Biomedical subjects
Publications and source records attributed to J S Pirolo.
Whipple's disease is a systemic illness that can affect the heart, causing pericarditis, myocarditis, and valvular endocarditis. We describe a 43-year-old man without gastrointestinal symptoms who underwent mitral and aortic valve replacement for endocarditis, in whom a diagnosis of Whipple's disease was made at operation.
BACKGROUND: Coronary angiography is used to determine the severity of coronary artery disease; however, in a small group of patients, clinically significant angina and physiologic tests indicative of myocardial ischemia do not correlate with angiographically demonstrable critical coronary artery disease. In these patients intracoronary ultrasound may demonstrate the true severity of lesions. METHODS: Eight patients with angina and positive stress testing but without angiographically critical left main or left anterior descending artery stenoses were retrospectively identified. After intracoronary ultrasonic demonstration of critical left main or left anterior descending artery lesions, coronary artery bypass grafting was performed. Follow-up evaluation of clinical status and repeat stress testing were carried out. RESULTS: Intracoronary ultrasound demonstrated critical left main (n = 4) or proximal left anterior descending artery (n = 7) stenoses in all patients. Severity of angiographic versus intracoronary ultrasound-documented stenoses was (mean +/- standard error of the mean) 10% +/- 10% versus 65% +/- 10% for left main lesions and 30% +/- 5% versus 75% +/- 5% for left anterior descending artery lesions. After coronary artery bypass grafting all patients had decreased angina and normalization of stress testing. CONCLUSIONS: In patients with clinical presentations indicative of significant coronary artery disease but with angiographically noncritical lesions, intracoronary ultrasound can accurately assess the severity of stenoses. Coronary artery bypass grafting guided by intracoronary ultrasonic findings successfully treats myocardial ischemia in these patients.
Accessory atrioventricular (AV) pathways responsible for the Wolff-Parkinson-White syndrome have been treated successfully by surgical and radiofrequency catheter ablation techniques. In this study, we explored the feasibility of permanent chemical ablation of accessory pathways by direct injection of 100% ethanol into the canine AV groove. Right coronary artery blood flow and AV compartment pressure were measured in 5 adult mongrel dogs (part I) during injection of saline solution (10 to 15 mL) into the right AV groove. Atrioventricular groove compartment pressure increased from 1 +/- 1 to 31 +/- 12 mm Hg (p < 0.0001) and right coronary artery blood flow increased slightly from 117 +/- 17 to 138 +/- 44 mL/min (p = not significant). In 8 additional dogs (part II), 100% ethanol (10 mL) was injected into the left AV groove. After 6 weeks (n = 6) or 12 weeks (n = 2), histologic examination of the left AV groove demonstrated localized fibrous replacement of injured epicardial muscle, with only scant inflammatory infiltrate. Mild intimal fibrosis and intimal proliferation were present in the circumflex artery and its larger branches, but no significant luminal narrowing was evident. Angiograms at 12 weeks (n = 2) demonstrated no significant narrowing of the circumflex artery. In summary, injection of 100% ethanol into the AV groove is capable of locally ablating myocardial tissue, presumably including conductive tissues, while sparing the coronary arteries.
A new experimental method for the evaluation of myocardial constitutive models combines magnetic resonance (MR) radiofrequency (RF) tissue-tagging techniques with iterative two-dimensional (2-D) nonlinear finite element (FE) analysis. For demonstration, a nonlinear isotropic constitutive model for passive diastolic expansion in the in vivo canine heart is evaluated. A 2-D early diastolic FE mesh was constructed with loading parameters for the ventricular chambers taken from mean early diastolic-to-late diastolic pressure changes measured during MR imaging. FE solution was performed for regional, intramyocardial ventricular wall strains using small-strain, small-displacement theory. Corresponding regional ventricular wall strains were computed independently using MR images that incorporated RF tissue tagging. Two unknown parameters were determined for an exponential strain energy function that maximized agreement between observed (from MR) and predicted (from FE analysis) regional wall strains. Extension of this methodology will provide a framework in which to evaluate the quality of myocardial constitutive models of arbitrary complexity on a regional basis.
