Mark V. Sherrid

Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy

OBJECTIVES The goal of this study was to determine the impact of race on identification of hypertrophic cardiomyopathy (HCM). BACKGROUND Sudden death in young competitive athletes is due to a variety of cardiovascular diseases (CVDs) and, most commonly, HCM. These catastrophes have become an important issue for African Americans, although HCM has been previously regarded as rare in this segment of the U.S. population. METHODS We studied the relationship of race to the prevalence of CVDs causing sudden death in our national athlete registry, and compared these findings with a representative multicenter hospital-based cohort of patients with HCM. RESULTS Of 584 athlete deaths, 286 were documented to be due to CVD at ages 17 +/- 3 years; 156 (55%) were white, and 120 (42%) were African American. Most were male (90%), and 67% participated in basketball and football. Among the 286 cardiovascular deaths, most were due to HCM (n = 102; 36%) or anomalous coronary artery of wrong sinus origin (n = 37; 13%). Of the athletes who died of HCM, 42 (41%) were white, but 56 (55%) were African American. In contrast, of 1,986 clinically identified HCM patients, only 158 (8%) were African American (p < 0.001). CONCLUSIONS In this autopsy series, HCM represented a common cause of sudden death in young and previously undiagnosed African American male athletes, in sharp contrast with the infrequent clinical identification of HCM in a hospital-based population (i.e., by seven-fold). This discrepancy suggests that many HCM cases go unrecognized in the African American community, underscoring the need for enhanced clinical recognition of HCM to create the opportunity for preventive measures to be employed in high-risk patients with this complex disease.

Time delays in the diagnosis and treatment of acute myocardial infarction: A tale of eight cities Report from the Pre-hospital Study Group and the Cincinnati Heart Project

To establish the magnitude of prehospital and hospital delays in initiating thrombolytic therapy for acute myocardial infarction, the time from telephone 911 emergency medical system (EMS) activation to treatment and its components were analyzed from eight separate ongoing trials. This included estimates of ambulance response time, prehospital evaluation and treatment time, and time from admission to the hospital to initiation of thrombolytic therapy. The average time from EMS activation to patient arrival at the hospital was prospectively determined to be 46.1 +/- 8.2 minutes in 3715 patients from eight centers. The time from admission to the hospital to initiation of thrombolytic therapy was retrospectively determined to be 83.8 +/- 55.0 minutes in a separate group of 730 patients from six centers. Both the prehospital and hospital time delays were much longer than those perceived by paramedics and emergency department directors. Shorter hospital time delays were observed in patients in whom a prehospital ECG was obtained as part of a protocol-driven prehospital diagnostic strategy and a diagnosis of acute infarction made before arrival at the hospital (36.3 +/- 11.3 minutes in 13 patients). These results show that the magnitude of time required to evaluate, transport, and initiate thrombolytic therapy will preclude initiation of treatment to most patients within the first hour of symptoms. Implementation of a protocol-driven prehospital diagnostic strategy may be associated with a reduction in time to thrombolytic therapy.

Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy.

OBJECTIVES The purpose of this study was to determine whether the dynamic cause for mitral systolic anterior motion (SAM) is a Venturi or a flow drag (pushing) mechanism. BACKGROUND In obstructive hypertrophic cardiomyopathy (HCM), if SAM were caused by the Venturi mechanism, high flow velocity in the left ventricular outflow tract (LVOT) should be found at the time of SAM onset. However, if the velocity was found to be normal, this would support an alternative mechanism. METHODS We studied with echocardiography 25 patients with obstructive HCM who had a mean outflow tract gradient of 82 +/- 6 mm Hg. We compared mitral valve M-mode echocardiogram tracings with continuous wave (CW) and pulsed wave (PW) Doppler tracings recorded on the same study. A total of 98 M-mode, 159 CW, and 151 PW Doppler tracings were digitized and analyzed. For each patient we determined the LVOT CW velocity at the time of SAM onset. This was done by first determining the mean time interval from Q-wave to SAM onset from multiple M-mode tracings. Then, CW velocity in the outflow tract was measured at that same time interval following the Qwave. RESULTS Systolic anterior motion began mean 71 +/- 5 ms after Q-wave onset. Mean CW Doppler velocity in the LVOT at SAM onset was 89 +/- 8 cm/s. In 68% of cases SAM began before onset of CW and PW Doppler LV ejection. CONCLUSIONS Systolic anterior motion begins at normal LVOT velocity. At SAM onset, though Venturi forces are present in the outflow tract, their magnitude is much smaller than previously assumed; the Venturi mechanism cannot explain SAM. These velocity data, along with shape, orientation and temporal observations in patients, indicate that drag, the pushing force of flow, is the dominant hydrodynamic force that causes SAM.

