Accuracy of echocardiographic assessment of pulmonary hypertension severity and right ventricular dysfunction in patients with chronic thromboembolic pulmonary hypertension.

AIM: Chronic thromboembolic pulmonary hypertension (CTEPH) results from chronic thrombotic occlusion of the pulmonary arterial circulation and may be potentially cured by pulmonary thromboendarterectomy. Echocardiography is the most practical modality for the assessment of right ventricular function and right heart pressures before and after surgery. However, there is scant data on how these estimates compare with the "gold standards" of invasive right heart catheterization and CT and MR scanning. METHODS: The records of 100 consecutive patients with CTEPH who subsequently underwent pulmonary thromboendarterectomy at our institution were studied. Right atrial (RA) and right ventricular (RV) systolic pressure estimated at preoperative echocardiography were compared with measurements at preoperative cardiac catheterization. In addition, preoperative echocardiographic estimates of RV systolic function by visual assessment and by calculation of RV index of myocardial performance were compared with preoperative measurements of RV ejection fraction (EF) by computed tomography (CT) or magnetic resonance (MR) scanning. RESULTS: Although estimates of RA and PA systolic pressures by echocardiography correlated significantly with those at cardiac catheterization (p<0.0001) in patients with CTEPH, Bland-Altman analysis demonstrated significant variation in these measurements compared with cardiac catheterization. Cohen's Kappa analysis demonstrated that agreement between echo and cath derived values was slight (κ=0.1). RVEF assessed by CT or MR scanning correlated with echocardiographic visual assessment of RV systolic function (P<0.0001), and with RIMP (P=0.001), but actual measurements of right ventricular ejection fraction at a given assessment of right ventricular function by RIMP or visual assessment varied widely CONCLUSION: Caution is warranted in over-reliance on echo derived measurements of right heart hemodynamics and function in the setting of pulmonary hypertension, and where the clinical scenario calls the data into question, a low threshold should be maintained for proceeding to more advanced and invasive modalities of evaluation.

In vivo effects of contrast media on coronary thrombolysis.

OBJECTIVES: The aim of the present study was to evaluate the influence of radiographic contrast media (CM) on alteplase-induced coronary thrombolysis. BACKGROUND: Contrast media inhibit fibrinolysis in vitro and interact with endothelial cells, platelets and the coagulation system. The in vivo effects of CM on thrombolysis are not known. METHODS: Occlusive coronary artery thrombosis was induced in 4 groups of 10 dogs by the copper coil technique. After 70 min of occlusion the dogs were randomized to intracoronary injection of 2 ml kg(-1) of either saline, a low-osmolar ionic CM (ioxaglate), a low-osmolar nonionic CM (iohexol) or a high-osmolar ionic CM (amidotrizoate). Thrombolysis with alteplase and co-therapy with aspirin and heparin was initiated after 90 min of occlusion. The coronary artery flow was monitored with an electromagnetic flowmeter throughout the experiment. RESULTS: Iohexol and amidotrizoate, but not ioxaglate, were associated with longer reperfusion delays (time to optimal reperfusion: 67+/-48 min and 65+/-49 min, respectively, vs. 21+/-11 min after placebo; p < 0.05) and shorter periods of coronary perfusion (optimal perfusion time: 21+/-26 min and 21+/-28 min, respectively, vs. 58+/-40 min after placebo; p < 0.05). No significant differences were observed between groups with regard to activated partial thromboplastin times, circulating thrombin-antithrombin III complex concentrations and fibrinogen. CONCLUSIONS: In this animal model administration of iohexol and amidotrizoate before thrombolysis significantly delayed reperfusion. This interaction should be considered in the design of clinical trials of thrombolytic therapy that evaluate coronary artery patency and in patients receiving local infusions of fibrinolytic agents.

Repeated stunning precedes myocardial hibernation in progressive multiple coronary artery obstruction.

OBJECTIVE: The aim of this study was to characterize a regional myocardial flow-function relationship in collateral dependent myocardium produced by multiple coronary artery obstruction. METHODS: Ameroid constrictors were placed around the proximal right (RC) and circumflex (CX) coronary arteries and a silicon tubing cuff around the proximal LAD (left anterior descending artery) (luminal stenosis +/- 77%) in 18 dogs. Weekly two-dimensional echocardiography was performed for regional function (anterior [A], inferoposterior [IP], wall thickening [WT]), and fractional shortening (FS). Colored microspheres injected at baseline and before sacrifice, before and after dipyridamole (0.5 mg/kg) injection, determined resting flow (RF) and coronary reserve (CR), respectively. RESULTS: Coronary angiography performed at four weeks after surgery confirmed occlusion of RC and CX with collateralization and a tight stenosis of LAD. Initially, an episodic reduction in A and IP WT was observed which became persistent later (AWT: 16 +/- 3%; IPWT: 16 +/- 4%, FS: 20 +/- 4%, p < 0.005 vs. baseline [BS]). With dobutamine a biphasic response (improvement in A and IP WT between 5-15 and dysfunction between 20-30 microg/kg/min) was observed. Seven dogs were sacrificed at eight weeks and showed normal RF but reduced transmural CR (A: 75 +/- 18%; IP: 46 +/- 22% of control). Seven dogs underwent PTCA of the LAD at eight weeks and showed gradual improvement in AWT with normalization at 12 weeks (AWT: 30 +/- 5%, p < 0.001 vs. eight weeks). At sacrifice RF and CR in the A wall were normal but there was reduced subendocardial RF in the IP region (64% of BS). Further, biopsy samples showed normal histological findings and high energy phosphate content in all dogs. Radioligand binding assays using 125I-iodocyanopindolol showed downregulation of beta-adrenergic receptor density in the dysfunctional regions compared with control. CONCLUSIONS: In this canine model of viable, collateral dependent and reversibly dysfunctional myocardium, there was early episodic dysfunction followed by persistent dysfunction which was initially associated with normal RF and later with subendocardial hypoperfusion.

