy is used to exclude a proximal endobronchial source of bleeding, to confirm the intra-alveolar source of bleeding by demonstration of a progressively bloody BAL return with >20% hemosiderin-laden macrophages, and to exclude infection/malignancy.
The information at the time of transfer argued against pneumonia, aspiration, acute eosinophilic pneumonia, acute respiratory distress syndrome, or a diffuse pulmonary malignancy. This helped to narrow the differential diagnosis for DAH. The reported absence of capillaritis (inflammation of the alveolar walls) on the locally obtained lung biopsy argued against an immune-mediated cause for the DAH such as vasculitis and connective tissue disorders. Therefore, there was suspicion of a bland DAH. In the absence of apparent bleeding disorder, infection, or malignancy, either idiopathic pulmonary hemosiderosis or a condition causing increased left ventricular end-diastolic pressure was under consideration. We sought to expand the history (symptoms of systemic disorders, relevant exposures/drugs) and physical examination (signs of vasculitis, connective tissue disorders, or heart disease), to obtain prior laboratory results and broaden testing as needed, to review the lung biopsy specimen, and to obtain input from our cardiology consult team. The relevance of obstructive HCM to the presentation was of unclear significance.
Patient presentation (continued): His medical history was significant for systemic hypertension, hyperlipidemia, type 2 diabetes mellitus, and recently diagnosed obstructive HCM. There was no known history of bleeding abnormalities or relevant environmental/occupational exposures. The patient was a lifelong nonsmoker and denied illicit drug use. His medications included metformin, glipizide, lisinopril, hydrochlorothiazide, pravastatin, and recently initiated metoprolol tartrate, increased to 100 mg twice daily before transfer. The family history was noncontributory.
On physical examination, the patient was in no distress and afebrile. Systemic blood pressure was 122/72 mm Hg and oxygen saturation was 92% on room air with a respiratory rate of 18 breaths per minute. Cardiac examination demonstrated a regular rhythm with a rate of 73 bpm, impalpable apex beat, and grade 3/6 pansystolic ejection murmur heard across the precordium. There was no evidence of jugular venous distension at 45° with mild hepatojugular reflux. Lung examination revealed bibasilar rales without wheezing. There was bilateral pitting lower-extremity edema (2+) below the knees. There were no relevant cutaneous findings.
Laboratory work revealed normocytic anemia (hemoglobin, 7.9 g/dL) with reticulocytosis and leukocytosis of 14.5×109/L with left shift. Erythrocyte sedimentation rate was 3 mm/h. Iron studies were normal. Serum haptoglobin was undetectable; lactate dehydrogenase was elevated (350 U/L [normal range, 122–222 U/L]). Electrolytes, serum creatinine, and liver function studies were normal, except for an indirect hyperbilirubinemia (total bilirubin, 2.8 mg/dL; direct bilirubin, 0.6 mg/dL). A baseline ECG(Figure 1) demonstrated normal sinus rhythm, left atrial enlargement, and left ventricular hypertrophy by the Sokolow-Lyon index (S in V1+R in V6 >35 mm) with secondary repolarization abnormalities. A chest x-ray on admission(Figure 2) showed bilateral lung opacities.
Dr Michelena (cardiology consultant): This 46-year-old white man had been admitted with persistent cough for 2 to 3 weeks, hemoptysis, severe anemia, intermittent acute dyspnea requiring intubation during one episode, and proven alveolar hemorrhage apparently without capillaritis. His chest x-ray was strikingly abnormal but nonspecific, compatible with alveolar hemorrhage versus flash pulmonary edema versus infection. Despite this, the patient was remarkably stable on physical examination without any active dyspnea or distress, tolerating decubitus. Although a limited historian, he reported a long-standing history of a “heart murmur” with no significant dyspnea on exertion except for the previous 2 weeks. He reported no chest pain on exertion. He denied fevers, chills, night sweats, recent travel, purulent sputum production, rashes, or arthralgias. Importantly, he denied a family history of HCM or sudden cardiac death, autoimmune or pulmonary disease, and a personal history of palpitations or syncope. He was unclear about the presence of paroxysmal nocturnal dyspnea, but his cough clearly worsened when supine and by straining, a critical historical feature suggestive of possible triggered episodes of acutely elevated left ventricular pressures causing the reported bouts of dyspnea in the setting of obstructive HCM. The ejection systolic murmur was prominent and compatible with obstructive HCM by maneuvers (ie, systolic murmur increased in intensity on standing after squatting and with Valsalva maneuver), and even though he had some below-the-knee edema, he had no appreciable jugular venous distention. However, he did have bilateral lung rales, suggesting the possibility of predominant left ventricular failure, which in his case was rather episodic. However, the lung rales could very well have been the result of DAH of noncardiac origin.