BACKGROUND: In humans, chronic ventricular tachycardia (VT) is usually associated with myocardial infarcts that involve the interventricular septum. In an effort to more closely mimic the anatomic substrate that gives rise to chronic VT in humans, we developed a canine model of VT in which the anterior septal coronary artery was ligated. The site of earliest activation, the subsequent activation sequence, and the mechanism of VT associated with the resultant ventricular septal infarct was then evaluated to determine if this model accurately reflected the characteristics of human VT. METHODS AND RESULTS: Seventeen dogs underwent occlusion-reperfusion ventricular septal infarcts. Four to 7 days later, electrophysiological studies were performed. VT was initiated by programmed electrical stimulation and terminated by pacing at a cycle length of 50% to 75% of the VT cycle length. Electrophysiological studies were performed using a 256-channel mapping system. A total of 15 VT morphologies were mapped in 9 animals. Fourteen of 15 morphologies had septal subendocardial sites of earliest activation and 1 had a septal midwall site of earliest activation. VT ablation was performed using a nitrous oxide cryoprobe and confirmed the site of earliest activation by subsequently rendering VT noninducible. Electrophysiological studies demonstrated four distinct VT activation sequences: (1) circular reentrant (n = 7), (2) concentric spread (n = 5), (3) figure-of-eight (n = 2), and (4) septal midwall (n = 1). CONCLUSIONS: This canine model of ventricular septal infarction produces VTs with sites of earliest activation and activation sequences similar to those in humans. A reentrant mechanism as the basis of these arrhythmias is supported by the following observations: (1) all VT was initiated and terminated with programmed electrical stimulation; (2) VT activation sequences were consistent with reentry; and (3) precise interruption of the sequence terminated the VT and rendered it noninducible.
Noninvasive telemetric monitoring of canine heterotopic cardiac allograft unipolar peak-to-peak amplitude (UPPA) has permitted prospective surveillance for rejection; moreover, this technique is able to reliably detect rejection before the development of histologic evidence of myocyte necrosis. This study was performed to determine whether early cardiac allograft rejection and the accompanying decline in allograft UPPA were associated with alterations in regional myocardial blood flow (RMBF). Seven heterotopic, intrathoracic canine cardiac transplantations were performed using triple-drug immunosuppression. Native hearts and allografts were instrumented with right ventricular and left ventricular epicardial screw-in electrodes connected to subcutaneous telemeters. Daily measurement of native and graft UPPA was performed; using radioactive microspheres, native and graft RMBF were determined during the control period and when UPPA had declined by 15%, 30%, and 45%. Graft histologic status was determined by endomyocardial biopsy at the time of RMBF determination. Mean duration of the study was 19.7 +/- 3.9 days. Rejection was documented in all animals. The UPPA was stable in native hearts; UPPA declined in the allografts after the onset of rejection. A biphasic change in allograft blood flow was seen. Initially RMBF increased as UPPA declined; a 30% to 45% reduction in UPPA was associated with a 41% increase in RMBF (p = 0.028 versus allograft control). Subsequently, a significant decline in blood flow was observed for reductions in UPPA greater than 45% (0.68 +/- 0.44 versus 1.07 +/- 0.47 mL.g-1 x min-1 for a 30% to 45% decline in UPPA; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)
Electrocardiographically gated magnetic resonance (MR) image acquisition is not optimal for the quantification of in vivo cardiac deformation, because of the cycle-length dependence of cardiac mechanical events. The authors developed a method for acquisition of cardiac MR images gated to the first derivative of left-ventricular-developed pressure and used the method in a canine model. Application of this method may improve myocardial stress-strain analyses.