An echocardiographic study of the fluid machanics of obstruction in hypertrophic cardiomyopathy

OBJECTIVES The goal of this study was to investigate the hydrodynamic cause of mitral-septal contact and obstruction in patients with hypertrophic cardiomyopathy. BACKGROUND Mitral-septal apposition has been shown to be the cause of obstruction in patients with hypertrophic cardiomyopathy. With obstruction, characteristic continuous wave Doppler tracings show an increasing acceleration of flow. (Tracing is concave to the left.) METHODS We studied 24 consecutive patients who had a Doppler echocardiographic pressure gradient > or = 36 mm Hg. We pursued two lines of inquiry. 1) Before the onset of obstruction, we systematically measured the angle between the direction of left ventricular Doppler color flow and the protruding mitral leaflet in early systole. 2) After the onset of obstruction, we qualitatively analyzed the concave contour of the continuous wave Doppler tracings in our patients and developed a hydrodynamic theory of the obstruction phase to explain the characteristic tracings. We present a mathematic model to support this concept. RESULTS We measured 129 angles. Just before mitral-septal contact, the protruding mitral leaflet projects at a mean 40 degrees and 45 degrees relative to flow in the apical long-axis and apical five-chamber views, respectively. At mitral-septal contact, the obstructing leaflet projects at a mean 52 degrees and 58 degrees relative to flow in the same respective views. Even very early in systole, at leaflet coaptation, 11 of 23 patients had angles > 15 degrees relative to flow. After mitral-septal apposition, obstruction across a cowl-shaped orifice begins. During this stage, the obstructing leaflet projects at a mean 55 degrees and 63 degrees relative to flow. In 22 patients, the continuous wave Doppler tracing of the left ventricular outflow jet showed an increasing acceleration of flow. CONCLUSIONS Just before mitral-septal contact, the protruding leaflets project at high angles relative to flow. At these high angles, flow drag, the pushing force of flow, is the dominant hydrodynamic force on the protruding leaflet and appears to be the immediate cause of obstruction. The high angle between flow direction and the protruding leaflet precludes significant Venturi effects. Even earlier in systole, at leaflet coaptation, flow drag is dominant in half of the patients, with angles relative to flow > 15 degrees. After obstruction is triggered, it appears from our data and model that the leaflet is forced against the septum by the pressure difference across the orifice. The increasing acceleration of Doppler flow is explained by a time-dependent amplifying feedback loop in which the rising pressure difference across the orifice leads to a smaller orifice and a higher pressure difference.

Gene Mutations in Apical Hypertrophic Cardiomyopathy

Background— Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood. Methods and Results— Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2. Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (n=16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members. Conclusions— Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.

Obstructive hypertrophic cardiomyopathy: echocardiography, pathophysiology, and the continuing evolution of surgery for obstruction

Our understanding of the pathophysiology of obstruction in hypertrophic cardiomyopathy has evolved since initial descriptions in the late 1950s. This review addresses the cause of obstruction, from early ideas that a muscular outflow tract sphincter was the cause, through the discovery of systolic anterior motion (SAM) of the mitral valve, to current understanding that flow drag, the pushing force of flow, is the dominant hydrodynamic mechanism for SAM. The continuing redesign and modification of surgical procedures to relieve outflow obstruction have corresponded to ideas about the cause of this condition. In this review we discuss the evolution of surgical procedures to relieve obstruction and review modern surgical approaches. Medical and nonsurgical methods for reducing obstruction are reviewed, as well as efforts to prevent sudden arrhythmic cardiac death. Echocardiography has become central to understanding this complex phenomenon, and for clinical diagnosis, operative planning and intraoperative management.

Mechanism of Benefit of Negative Inotropes in Obstructive Hypertrophic Cardiomyopathy

BACKGROUND Drugs with negative inotropic effect are widely used to decrease obstruction in hypertrophic cardiomyopathy (HCM). However, the mechanism of therapeutic benefit has not been studied. METHODS AND RESULTS We used M-mode, two-dimensional, and pulsed Doppler echocardiography to study 11 patients with obstructive HCM before and after medical elimination of left ventricular outflow tract obstruction. We measured 148 digitized pulsed Doppler tracings recorded in the left ventricular cavity 2.5 cm apical of the mitral valve. Successful treatment slowed average acceleration of left ventricular ejection by 34% (P=.001). Mean time to peak velocity in the left ventricle was prolonged 31% (P=.001). Mean time to an ejection velocity of 60 cm/s was prolonged 91% (P=.001). Before treatment, left ventricular ejection velocity peaked in the first half of systole; after successful treatment, it peaked in the second half (P=.001). In contrast, after treatment, we found no change in peak left ventricular ejection velocity. We also found no change in the distance between the mitral coaptation point and the septum, as measured in two planes, indicating no treatment-induced alteration of this anatomic relationship. CONCLUSIONS Medical treatment eliminates mitral-septal contact and obstruction by decreasing left ventricular ejection acceleration. By slowing acceleration, treatment reduces the hydrodynamic force on the protruding mitral leaflet and delays mitral-septal contact. This, in turn, results in a lower final pressure gradient.