A young man with symptomatic obstructive HCM would typically present with chronic dyspnea on exertion and less likely with florid left-sided heart failure or episodic flash pulmonary edema, unless he had very severe intermittent associated functional mitral regurgitation or advanced HCM with systolic dysfunction. His prominent DAH, in addition to being very uncommon as a manifestation of left ventricular failure, seemed out of proportion to his general and cardiac physical examination, casting doubts on HCM as the predominant underlying cause for his presentation. In addition, not only was his anemia related to DAH, but there was a hemolytic component as evidenced by undetectable haptoglobin, elevated lactate dehydrogenase, and indirect hyperbilirubinemia. This could represent an autoimmune or mechanical phenomenon of as-yet unknown origin. Notwithstanding, his BAL cytology and cultures were negative for infection or malignancy, he had no infectious or autoimmune symptomatology, and his sedimentation rate was low.
In clinical medicine, diagnostic parsimony advocates that the source of multiple findings or symptoms should be ascribed to only 1 disorder if possible. In this particular case, given the complexity of the clinical presentation, one must rule out other single diagnostic alternatives before committing to HCM as the underlying disorder. It is also important to recognize that there could be >1 disorder explaining the findings, such that our patient could have both underlying lung or systemic disease and symptomatic obstructive HCM. When faced with the prospect of recommending any invasive treatment not devoid of risk (ie, surgical myectomy or alcohol septal ablation for obstructive HCM), one must guarantee, to the highest possible extent, that the patient’s symptoms or mortality will be positively affected by that procedure. For these reasons, before committing to HCM as the underlying disorder, the recommendation was to fully exclude autoimmune disease, to investigate the nature of the hemolysis, and to rule out pulmonary causes. We also recommended an N-terminal pro-brain natriuretic peptide level, TTE, and 24-hour Holter monitoring to rule out contributory arrhythmias (ie, atrial fibrillation, ventricular tachycardia).
Patient presentation (continued): The outside chest computed tomography was reviewed(Figures 3 and 4) and showed bilateral patchy ground-glass opacities, consistent with DAH of unclear origin. Hepatitis and HIV serologies were negative. Coagulation parameters were normal. Combined laboratory testing from the referring institution and our facility to assess for an underlying immune cause for DAH was negative, including anti-nuclear antibody, rheumatoid factor, anti-cyclic citrullinated antibodies, anti-neutrophilic cytoplasmic antibody panel, extractable nuclear antigen panel, and anti-glomerular basement membrane. Coombs test was negative. The pathology from the pulmonary wedge biopsy was reviewed at our institution and demonstrated abundant hemosiderin-laden macrophages without capillaritis(Figure 5).
Dr Olson: The negative, fully elaborated autoimmune laboratory panel and confirmation of absent capillaritis in the lung biopsy specimen further reinforced suspicion of a non–immune-mediated mechanism for the DAH. In addition, the chest computed tomography at transfer revealed smooth interlobular septal thickening in the lung bases and small bilateral pleural effusions, findings consistent with increased left ventricular filling pressure (Figure 4).
Patient presentation (continued): On the night of admission, the patient developed acute dyspnea with hypoxemia and small-volume hemoptysis, with oxygen requirements increasing to 5 L/min from room air. His symptoms and oxygen saturations improved with intravenous diuresis of 3 L. An N-terminal pro-brain natriuretic peptide level was obtained the next morning and was found to be severely elevated (7915 pg/mL). Holter monitor showed no evidence of atrial or ventricular arrhythmias. TTE(Figure 6 and Movie I in the online-only Data Supplement) demonstrated a hyperdynamic left ventricle (ejection fraction, 75%) with moderate concentric hypertrophy; dynamic left ventricular outflow tract (LVOT) obstruction with maximum Doppler gradient of 88 mm Hg at rest(Figure 7) with systolic anterior motion of the mitral leaflets causing moderate to severe posteriorly direct mitral regurgitation; normal right ventricular systolic function with right ventricular systolic pressure of 56 mm Hg (systolic blood pressure, 115 mm Hg); and mildly dilated inferior vena cava. There was a small pericardial effusion. Global averaged left ventricular longitudinal peak systolic strain was abnormal at −14% (normal, more negative than −18%).