A method for cardiac allograft surveillance that is less invasive than endomyocardial biopsy is needed. A fall in the unipolar peak-to-peak amplitude recorded from cardiac allografts has been shown to detect rejection when retrospectively compared with endomyocardial biopsy. This study was performed to assess the sensitivity and specificity of prospective telemetric unipolar peak-to-peak amplitude surveillance in detecting rejection of heterotopic canine cardiac allografts occurring through triple drug immunosuppression. Native heart and graft amplitudes were telemetrically acquired on a daily basis. A fall in normalized unipolar peak-to-peak graft amplitude to less than 85% was used as an indication for biopsy. A quantitative rejection score was calculated for each endomyocardial biopsy (rejection score greater than 0.66 = histologic rejection). Rejection was documented in all animals. Thirty-six biopsies were performed (10 control biopsies and 26 amplitude-directed biopsies); 25 of the 36 demonstrated rejection. Sensitivity and specificity were 88% and 91%, respectively. A linear correlation between unipolar peak-to-peak amplitude and rejection severity was seen (R = 0.87, p less than 0.001). The first true positive amplitude was associated with mild-to-moderate rejection (rejection score = 1.63 +/- 0.45). Unipolar peak-to-peak amplitude recorded from native hearts remained stable during allograft rejection. It is concluded that prospective, telemetric cardiac allograft surveillance can accurately detect rejection occurring through ongoing immunosuppression.
The instantaneous regional stress distribution within the myocardium, which cannot be directly measured, has been estimated using improved numerical methods and nonaxisymmetric biventricular geometry. To do this, we have employed computer-aided solid mathematical modeling to generate a three-dimensional representation for an ex vivo canine biventricular unit using magnetic resonance imaging. A two-dimensional transverse section was isolated from the solid mathematical model for regional stress analysis using p-version finite element analysis. Loading conditions and material property descriptions were taken from published reports. Analyses showed the maximum principal stresses to range from -1.76 X 10(5) to 8.52 X 10(5) dynes/cm2 during systolic loading, and from -3.85 X 10(4) to 1.13 X 10(5) dynes/cm2 during diastolic loading. This study demonstrates that magnetic resonance image-based solid mathematical biventricular models are suitable for regional stress analysis using p-version finite element analysis. p-Version finite element analysis using magnetic resonance image-based cardiac representations facilitates in vivo stress-strain analyses and may allow the clinical estimation of regional myocardial stress.
An improved method of cardiac allograft surveillance, less invasive than endomyocardial biopsy (EMB), is required as the scope of cardiac transplantation increases. The correlation between changes in telemetrically recorded intramyocardial electrograms and the degree of rejection was examined. The electrophysiological parameter assessed was the unipolar peak-to-peak amplitude (UPPA), defined as the magnitude of the first, fast negative deflection of the QRS complex in unipolar electrograms. A canine model of intrathoracic heterotopic cardiac transplantation was employed in which each graft was instrumented with four unipolar intramyocardial electrodes (two left ventricle [LV] and two right ventricle [RV]) connected to two telemetric pacemakers. Immunosuppression was begun at operation and continued for a variable period of time following the acquisition of control data (postoperative days 6-10). Graft status was monitored via biweekly EMB. Intramyocardial electrograms were recorded from each lead during sinus rhythm and 36 atrial and ventricular pacing protocols on a daily basis. The daily UPPA was calculated for each rhythm sequence and expressed as percent of control UPPA. EMBs were qualitatively graded and assigned a quantitative rejection score (0 = none; 3 = severe). Criteria for rejection were rejection score (RS) greater than or equal to 0.66 or daily UPPA less than 85% control. Eight animals were included for study and, in all animals, rejection was documented. A total of 30 EMBs were obtained; in 11 EMBs rejection was present by histological criteria. Analysis of grouped UPPA data from all four leads revealed a sensitivity and specificity of 91% and 84%, respectively, in the detection of rejection. Analysis of grouped sinus UPPA data from the two LV leads revealed a sensitivity of 94% and 91%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The reasons for the marked variability in expansion of myocardial infarcts are unknown. To examine this question, the hearts in 204 patients with a single myocardial infarct, autopsied at The Johns Hopkins Hospital and studied after coronary arteriography and fixation in distension, were reviewed. There were 58 (28%) hearts with marked infarct expansion, 34 (17%) with moderate expansion and 112 (55%) with no or minimal expansion. The degree of expansion was greater in larger, more transmural infarcts (p less than 0.001). Infarcts with greater expansion had significantly more endocardial thrombus (p less than 0.001) and endocardial fibroelastosis (p less than 0.01). Larger heart weight and degree of left ventricular hypertrophy had a significant negative correlation with infarct expansion (p less than 0.05). A markedly greater degree of expansion was noted in the 101 infarcts (50%) caused by lesions in the distribution of the left anterior descending coronary artery as compared with the 57 infarcts (28%) secondary to right coronary lesions and the 46 infarcts (23%) in the distribution of the left circumflex coronary artery (p less than 0.001). The results show that expansion is associated with large infarcts but is less marked in hearts with ventricular hypertrophy. Expansion occurs predominantly in infarcts in the left anterior descending coronary artery distribution, that is, regions of the left ventricular myocardium with the greatest curvature. These results suggest that the degree to which an infarct expands may be influenced by the preinfarction thickness of the ventricular wall.
