Clinicopathologic Session
Clinicopathologic Session
(Case 3/99 - A 45 - year-old woman with hypertrophic cardiomyopathy and cardiogenic shock
Heart Institute - Incor - HCFMUSP - São Paulo - Brazil)
A 45-year-old woman was admitted to the hospital for the treatment of hypertrophic cardiomyopathy. The patient reported a syncope at the age of 36 years (1989) following major physical exercise. At that time the diagnosis of heart disease was made. When she was 40 years old (May 93) she had an episode of acute onset severe dyspnea, cough and wheezing requiring hospitalization. Heart failure secondary to hypertrophic cardiomyopathy and mitral regurgitation was diagnosed. She suffered from that time on from dyspnea and chest pain on exertion. Her brother had heart disease and her mother, who died of a stroke, had Chagas' heart disease. The patient was referred to the Heart Institute for treatment.
On physical examination, her pulse was regular, with a heart rate of 80 beats per minute and blood pressure was 130/80mmHg. The lungs were normal. There were no abnormal heart sounds and a grade 3/4 holosystolic murmur was heard over the mitral area radiating to the left axilla. The examination of the abdomen was normal and there was no edema. The pulses could be palpated and were symmetrical.
Laboratory results (May 3rd, 1993) disclosed: hemoglobin - 11.8g/dL, hematocrit - 38%, creatinine - 0.8mg/dL, sodium - 141mEq/L and potassium - 4.1mEq/L. Chagas´ disease serology was negative. The electrocardiogram showed left atrial and ventricular hypertrophy and the chest films showed an enlarged cardiac silhouette (++/4+), and signs of an enlarged left atrium (double contour). The patient was medicated with propranolol (80mg/day).
The echocardiogram performed in August of 93 showed asymmetric myocardial hypertrophy (tab. I).
During follow-up, the patient continued to complain of tiredness and dyspnea on exertion and nocturnal episodes of shortness of breath. Furosemide (40mg) was added to the therapeutic regimen. The patient continued to experience dyspnea on minimal exertion.
After seven months she was admitted to the hospital because of dyspnea. On physical examination, she had a heart rate of 80 beats per minute, blood pressure of 80/60mmHg, clear lungs, no abnormal heart sounds and a grade 2 systolic murmur at the apex radiating to the axilla. The abdomen was normal and there was no edema.
Laboratory results were: hemoglobin 9.7g/dL, hematocrit 31%, mean corpuscular volume 76µm3, mean corpuscular hemoglobin 24 pg, white cell count 5,600 cells/mm3, 182,000 platelets/mm3, creatinine 0.9mg/dL, urea 26mg/dL, glucose 107mg/dL, potassium 3.8mEq/L, sodium 139mEq/L.
The ECG disclosed sinus rhythm, heart rate of 75 bpm, QRS axis at 0° toward the back, poor R wave progression from V1 to V3, left ventricular hypertrophy and mild abnormalities of the ventricular repolarization (fig. 1).The chest films revealed slight enlargement of the cardiac silhouette, a bulging middle arch and increased pulmonary vessels. Data of the echocardiogram are presented in table I.
After the interruption of propranolol use the patient had an episode of acute pulmonary edema, which resolved after the intravenous infusion of 40 mg furosemide and 5mg propranolol. She received, daily, 320mg of propranolol, iron supplementation, vitamin B12 and folic acid for anemia.
Heart failure was compensated and she was released from the hospital. However, during the follow-up appointments she continued to complain of incapacitating dyspnea, that kept her seated or lying down most of the day. Due to frequent palpitations, a 24h Holter recording was requested, which did not disclose significant arrhythmia (tab. II).
The complaints of effort dyspnea and palpitations persisted, despite the medication. The induction of complete AV block by ablation at the level of the atrio-ventricular node, followed by permanent pacemaker insertion, was considered; however, the procedure was postponed.
She underwent a right ventricular biopsy, after 4 years. Physical examination disclosed a patient in good general health, with no shortness of breath at rest. Her pulse was regular at a frequency of 88 bpm and blood pressure was 110/80mmHg. The findings from a pulmonary examination were normal, and a grade ++++/4+ systolic murmur was heard at the apex. The liver edge could be palpated 8 cm below the right costal margin. There was no edema. The laboratory examination disclosed: hemoglobin 11.2g/dL, hematocrit 35%, mean corpuscular volume 71µm3, mean corpuscular hemoglobin 23pg, white cell count 6,100 cells/mm3, 239,000 platelets/mm3, creatinine 0.8mg/dL, urea 70mg/dL, glucose 114mg/dL, potassium 4.3mEq/L, sodium 144mEq/L.
