Heart attacks, heart rate, and gel electrodes: the invention of ambulatory cardiology.

Ambulatory cardiology began in 1959 in a department of pathology to answer a question raised at the autopsy table: are high heart rates in apparently healthy individuals a risk factor for developing coronary artery disease? This question led to the development of a miniature monitor and a new kind of electrode, which enabled clinicians to measure EKG signals during activity and over prolonged periods of time. These electrodes are now used universally for diagnosis and for monitoring the heart during a myriad of different activities and circumstances. The story of the development of the monitor and electrodes illustrates the ways in which ideas and discovery lead to applications and advances in medicine.

B-mode ultrasonographic characterization of carotid atherosclerotic plaques in symptomatic and asymptomatic patients.

OBJECTIVE: To identify features on B-mode ultrasonography (US) prevalent in symptomatic plaques and correlate these findings with histopathologic markers of plaque instability. METHODS: Carotid endarterectomy (CEA) plaques from symptomatic and asymptomatic patients with critical stenoses (>70%) were qualitatively assessed using preoperative B-mode US for echolucency and calcific acoustic shadowing. US echolucency was quantitated ex vivo using computerized techniques for gray-scale median (GSM) analysis. Histopathologic correlates for US plaque echolucency (percentage of necrotic core area) and acoustic shadowing (percentage of calcification area) were determined. RESULTS: Fifty CEA plaques were collected from 48 patients (46 unilateral and two bilateral); 26 of these plaques were from symptomatic patients. Age, degree of stenosis, and atherosclerotic risk factors were similar for the symptomatic and asymptomatic patients. Using preoperative B-mode US, 58%, 35%, and 7% of symptomatic plaques and 18%, 41%, and 41% of asymptomatic plaques were found to be echolucent, echogenic, and calcific, respectively (P < .05). Using ex-vivo B-mode US and GSM analysis, symptomatic plaques were more echolucent (41 +/- 19) than asymptomatic plaques (60 +/- 13), P < .03. A strong inverse correlation was found between the percent plaque necrotic area core and GSM (R = -0.9, P < .001). Percentage of calcification area in plaques with acoustic shadowing was 66% and only 27% in those without acoustic shadowing (P < .05). CONCLUSIONS: Using B-mode US, symptomatic plaques are more echolucent and less calcified than asymptomatic plaques and are associated with a greater degree of histopathologic plaque necrosis. Such features are indicative of plaque instability and should be considered in the decision-making algorithm when selecting patients with high-grade asymptomatic carotid stenosis for intervention.

Degree of carotid plaque calcification in relation to symptomatic outcome and plaque inflammation.

OBJECTIVE: We undertook this study to quantitate differences in the degree of calcification between symptomatic and asymptomatic plaques removed at carotid endarterectomy (CEA) and to determine associated extent of plaque macrophage infiltration, a histopathologic feature of plaque instability. METHODS: CEA plaques (n = 48) were imaged at 1.25-mm intervals with spiral computed tomography (CT; 10-15 images per plaque). Indications for CEA were transient ischemic attack (n = 16), stroke (n = 5), amaurosis (n = 4), and critical asymptomatic stenosis (n = 23). The percent area calcification for each plaque was determined in spiral CT serial sections and averaged for each plaque. In 31 of 48 plaques macrophage infiltration was quantitated in corresponding histologic sections with immunohistochemical techniques. RESULTS: The mean (+/- SD) age of patients with symptomatic and asymptomatic plaques was 66 +/- 7 years vs 71 +/- 7 years, respectively, and degree of stenosis was 76% versus 82%, respectively (P =.05). Atherosclerosis risk factors were similar between groups. Percent plaque area calcification was twofold greater in asymptomatic versus symptomatic plaques (48% +/- 19% vs 24% +/- 20%, respectively; P <.05). At receiver operating characteristic curve analysis, 80% of symptomatic plaques were below and 87% of asymptomatic plaques were above a cutoff point of 30% plaque area calcification. Macrophage burden was greater in the symptomatic plaques than in the asymptomatic plaques (52% vs 23%; P <.03). A strong inverse relationship between the degree of plaque calcification and macrophage infiltration was found in critical carotid stenoses (r = -0.87; P <.001). CONCLUSIONS: Symptomatic plaques are less calcified and more inflamed than asymptomatic plaques. Regardless of clinical outcome, a strong inverse correlation was found between the extent of carotid plaque calcification and the intensity of plaque fibrous cap inflammation as determined by the degree of macrophage infiltration. Carotid plaque calcification is associated with plaque stability, and is a potential spiral CT in vivo quantitative marker for cerebrovascular ischemic event risk.