Studies of myocardial function during ischaemic or anoxia would be assisted if it were possible to inhibit glycolysis completely and reversibly. Three methods of preventing glycolysis in isolated perfused ferret hearts were studied: (a) the removal of glucose from the perfusate followed by manoeuvres designed to deplete glycogen stores, (b) the use of 2-deoxyglucose, and (c) the use of iodoacetate. The rate of glycolysis before and after applying the three methods was assessed by measuring lactate production during short periods of anoxia. Metabolic changes associated with each method were investigated with phosphorus nuclear magnetic resonance, and other side effects associated with each method were assessed by measuring developed pressure. The results show that removal of glucose followed by glycogen depletion reduced the rate of glycolysis to any chosen extent and that the method was reversible. 2-Deoxyglucose treatment did not lead to complete inhibition of glycolysis, was not reversible, and reduced the concentrations of phosphocreatinine and adenosine triphosphate in the heart. Iodoacetate treatment completely blocked glycolysis, but it was not reversible and subsequent periods of anoxia lead to a rapid fall in adenosine triphosphate owing to the accumulation of phosphorylated glycolytic intermediates.
31P nuclear magnetic resonance was used to measure the relative concentrations of phosphorus-containing metabolites in Langendorff-perfused ferret hearts. Intracellular concentrations of inorganic phosphate ([Pi]i), phosphocreatine [( PCr]i), ATP ([ATP]i) and [H+] (pHi) were determined. Exposure of the heart to strophanthidin (10-40 microM) produced an increase in developed pressure over 5-10 min. In the presence of strophanthidin, [ATP]i was unchanged, [PCr]i showed a small fall, [Pi]i showed a small rise and there was a small acidosis. Exposure of the heart to a solution in which all the Na had been replaced by K (0 Na(K) solution) produced an increase of resting pressure which then decayed. During this contracture [PCr]i fell transiently and [Pi]i rose transiently with approximately the same time course as the contracture. However, [ATP]i remained constant throughout. The exposure to the 0 Na(K) solution also produced an intracellular acidosis. The changes in [PCr]i and [Pi]i and the intracellular acidosis were all increased during perfusion with 0 Na(K) if the heart had previously been exposed to strophanthidin. The efflux of lactate from the heart was increased during the exposure to the 0 Na(K) solution. The magnitude of this increase was enhanced by prior exposure to strophanthidin. The increase of intracellular lactate (calculated from this efflux) was sufficient to account for the observed intracellular acidification. An increase of lactate efflux could also be measured when an isolated papillary muscle was exposed to the 0 Na(K) solution. The intracellular acidification produced by Na removal was substantially decreased after prevention of glycolysis either by substrate depletion or by the application of iodoacetate. Elevation of the extracellular calcium concentration ([Ca2+]o) produced a large increase of developed pressure which was accompanied by a small transient increase of [Pi]i, a decrease of [PCr]i and a small intracellular acidosis. There was also an increase of lactate efflux. After exposure to strophanthidin the same increase of [Ca2+]o decreased developed pressure. The associated rise in [Pi]i and fall in [PCr]i were increased but there was no significant acidosis under these conditions. In addition to other explanations (Allen, Eisner, Pirolo & Smith, 1985a), it is likely that the fall of force is partly accounted for by the rise of [Pi]i.