The ECG (June 3,1997) showed sinus rhythm, heart rate 63 bpm, indeterminate QRS axis on the frontal plane, bilateral atrial hypertrophy and left ventricular hypertrophy, which was comparatively more severe than that of the previous ECG (fig. 2).
At the biopsy procedure, a small fragment was obtained in which myocyte hypertrophy was observed.
Another 24h Holter recording was obtained and disclosed frequent premature ventricular contractions and numerous episodes of nonsustained ventricular tachycardia (tab. II).
An abdominal ultrasonographic examination (June 12,1997) revealed hepatomegaly and ascites and no signs of parenchymal liver disease or portal hypertension.
The occlusion of the septal branch of the left anterior descending artery using alcohol during cardiac catheterization was proposed to the patient, in light of the severity of the symptoms, of the difficulty to control them with medical treatment and of the marked limitations imposed on the patient by the disease.
The patient underwent cardiac catheterization aimed at the selective occlusion of the first septal perforator through the infusion of 5mL of ethylic alcohol. Immediately after the infusion, complete heart block was observed, followed by rapidly reversed cardiac arrest and the transvenous implantation of a temporary pacemaker. The patient recovered consciousness and remained stable for 12h, when she developed cardiogenic shock, which was unresponsive to vasoactive drugs evolving to coma and death.
Discussion
Clinical aspects - The present case report descibes a 45-year-old woman with hypertrophic cardiomyopathy who had an unfavorable clinical course.
Hypertrophic cardiomyopathy is a genetically transmitted disease histologically characterized by the presence of myocardial hypertrophy, predominantly in the interventricular septum of a nondilated hyperdynamic left ventricle. In 50% of the cases there seems to be a mutation in one of the four genes controlling contractile protein synthesis in the muscle fibers 1,2 .
The main abnormality of the disease consists in the impairment of the diastolic relaxation causing the elevation of the end diastolic pressure of the left ventricle and leading to pulmonary congestion and dyspnea.
Since the systematic description of the disease in the late 50's and its clinical characterization and development of a therapeutic approach in the beginning of the 60's, the current interest has shifted toward the study of the natural history of the affection and of its prognostic factors. Genetic influences possibly justify the observed morphological, functional and clinical diversity of this entity 1,2.
The disease was believed to possess a malignant prognosis until this decade, when large population studies disclosed a more benign evolutive course 3.
Arteaga 4 studied 214 patients, observing that the long-term survival rate of selected patients in a reference center is probably similar to the general population, with a 0.4% annual mortality rate per year. Among the variables analyzed in that study, only the familial form was associated with increased mortality, with a 2.5 increase in the relative risk compared with the nonfamilial forms. Gender, age, clinical manifestations, the presence of systolic obstruction or mitral regurgitation did not significantly affect prognosis. Hence, the study of the genetic changes involved in the disease is important because it is hoped that genetic alterations associated with greater risk of sudden death can be identified.
In the majority of the cases, hypertrophic cardiomyopathy has few or no symptoms and, often, the disease is diagnosed when relatives of a known patient are investigated.
In the present case, the patient had an episode of syncope at 36 years of age, during intense exertion, when the diagnosis was established. After 4 years, she started complaining of dyspnea, the most common symptom of the disease, present in up to 90% of the symptomatic cases. Dyspnea is most often a consequence of increased left ventricular filling pressures, resulting from diastolic dysfunction.
The first therapeutic approach consists of the medical treatment with negative inotropic drugs, such as beta-blockers, which diminish myocardial oxygen consumption by decreasing heart rate, contractility and myocardial stress. These drugs also relieve left ventricular outflow obstruction, during exercise, leading to clinical improvement. As a second alternative, calcium channel blockers are also used, alone or associated with beta-blockers, because both the enhanced systolic function and the diastolic filling impairment may be related to calcium kinetic abnormalities, and these drugs may act through the improvement in ventricular relaxation 5,6. Diuretics are useful in helping to reduce symptoms of pulmonary congestion, particularly when combined with beta-blockers and calcium channel blockers. Angiotensin-converting enzyme inhibitors are useful in patients with severe systolic dysfunction, in advanced phases of the disease, occurring in approximately 10% of the cases.