The patient underwent catheterization of the right and left sides of the heart. Coronary angiogram showed normal coronary vasculature. Left-sided catheterization after diuresis demonstrated elevated left ventricular end-diastolic pressure of 22 mm Hg at rest and pulmonary capillary wedge pressure of 25 mm Hg with V waves up to 35 mm Hg. There was moderate type II pulmonary hypertension, with a mean pulmonary artery pressure of 35 mm Hg (52/20 mm Hg). Cardiac index was preserved at 2.95 L·min−1·m−2.
Dr Gersh (cardiologist, HCM specialist): This is an extremely unusual presentation for HCM, although the TTE and ECG findings are characteristic. The typical presentations of obstructive HCM are variable, but the most common symptoms are exertional dyspnea, chest discomfort, lightheadedness or syncope, and occasionally sudden cardiac death. Many patients are asymptomatic with HCM and are diagnosed incidentally by an ECG or echocardiogram. The dramatic presentation in this patient with frank pulmonary edema and DAH raises the question of an additional precipitant. Possibilities include acute volume overload in the setting of severe diastolic dysfunction, profound preload reduction exacerbating outflow tract obstruction leading to increased severity of mitral regurgitation, or sustained arrhythmia. None of these factors appear to have been responsible in this patient during his diagnosis and treatment at our institution. The association with hemolysis has been described but is extremely rare. A more common association is lower gastrointestinal bleeding resulting from acquired von Willebrand disease.3
The key principle in the management of obstructive HCM is to implement lifestyle measures such as avoiding dehydration or excessive vasodilation (ie, alcohol, saunas, nitrates, phosphodiesterase-5 inhibitors, and certain antihypertensive drugs). Providers must also assess for the risk of sudden cardiac death and the role of implantable cardioverter-defibrillators for primary prevention. It is also important to note that all first-degree relatives of these patients should be screened for the disease. In symptomatic patients, the goals of therapy are the same for all therapeutic modalities, namely control of symptoms. Initial therapy is pharmacological with β-blockade, but calcium channel blockers such as verapamil or diltiazem are additional options. Disopyramide is also an appropriate therapy but is probably underused. If medical therapy fails or is poorly tolerated, the next step is septal reduction therapy in experienced, high-volume centers. It should be emphasized that the goal of septal reduction therapy is symptom relief, and although we know that late outcomes in terms of HCM-related mortality are excellent, we do not have definitive data that surgical myectomy prolongs life. In younger, active patients, surgical myectomy remains the gold standard as a Class IIa recommendation in the American College of Cardiology/American Heart Association 2011 guidelines.4 In patients who are not good surgical candidates, alcohol septal ablation has a Class IIa recommendation (Figure 8). However, in patients who are good surgical candidates, alcohol septal ablation has a Class IIb recommendation “after a thorough and balanced discussion.”4 The 2014 European Society of Cardiology guidelines emphasize the role of surgery in the event that other concomitant procedures need to performed (ie, mitral valve repair) but otherwise grade surgical myectomy and alcohol septal ablation similarly.5 Nonetheless, in the case of this young patient with this highly atypical and dramatic presentation, it is hard to argue against surgical septal reduction therapy as a lifesaving procedure.
Patient presentation (continued): Despite β-blockade, with a heart rate of 65 bpm on metoprolol 100 mg twice daily, the patient remained symptomatic. Therefore, our colleagues from cardiovascular surgery recommended proceeding with septal myectomy.6 Intraoperative transesophageal echocardiogram demonstrated basal septum hypertrophy of 21 mm at end diastole, dynamic LVOT systolic obstruction with a peak gradient >90 mm Hg, and severe mitral regurgitation secondary to systolic anterior motion of the mitral leaflets(Figure 9 and Movies II and III in the online-only Data Supplement). The patient underwent successful extensive surgical myectomy(Figure 10 and Movie IV in the online-only Data Supplement) and intraoperative inspection of both lungs by a thoracic surgeon who reported evidence of intraparenchymal blood in all lung lobes without other abnormalities. Pathology demonstrated moderate to severe myocyte hypertrophy, myocyte disarray, and moderate endocardial fibrosis, consistent with HCM(Figure 11).