The pathologic correlate of the clinical terms subendocardial and transmural applied to myocardial infarcts is uncertain. To examine this question, we reviewed the morphology of 204 hearts with single myocardial infarcts studied at autopsy after coronary arteriography and fixation in distention. The thickness of surviving myocardium with the infarct (S) and the thickness of the adjacent noninfarcted myocardium (A) were measured microscopically and expressed as a ratio. The S:A ratios ranged from 0.00 to 0.83. Necrosis of the entire wall (S:A ratio = 0.00) was seen in 37 (18%) cases. Distribution of the remaining cases by 10% intervals of wall necrosis (ie, from 0.00 less than S:A ratio less than or equal to 0.10 through 0.90 less than S:A ratio less than or equal to 1.00) were present in 27, 33, 31, 24, 25, 12, 8, 6, 1, and 0 cases, respectively. A lower S:A ratio was correlated with infarct size, infarct expansion, infarct rupture, proximal location of the coronary artery lesion causing the infarct, recency of the infarct, and degree of endocardial mural thrombus. A higher S:A ratio was correlated with the degree of left ventricular hypertrophy. No correlation was observed between S:A ratio and several measures of coronary artery disease. Multivariate regression analysis showed that infarct expansion, infarct age, and rupture were distinct predictors of infarct thickness. The study shows that thickness of myocardium surviving with an infarct forms a continuum; there is no evidence of separate populations that would correspond to infarcts of transmural or subendocardial extent.
Electromechanical dissociation (EMD), defined as electrocardiographically adequate ventricular systolic complexes in the absence of detectable pulse or blood pressure, may occur in the terminal course of patients and is frequently unexplained. The 50 cases in the autopsy files of The Johns Hopkins Hospital in which the patients had died after documented episodes of EMD were reviewed. Four major categories of patients were identified: In 22 of 50 cases (44 per cent) myocardial ischemia appeared to precipitate EMD; in 14 of these 22 cases (64 per cent) myocardial ischemia was global in extent, while in eight (36 per cent) myocardial ischemia was regional, occurring in the distribution of an occluded coronary artery. A subset of ten patients with ischemia had terminal ventricular tachycardia or fibrillation, which was converted to EMD following resuscitation maneuvers. In 12 of 50 cases (24 per cent) systemic shock preceded the development of EMD; in nine of these 12 (75 per cent) hypotension was due to myocardial or arterial rupture, while in three (25 per cent) hypotension was secondary to sepsis. In ten of 50 cases (20 per cent) pulmonary vascular compromise was the apparent cause of EMD. Of these ten cases, eight (80 per cent) were secondary to pulmonary embolization, and two (20 per cent) were due to pneumothorax. In six of 50 cases (12 per cent) the precise cause of EMD could not be determined. The results of this study indicate that in the dying patient with electromechanical dissociation the differential diagnosis should include myocardial ischemia, systemic shock, and pulmonary vascular compromise.