Sustained inhibition of experimental neointimal hyperplasia with a genetically modified herpes simplex virus.

OBJECTIVE: Reported herein is a potential strategy for sustained smooth muscle cell (SMC) inhibition with a virulence-attenuated herpes simplex virus (HSV). Experiments were conducted in vitro to demonstrate selective SMC cytotoxicity and in vivo to demonstrate reduced neointimal hyperplasia (NIH) in a clinically relevant animal model. METHODS: In vitro: Cultured human umbilical artery smooth muscle cells (UASMC) and venous endothelial cells (HUVEC) were exposed to varying multiplicities of infection (MOI) of a gamma(1)34.5-deleted HSV-1 virus (R849). Cell survival was assessed at 48 and 72 hours with a colorimetric MTT viability assay. In vivo: New Zealand White rabbit external jugular veins (n = 21) were exposed to R849 (2.5 x 10(6) pfu/mL) or culture medium at 110 to 120 mm Hg for 10 minutes, then fashioned as vein patches on carotid arteries. Carotid arteries were ligated distally to decrease blood flow and stimulate a hyperplastic response (ultra-low shear stress model). After 2, 4, 12, and 24 weeks, patched segments were perfusion-fixed with glutaraldehyde and morphometrically examined for NIH formation. RESULTS: In vitro: At 48 hours, R849 exhibited preferential cytotoxicity to UASMC compared with HUVEC, with 11% +/- 10% of UASMCs and 49% +/- 8% of HUVECs surviving after infection with MOI = 25 (P <.05). Higher MOI resulted in poor survival of both cell lines. In vivo: Blood flow was similarly reduced in all animals both at surgery (0.9 +/- 0.1 mL/min vs 1.6 +/- 0.3 mL/min) and at harvest (2.7 +/- 0.4 mL/min vs 2.5 +/- 0.5 mL/min). R849-infected patches exhibited markedly less NIH than control patches did at 2 weeks (162 +/- 14 microm vs 49 +/- 6 microm; P <.05), 4 weeks (190 +/- 27 microm vs 67 +/- 8 microm; P <.05), and 12 weeks (233 +/- 18 microm vs 113 +/- 2 microm; P <.05). CONCLUSION: The virulence-attenuated HSV strain R849 demonstrates selective cytotoxicity for SMC and is capable of sustained inhibition of NIH in an experimental model of vein graft failure.

Human RPE cell lysis of extracellular matrix: functional urokinase plasminogen activator receptor (uPAR), collagenase and elastase.

Age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR) and uveitis are characterized by RPE motility through the ECM of retinal lesions. The purpose of this study was to test the hypothesis that multiple proteolytic systems are functionally intact at the HRPE surface and peri-cellular region and that these activities are differentially modulated by IL-1beta. HRPE cells were evaluated: (1). as individual cells or cell extracts, (2). during migration across three-dimensional ECM-like layers and (3). in tissue sections. The urokirase plasminogen activator receptor (uPAR; CD87) was detected on HRPE cells as well as its functional activity. Although uPAR was associated with CD11b (CR3) on live resting cells, polarized migratory HRPE cells were found to dissociate uPAR from CR3; uPAR then translocated to anterior pole of the cell, where it enhanced PAI-1-inhibitable local proteolytic activity. The relative contribution of uPAR and collagenase in HRPE migration was evaluated using three-dimensional gelatin matrices. Interestingly, uPAR/uPA was found to play a key role in migration across these layers. IL-1 upregulated uPAR, collagenase, and elastase activities, suggesting that cytokines may affect the invasive program of HRPE cells in vivo. Immunohistochemistry for uPAR was performed in sections of human retina. Immunoreactive uPAR was present along the HRPE basolateral membrane in retinal sections and in sections of diseased retinal tissue at an enhanced level. Our results suggest that multiple proteolytic systems are present in association with HRPE and that the uPAR/uPA system may be particularly important.