The patient’s postoperative course was uneventful. His hemoptysis and dyspnea completely resolved. Chest x-ray(Figure 12) showed resolution of the bilateral infiltrates. Repeat TTE revealed no dynamic LVOT obstruction with an LVOT peak gradient of 26 mm Hg(Figure 13) related to residual anemia, as well as mild mitral regurgitation. At the 4-month local follow-up, his hemoglobin, direct bilirubin, lactate dehydrogenase, and haptoglobin normalized. His brain natriuretic peptide level decreased to 200 pg/mL. Follow-up with our HCM clinic for discussion of genetic testing and family screening was recommended.
HCM is a genetically and phenotypically heterogeneous disease7 with a wide spectrum of clinical outcomes ranging from a benign asymptomatic course to a rare few who experience sudden cardiac death.8 This case demonstrates that this relatively common genetic cardiac disease, affecting ≈0.2% of the general population, can present quite atypically.7
The characteristic clinical presentation of obstructive HCM is a nonradiating systolic ejection murmur.8 Patients may be completely asymptomatic or may present with exertional dyspnea, angina, or presyncope. A small subset of patients (1%) are at increased risk of sudden cardiac death; they may be identified by a history of syncope or ventricular arrhythmia or a family history of sudden cardiac death.9,10 Some patients with HCM may be incidentally identified by the presence of left ventricular hypertrophy on a screening ECG. Once patients present, they should be assessed by 2-dimensional Doppler echocardiogram to determine the presence of obstructive physiology. About 75% of patients have no evidence of LVOT obstruction, and observation alone can be used for their management.10 However, if obstruction is present or the patient is symptomatic, then pharmacological intervention with β-blockade or mechanical intervention may be required.5,7
Our patient had several atypical features worth mentioning. Most notable was the presence of hemoptysis caused by DAH. This “red herring” symptom led us to assess for primary pulmonary or autoimmune diseases. Review of the literature on hemoptysis indicates that left-sided heart failure presenting as hemoptysis is very uncommon, accounting for ≈4% of hemoptysis cases in an epidemiological study (Table 2).11 In the case of our patient, we propose that both significant LVOT obstruction and mitral regurgitation were responsible for causing acute episodes of diastolic left ventricular failure resulting in flash pulmonary edema. These tended to occur at night with the patient recumbent, likely reflecting a very significant contribution of myocardial diastolic dysfunction, overwhelming any benefit of left ventricular cavity size increase on decubitus. The resulting acute severe pulmonary hypertension was the likely mechanism for the bland DAH, possibly further facilitated by acquired Von Willebrand disease in the setting of obstructive HCM.3 Unfortunately, we did not evaluate our patient for loss of Von Willebrand factor.
LVOT obstruction presenting as hemolytic anemia has been associated with obstructive HCM in only a few case reports12–17; it is more notably associated with prosthetic valves.18 These case reports proposed that gradients >50 mm Hg may create significant shear stress, causing red blood cell fragmentation and subsequent hemolysis.12 They further showed that if pharmacological or surgical management could lower the gradient to <50 mm Hg, the hemolysis would resolve.17 One case series demonstrated that mild anemia was present in several patients with obstructive HCM and elevated LVOT gradient, implying that hemolysis may be common but not regularly recognized.19 We propose that our patient’s LVOT obstruction generated mechanical hemolysis, which worsened the already existing DAH-related anemia, which in turn increased left ventricular contractility and worsened LVOT obstruction, thus creating a vicious circle, undoubtedly leading to his severely symptomatic presentation. We cannot directly prove that his hemolysis was related to high shear stress related to LVOT obstruction, but the resolution of anemia and normalcy of haptoglobin and lactate dehydrogenase values at follow-up provide indirect evidence that obstructive HCM-related hemolysis was indeed the case.
HCM can present quite atypically, as demonstrated by this case, in which flash pulmonary edema–related DAH, mechanical hemolysis, and anemia were the debuting features. As illustrated in our case, HCM with severe obstruction and significant mitral regurgitation may present with episodic flash pulmonary edema, leading to respiratory insufficiency. Hemoptysis secondary to bland alveolar hemorrhage is a rare sign of left ventricular congestive heart failure and should be considered if there is evidence of elevated left-sided filling pressures or valvular heart disease after other potential pulmonary and systemic underlying causes have been carefully ruled out. The presence of mechanical hemolytic anemia in patients with obstructive HCM is rare but must be recognized.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.018730/-/DC1.
- © 2016 American Heart Association, Inc.
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