Practical applications in stress echocardiography: Risk stratification and prognosis in patientswith known or suspected ischemic heart disease

OBJECTIVES The purpose of this study was to define appropriate parameters for risk stratification and prognosis in patients undergoing stress echocardiography. BACKGROUND Stress echocardiography is an established technique for the diagnosis of coronary artery disease. However, current data on risk stratification of patients undergoing stress echocardiography are limited. METHODS We evaluated 1,500 patients (59 +/- 13 years old; 51% male) undergoing stress echocardiography (34% with treadmill exercise and 66% with dobutamine). Resting left ventricular ejection fraction (EF) and regional wall motion were assessed by the consensus of two echocardiographers. Follow-up (mean 2.7 +/- 1.0 years) for confirmed non-fatal myocardial infarction (n = 31) and cardiac death (n = 44) were performed. RESULTS By univariate analysis, both the peak wall motion score index (WMSI) (p < 0.0001) and EF (p < 0.0001) were significant predictors of cardiac events. Peak WMSI effectively risk stratified patients into low (0.9%/year), intermediate (3.1%/year), and high (5.2%/year) risk groups (p < 0.0001). A threshold of 45% EF provided further risk stratification of all WMSI groups. By multivariate logistic regression analysis, peak WMSI (relative risk [RR] 2.1, 95% confidence interval [CI] 1.0 to 4.4; p = 0.04) and EF (RR 1.0, 95% CI 0.9 to 1.0; p = 0.01) were both predictors of cardiac events. CONCLUSIONS Stress echocardiography yields prognostic information for risk stratification of patients with known or suspected ischemic heart disease. A normal stress echocardiographic study (peak WMSI = 1.0) confers a benign prognosis (0.9%/year cardiac event rate). Peak WMSI >1.7 and EF < or =45% are independent markers of patients at high risk of an adverse clinical outcome.

Oral disopyramide therapy for obstructive hypertrophic cardiomyopathy

Seven patients with obstructive hypertrophic cardiomyopathy (HC) were treated with oral disopyramide. Left ventricular outflow tract gradients were estimated using either Doppler or M-mode echocardiography. Gradients were measured before treatment, after acute and chronic dosing, after washout and after rechallenge. Disopyramide serum levels were measured at the time of echocardiography. With the first dose, mean outflow gradient decreased from 64 to 14 mm Hg (p less than 0.0001). This decrease in gradient was still present after long-term oral treatment 23 days later, with a mean gradient of 13 mm Hg (p less than 0.001). After withdrawal from the drug, gradient returned to the pretreatment value, 79 mm Hg. After rechallenge, the gradient once again declined to 30 mm Hg (p less than 0.001). High disopyramide serum levels correlated with lower outflow tract gradients, r = -0.77 (p less than 0.0001). Even at low therapeutic drug levels, there was a 49% reduction in outflow tract gradient. Four patients were symptomatically improved and have been maintained on disopyramide for greater than 1 year. In symptomatic patients, disopyramide acutely decreases obstruction and also provides sustained pharmacologic control of obstruction. Disopyramide should be considered as a good alternative to treatment with adrenergic blockers, calcium antagonists or surgery.

Clinical and echocardiographic characteristics of left atrial spontaneous echo contrast in sinus rhythm

OBJECTIVES In this study we attempt to define the clinical and echocardiographic characteristics of patients with left atrial spontaneous echo contrast (LASEC) in sinus rhythm (NSR). BACKGROUND Left atrial spontaneous echo contrast in atrial fibrillation (AF) is associated with increased risk of thromboembolism. Little is known about its significance in NSR. METHODS We reviewed reports of 1,288 transesophageal echocardiogram (TEE) studies done with a 5 MHz probe. Patients with swirling LASEC who were in NSR during TEE were analyzed. We compared them with a control group of 45 age matched patients selected to have NSR, left atrium (LA) > 4.0 cm but no SEC. RESULTS Spontaneous echo contrast in NSR was noted in 24 patients (2%) and formed our study group. All patients with SEC had enlarged LA, mean 5.6 cm +/- 0.6 cm. There was a higher prevalence of cerebrovascular accident (CVA) in patients with SEC when compared with controls with no SEC, 83% versus 56%, p = 0.02. Patients with SEC had larger LA, 5.6 versus 4.9 cm, p < 0.0001 and lower mean peak left atrial appendage emptying velocity (LAAEV), 38 versus 56 cm/s, p = 0.001. Thirteen percent of patients with SEC had LA thrombus as compared with none in the control group, p = 0.02. By multivariate analysis, SEC in NSR was found to be associated with CVA, larger LA size and decreased mean LAAEV. Even after adjusting for LA size, patients with SEC had a higher prevalence of CVA than controls, p = 0.03. CONCLUSIONS Spontaneous echo contrast in NSR occurs in patients with significantly dilated LA and depressed atrial function. Left atrial thrombus is noted in 13% of such patients despite NSR. Spontaneous echo contrast in NSR is associated with a higher prevalence of CVA. Further, SEC is found to be an independent and more powerful correlate of CVA than reduced LAAEV or atrial size. These data indicate that LASEC in NSR is a prothombotic condition.