Amiodarone has been used in the control of arrhythmia, and there are some studies demonstrating its usefulness in patients refractory to beta-blockers and calcium antagonists, when it improves symptoms and increases exercise capacity, probably through the decrease in heart rate, the improvement of the diastolic function or the negative inotropic effect 7.
There is a subset of patients who have evidence of left ventricular outflow obstruction caused by the contraction of the hypertrophied interventricular septum and by the anterior systolic movement of the mitral valve, associated with functional mitral regurgitation.
Therapeutic maneuvers that reduce the intracavitary pressure gradient, improve myocardial perfusion, ventricular filling pressure and, consequently, the symptoms.
When the intraventricular pressure gradient can no longer be adequately reduced by negative inotropic drugs, the modification of the ventricular excitation, by a two-chamber pacemaker (DDD mode), is an alternative to the surgical resection of the interventricular septum, which was for a long time the sole therapeutic option.
The two-chamber pacemaker acts by inducing a paradoxical movement of the interventricular septum, by enlarging the left ventricular outflow tract, by reducing flow velocity, by decreasing the gradient and by diminishing the anterior systolic movement of the mitral valve. There are studies demonstrating the hemodynamic benefits of pacemaker implantation in hypertrophic cardiomyopathy after five years, and prognosis following pacemaker implantation seems to be similar to that of patients with less severe forms of the disease or without symptoms 8,9. However, there are various reasons for failure of this therapeutic maneuver, because the ability of the pacemaker to relieve the left ventricular outflow obstruction is dependent on programming.
Additionally, 60% of the patients need the association of medical therapy due to the persistence of symptoms, to reduce diastolic dysfunction or to control atrial or ventricular arrhythmia.
The most used surgical technique to reduce the intraventricular gradient is the Morrow procedure 10, which consists of the myectomy of the basal portion of the interventricular septum via the aorta. Its objective is to relieve the existing left ventricular outflow tract obstruction, with improvement in the pressure gradient and mitral regurgitation. The results are good with improvement in symptoms in 70% of the patients and increase in exercise capacity, without compromising left ventricular function. However, it requires cardiopulmonary bypass and carries a mortality risk of around 5%. There is improvement in the quality of life but not prognosis, since the procedure does not reduce the incidence of sudden death.
Observing the significant contribution of the hypertrophied interventricular septum to the flow dynamics of the left ventricular outflow tract in hypertrophic cardiomyopathy, Sigwart demonstrated in 1982 that a brief occlusion of the septal artery with a balloon reduced transiently the intraventricular pressure gradient. In 1995, he published a report describing the induction of localized septal myocardial infarcts via the infusion of ethanol into the septal artery of three patients 11. The aim of the technique was to selectively destroy the hypertrophied part of the left side of the septum. All three patients reported improvement in symptoms, already in the first few days after the operation. The procedure is appealing because of its simplicity, safety and the fact that the effect of the ablation can be predicted by a temporary occlusion of the target vessel.
The results of the first series of patients treated using the technique proposed by Sigwart were published recently 12. All 18 patients had echocardiographic evidence of significant flow obstruction and symptoms of angina or dyspnea despite medical management. The intraventricular pressure gradient was reduced or abolished immediately, within seconds of the alcohol infusion. In the majority of the patients the reduction of the obstruction and the improvement in symptoms persisted during the three month follow-up. Therefore, the results of the first reported series of nonsurgical septal reduction suggest that the procedure produces significant hemodymanic benefit, seems to be acceptable in terms of safety and does not induce the development of left ventricular dilatation or arrhythmia. Recently, in February of 1998, acute and three-month follow-up results of another 25 patients were reported, which describe a similar clinical course 13.
Complications associated with the method are, in all patients, the development of chest pain during the procedure; in 60% of the patients, the development of three fascicular block, with the necessity of permanent pacemaker implantation in 20% of the cases. As with the surgery, this technique can also induce the formation of ventricular septal defects 12,13.