Diurnal heart rate reactivity: a predictor of severity of experimental coronary and carotid atherosclerosis.

BACKGROUND: Elevated awake resting heart rate (HR) has been shown to be a major risk factor for cardiovascular disease. Since coronary ischaemic events appear to peak during transition from sleep to awake HR, we sought to determine whether the degree of diurnal HR fluctuation (dHRV) is an independent predictor of coronary and peripheral atherogenesis. In this study, we varied both baseline HR and dHRV using sino-atrial node ablation (SNA) in a primate model of diet-induced atherogenesis and determined the degree of plaque formation relative to both HR parameters. METHODS: HR was recorded continuously for 6 months by an implantable intraaortic sensor/transmitter in 17 active unrestricted male cynomolgus monkeys. In nine monkeys, SNA was employed to create a wide spectrum of dHRV, and the power amplitude of dHRV was determined for the daily HRV cycle with power spectral analysis. After a 6-month diet induction period, percent coronary and carotid stenosis, intimal thickness and area were quantitated in each animal. RESULTS: Total serum cholesterol and mean HR were no different between high ( n= 10) and low ( n= 7) dHRV groups (866 mg% vs. 740 mg%, P> 0.2 and 130 +/- 22 and 115 +/- 13, P> 0.1, respectively). Percent carotid stenosis was markedly greater in both high HR and dHRV animals ([HR], 54 +/- 19 vs. 35 +/- 10, P< 0.04) and ([dHRV], 54 +/- 17 vs. 32 +/- 10, P< 0.01). Significant increases in all measures of coronary atherogenesis were found in high dHRV animals when compared with those with low dHRV (percent stenosis: 48% +/- 22 vs. 23% +/- 16, P< 0.02), (lesion area: 1.2 +/- 0.8 vs. 0.3 +/- 0.3, P< 0.02), and (intimal thickness: 0.3 +/- 0.1 vs. 0.1 +/- 0.1, P< 0.01), respectively. While there was a trend towards greater coronary atherogenesis in animals with high HR, this did not reach statistical significance. CONCLUSION: Elevated HR and dHRV are both associated with enhanced experimental atherosclerotic plaque formation. However, a greater degree of carotid and coronary atherogenesis is observed in animals with high dHRV. These findings suggest that elevated dHRV is a stronger predictor for susceptibility to atherogenesis than elevated HR alone. Such a relationship may be attributed to the potential role of dHRV in modulating the frequency of adverse near wall haemodynamic forces, which have been shown to induce atherosclerotic plaques. Lowering of dHRV in humans by exercise or pharmacological agents may have a beneficial role in retarding atherosclerotic plaque induction, progression and complication.

Paravisceral aortic thrombus as a source of peripheral embolization--report of three cases and review of the literature.

Spontaneous embolization resulting in peripheral arterial occlusion remains a significant cause of morbidity and limb loss. Accurate localization and correction of the embolic source is paramount for the prevention of further episodes and for the preservation of long-term patency and limb salvage. Common well-recognized embolic sources include intracardiac thrombus or myxoma, and thrombus within arterial aneurysms or complex atherosclerotic plaques. Less common is thrombus arising de novo in an otherwise normal aorta, possibly as a result of prior trauma, occult arteriopathy, and/or hypercoagulability. Reported herein are three cases of peripheral or mesenteric embolization arising from large thrombi within the visceral aortic segment, with minimal evidence for atherosclerosis or other aortic pathology. Each patient was treated with visceral aortic thrombectomy using a direct surgical approach.

Biphasic response of tropoelastin at the poststenotic dilation segment of the rabbit aorta.