31P nuclear magnetic resonance was used to measure the relative concentrations of phosphorus-containing metabolites in Langendorff-perfused ferret hearts. Intracellular concentrations of inorganic phosphate ([Pi]i), phosphocreatine ([PCr]i), ATP ([ATP]i) and H+ (pHi) were monitored under control conditions and while oxidative phosphorylation and/or glycolysis were prevented. Mechanical performance was assessed by recording the pressure developed in a balloon placed in the left ventricle. Oxidative phosphorylation was prevented either by replacement of O2 with N2 or by addition of cyanide. When the rate of oxidative phosphorylation was reduced by either method, developed pressure fell to a stable level of about 35% of control after 5 min. The pHi (control value 6.98) first increased to a peak of 7.07 after 2 min but then decreased to give a stable acidosis (pH 6.85). [PCr]i decreased rapidly to about 15% of the control value after 5 min whereas [ATP]i declined very slowly, reaching about 90% of the control value after 10 min. Reduction in the rate of glycolysis was achieved either (i) by removal of external glucose and depletion of glycogen stores by a long (1-2 h) period of stimulation or (ii) by removal of glucose and application of 2-deoxyglucose (1 mM) for 30-60 min. These procedures had only a small effect on pressure development, [ATP]i, [PCr]i and pHi. Measurements of lactate production showed that these procedures reduced the rate of glycolysis by a factor of about 10. When oxidative phosphorylation was prevented during periods when the rate of glycolysis was reduced, developed pressure fell to less than 5% of control after 5 min and there was a subsequent increase in resting pressure (hypoxic contracture). pHi (control value 7.03) first increased to a peak of 7.12 and then declined to about pH 7.00, but there was no subsequent acidosis. [PCr]i fell rapidly to about 10% of control after about 5 min while [ATP]i declined to about half of its control value over 10 min. It is concluded that (i) when oxidative phosphorylation alone is prevented, the changes in pHi can account for a substantial part of the changes in developed pressure. The increase in [Pi]i probably also contributes to the decline of developed pressure. (ii) When oxidative phosphorylation was prevented under conditions in which the rate of glycolysis was also reduced, the more pronounced decline in developed pressure which occurs within 5 min cannot be accounted for by pHi changes and is probably not explained by the rise in [Pi]i or by the moderate fall of [ATP]i.(ABSTRACT TRUNCATED AT 400 WORDS)
The photoprotein aequorin was microinjected into cells on the surface of ferret papillary muscles. Tension and aequorin light, a function of intracellular Ca concentration ([Ca2+]i), were monitored. The preparations were exposed to increased concentrations of extracellular Ca ([Ca2+]o). Small increases in [Ca2+]o led to the usual increase in both the systolic light signal and the developed tension. However, high [Ca2+]o led to a fall in developed tension known as Ca overload. This fall of tension was seen at lower [Ca2+]o if the experiment was performed in the presence of strophanthidin. In conditions of Ca overload, the systolic light signal was either similar in amplitude or larger than the systolic light observed under conditions which did not lead to Ca overload. Oscillations of diastolic light were invariably present under conditions of Ca overload. These oscillations were accompanied by after-contractions which were small in relation to the magnitude of the aequorin light oscillations. During Ca overload, the variance of the amplitude of the systolic light signal was greater than could be accounted for by the random nature of the arrival of photons. Small systolic light signals occurred when there had been an oscillation of light in the diastolic period immediately preceding the systolic light signal. Large systolic light signals occurred when the preceding period (approximately 1 s) was free of oscillations of light. These observations suggest that if the sarcoplasmic reticulum (s.r.) has spontaneously released its contents of Ca as shown by a diastolic [Ca2+]i oscillation, then a stimulated systolic Ca signal occurring within about the next second is smaller, possibly because it takes longer than this period for the s.r. to reload with Ca. If this process occurs randomly in the various cells of the preparation, developed tension will be reduced because those cells which have a small Ca release will act as a compliance in series with cells which have a large Ca release.
The nature of the changes occurring in the border zone of myocardial infarcts is uncertain. To study this question, the authors analyzed a number of morphologic features in hearts studied after postmortem arteriography and fixation in distention from 204 patients with single myocardial infarcts autopsied at The Johns Hopkins Hospital. Vacuolization of myocytes was observed in 53 (26%) cases, predominantly in surviving subendocardium and trabecular myocardium within the infarct. Lateral myocardium seldom and subepicardial myocardium almost never showed vacuolar change. Myocyte vacuolization progressively developed and then decreased with time: 1/20 (5%) hearts with infarcts less than 2 days old, 17/48 (35%) infarcts 2-14 days old, 13/27 (48%) infarcts 15-60 days old, 4/12 (33%) infarcts 61-365 days old, and 18/97 (19%) infarcts greater than 365 days old. Reduction in vacuolization with time was not explained by necrosis of vacuolated cells; rather, the myocardium showed normal morphology. Presence of vacuolization in old infarcts was associated with severe multivessel coronary artery disease and endocardial fibroelastosis. The results suggest that infarct border zone myocyte vacuolization may be correctable by reversal of regional ischemia; however, only a trivial amount of myocardium, relative to infarct size, undergoes vacuolar change.