Nonsurgical septal reduction produces significant hemodynamic and symptomatic improvement during medium term follow-up; however, there is the need for prospective randomized studies comparing catheter ablation with other forms of treatment, such as pacemaker insertion or surgery.
In the present case, the patient underwent selective occlusion of the first septal branch by the infusion of 5mL of ethanol. This treatment was indicated because of refractory symptoms. Following the intervention there was total AV block, cardiac arrest, which responded quickly, and the need for pacemaker insertion. After 12 hours of stability, the patient developed unresponsive cardiogenic shock and death. It may be hypothesized that the cause of death was the development of a ventricular septal defect (still not reported in the literature) or more likely the occurrence of diastolic dysfunction, which consists of the very pathophysiological basis of the disease and which could have been worsened by the use of vasoconstricting and inotropic agents.
(Dr. Maria Fernanda Maretti Antunes Garcia)
Clinical diagnoses - a) Pathogenesis: hypertrophic cardiomyopathy; b) final event: cardiogenic shock caused by diastolic dysfunction.
Autopsy
The heart weighed 450g. On the longitudinal slices, severe asymmetrical left ventricular hypertrophy was noted with the left ventricle having greater thickness in the base of the septum (3cm), when compared with the left ventricular free wall (2.0cm). The left ventricular cavity was not dilated. A change in color of the basal region of the interventricular septum was noted. There was a slight right ventricular hypertrophy and the right atrium was dilated, with thrombosis (fig. 3).Whitish focal thickening of the endocardium of the anterior leaflet of the mitral valve and of the left ventricular outflow tract was observed (fig. 4).
Histological examination of the myocardium showed a recent infarct of the basal portion of the interventricular septum, corresponding to the area of color change described above, compatible with a 12-hour evolution. In this region, necrosis of the myocardial small arteries was observed, with areas of inflammatory neutrophilic infiltrate and luminal thrombosis (fig. 5).There was focal myocardial cellular disarray in the left ventricle. Microscopic slices of the middle and apical interventricular septum and of the left ventricular free wall disclosed small sparse areas of recent infarction. There was a small artery of the right ventricle with necrosis of the wall. There were morphological changes suggestive of chronic passive congestion of the lungs and liver.
(Dr. Luiz Alberto Benvenuti)
Pathological diagnosis - 1) Asymmetrical hypertrophic cardiomyopathy; 2) parietal necrosis and thrombosis of small myocardial arteries, with a recent transmural myocardial infarction of the basal portion of the interventricular septum.
Comments
This is a case of the classical form of asymmetric cardiomyopathy, described by Teare, in 1958, when there is a predominance of ventricular septal hypertrophy. In cases with left ventricular outflow tract obstruction, focal endocardial thickening is commonly observed, located on the anterior leaflet of the mitral valve and in the left ventricular outflow tract (mirror image of the anterior leaflet), consequent to the friction produced by the contact of these structures during the anterior systolic movement of the mitral valve, generated by the high pressure gradient of the left ventricular outflow tract 14.
Recently, the nonsurgical septal reduction in hypertrophic cardiomyopathy has been obtained through the induction of an infarction in the basal portion of the interventricular septum by the infusion of alcohol into the first septal branch of the anterior interventricular artery. Analysis of 18 patients who underwent this procedure showed a significant reduction of the left ventricular outflow tract. One of these patients had episodes of ventricular tachycardia, ST-segment elevation on the ECG, severe increase in CK levels (14,960 IU) and transient occlusion of the anterior interventricular artery. These complications were interpreted as secondary to the leakage of alcohol into the anterior interventricular artery 12.
In the present case, due to the fact that areas of recent infarction were observed in the middle and apical portions of the septum and in the ventricular free wall, it is possible that there was alcohol leakage into other coronary branches besides the first septal branch. The observation of an artery of the right ventricle with parietal necrosis supports this hypothesis. It is possible that the infarct actually produced was larger than necessary, leading to the patient's cardiogenic shock, which constituted in the final cause of death.
(Dr. Luiz Alberto Benvenuti)
Editor: Alfredo José Mansur
Editores Associados: Desidério Favarato; Vera Demarchi Aiello
Corespondência: Alfredo José Mansur - Incor - Av. Dr. Enéas C. Aguiar, 44 -05403-000 - São Paulo, SP
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Publication Dates
-
Publication in this collection
08 Jan 2002 -
Date of issue
June 1999