OBJECTIVE: The purpose of this study was to assess the time course of tropoelastin gene expression in the poststenotic dilatation segment of rabbit aorta with experimental coarctation. METHODS: Midthoracic aortic coarctation was created in rabbits to produce a PSD. The time points of the study after coarctation were 1, 3, and 7 days and 2, 4, and 8 weeks (n = 3 each). Additional animals (n = 6) were subjected to hypercholesterolemia for analysis of tropoelastin expression in intimal lesions. Northern and Western blot analyses were used to quantitate tropoelastin messenger RNA (mRNA) and protein, and immunohistochemistry was used to analyze tropoelastin distribution. RESULTS: Thoracic aortic coarctation produced a moderate stenosis, which resulted in PSD. mRNA levels in the PSD segment decreased at days 1 and 3, followed by an increase at 2 and 4 weeks (P <.05 versus controls). This biphasic change in tropoelastin mRNA was associated with increase in tropoelastin protein levels at 2 and 4 weeks (P <.05 versus controls). PSD diameter reached a maximum at 4 weeks and did not increase significantly thereafter. The number of medial elastic laminae in PSD was reduced slightly, but media thickness was unchanged. Intimal lesions were much smaller in the PSD segment than in the proximal segment in animals with hypertension superimposed with hypercholesterolemia. Moreover, tropoelastin protein distributed not only in the intima but also in the media of the PSD. CONCLUSION: Tropoelastin gene expression is regulated in a biphasic pattern and precedes PSD formation. The differential distribution of tropoelastin in the media suggests a role for tropoelastin in the poststenotic adaptation response, which may provide increased elasticity to the PSD wall.

Relative contribution of wall shear stress and injury in experimental intimal thickening at PTFE end-to-side arterial anastomoses.

BACKGROUND: Intimal hyperplastic thickening (IHT) is a frequent cause of prosthetic bypass graft failure. Induction and progression of IHT is thought to involve a number of mechanisms related to variation in the flow field, injury and the prosthetic nature of the conduit. This study was designed to examine the relative contribution of wall shear stress and injury to the induction of IHT at defined regions of experimental end-to-side prosthetic anastomoses. METHODS AND RESULTS: The distribution of IHT was determined at the distal end-to-side anastomosis of seven canine Iliofemoral PTFE grafts after 12 weeks of implantation. An upscaled transparent model was constructed using the in vivo anastomotic geometry, and wall shear stress was determined at 24 axial locations from laser Doppler anemometry measurements of the near wall velocity under conditions of pulsatile flow similar to that present in vivo. The distribution of IHT at the end-to-side PTFE graft was determined using computer assisted morphometry. IHT involving the native artery ranged from 0.0+/-0.1 mm to 0.05+/-0.03 mm. A greater amount of IHT was found on the graft hood (PTFE) and ranged from 0.09+/-0.06 to 0.24+/-0.06 mm. Nonlinear multivariable logistic analysis was used to model IHT as a function of the reciprocal of wall shear stress, distance from the suture line, and vascular conduit type (i.e. PTFE versus host artery). Vascular conduit type and distance from the suture line independently contributed to IHT. An inverse correlation between wall shear stress and IHT was found only for those regions located on the juxta-anastomotic PTFE graft. CONCLUSIONS: The data are consistent with a model of intimal thickening in which the intimal hyperplastic pannus migrating from the suture line was enhanced by reduced levels of wall shear stress at the PTFE graft/host artery interface. Such hemodynamic modulation of injury induced IHT was absent at the neighboring artery wall.

Gene expression of tropoelastin is enhanced in the aorta proximal to the coarctation in rabbits.

To assess elastin biosynthesis in the aortic wall in response to acute elevation of blood pressure, we studied the aortic gene expression of tropoelastin in a rabbit midthoracic aortic coarctation model. The time points of the study were 1, 3, and 7 days and 2, 4, and 8 weeks after coarctation. Additional animals were subjected to hypercholesterolemia for analysis of tropoelastin expression in the intimal lesion. mRNA for tropoelastin was quantitated by Northern blot analysis and its distribution was revealed by in situ hybridization. The 65-kDa tropoelastin was analyzed by Western blotting and immunohistochemistry. Tropoelastin mRNA proximal to the coarctation was increased at 2 weeks and returned to baseline by 8 weeks (P < 0.05 versus control). Changes in 65-kDa tropoelastin corresponded to those of mRNA. Tropoelastin gene was expressed mainly in the intima and in the outer media at the proximal region to the stenoses, which was particularly remarkable in the intimal lesion. The results indicate that tropoelastin gene expression was enhanced in the early remodeling response to elevated blood pressure. The distribution of newly synthesized tropoelastin in the outer media suggests a reenforcement role of tropoelastin, which preserves mechanical resiliency in response to changes in tensile stress.