TNK-tPA for acute myocardial infarction: the clinical experience.

Thrombolytic therapy has become the mainstay of treatment for acute transmural myocardial infarction. Present fibrinolytic regimens have a number of shortcomings, including the failure to induce early and sustained reperfusion in as many as 40-50% of the patients, and to prevent reocclusion in another 10-20% of the patients. The efforts for improving thrombolysis are focused on the development of new agents (fibrinolytics, anticoagulants, and antiplatelet agents). TNK-tPA is a triple combination mutant of wild-type tissue plasminogen activator that exhibits a longer plasma half-life, an enhanced fibrin-specificity, and an increased resistance to the plasminogen activator inhibitor-1. This paper summarizes the results of clinical trials with TNK-tPA in acute myocardial infarction.

Comparison of a synthetic antithrombin III-binding pentasaccharide and standard heparin as an adjunct to coronary thrombolysis.

The effects on alteplase-induced thrombolysis of the synthetic ATIII-binding pentasaccharide SR90107A/ORG 31540 (synthetic pentasaccharide, SP) and of standard heparin (SH) were compared in a copper coil model of coronary artery thrombosis in 6 groups of 10 dogs. After 1 h of occlusion, all animals received intravenously alteplase and aspirin, and were randomly assigned to a 2 h infusion of either saline, or one of two doses of SH (100 IU/kg bolus plus 50 IU/kg/h infusion, or 200 IU/kg bolus plus 100 IU/kg/h infusion), or one of three doses of SP (100 nmol/kg bolus plus 50 nmol/kg/h infusion, 200 nmol/kg bolus plus 100 nmol/kg/h infusion, or 400 nmol/kg bolus plus 200 nmol/kg/h infusion). Coronary angiography was performed every 10 min for 4 h. Appropriate doses of SP and SH enhanced alteplase-induced thrombolysis to a similar extent. In contrast, SP was devoid of any anti-IIa activity or aPTT prolongation.

Are changes in myocardial integrated backscatter restricted to the ischemic zone in acute induced ischemia? An in vivo animal study.

Integrated backscatter (IB) from a myocardial region, calculated from radiofrequency echocardiographic data, has been proposed as a useful parameter for investigating changes in myocardial tissue induced by ischemia. In 10 closed-chest dogs, 5 minutes of myocardial ischemia was induced by either a proximal occlusion of the circumflex coronary artery (CX) (5 dogs), resulting in extensive ischemia in the posterior wall, or by occluding the distal CX vessel (5 dogs) to produce a small localized ischemic zone in the posterior wall. High-resolution digital radiofrequency data from the whole left ventricular myocardium, in the imaging plane during one complete heart cycle, were acquired with a whole-image real-time acquisition approach. Regions in the septum and posterior wall (both ischemic tissue and, in the case of distal occlusions, tissue surrounding the ischemic zone) were chosen for analysis, and IB and cyclic variation (CV) of IB were calculated. Post occlusion, an increase in mean IB values was found in the ischemic segment. However, an increase in CV was also observed in the peri-ischemic zone for the distal CX occlusion and in the septum after proximal CX occlusion. These findings show that changes in CV are not restricted to the ischemic zone but may also occur in distal myocardium. This may be explained by changes in the regional contractile state and loading conditions of the "normal" myocardium, which are altered in response to the distal ischemia.

Is there a change in myocardial nonlinearity during the cardiac cycle?

The distortion of a sound wave during propagation results in progressive transfer of the energy from fundamental to higher harmonics, and is dependent on the nonlinearity of the medium. We studied if relative changes in acoustical nonlinearity occur in healthy myocardium during the cardiac cycle. Radiofrequency data were acquired from transthoracic echocardiography (2.5 and 3.5 MHz), parasternal long axis view, from five dogs and nine healthy volunteers. Integrated backscatter was calculated after filtering for fundamental (FIB) and second harmonic frequencies (SHIB), from a region in the posterior myocardial wall. The results suggest that there is little difference between the SHIB and FIB, although there were large variations between individuals. The maximal changes in nonlinearity, as estimated by SHIB/FIB ratio, mostly occurred during systole. SHIB presented similar cyclic variation with FIB (p = NS). Further studies are necessary to separate the role of myocardial nonlinearity, attenuation, propagating distance, or acoustical properties of the blood. The results are important in further tissue characterization studies employing second harmonic data.

Infarct size, myocardial hemorrhage, and recovery of function after mechanical versus pharmacological reperfusion: effects of lytic state and occlusion time.

BACKGROUND: Whether myocardial reperfusion obtained with thrombolysis or primary angioplasty is associated with a similar recovery of function and with the same risk of hemorrhagic infarction is unknown. We evaluated the effects of mechanical and pharmacological reperfusion (with or without a plasma lytic state) on infarct size, myocardial hemorrhage, and left ventricular (LV) function in a canine model. METHODS AND RESULTS: Six groups of six dogs were subjected to balloon occlusion of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion. The study had a two-by-three factorial design with two occlusion periods (90 and 240 minutes) and three different reperfusion strategies (placebo, 0.4 mg/kg recombinant tissue plasminogen activator, and 40 microg/kg recombinant staphylokinase). In a seventh control group, LAD occlusion was maintained without reperfusion. All dogs received aspirin and heparin. A systemic lytic state was present in staphylokinase-treated dogs. Planimetry of LV slices showed larger infarcts (percent of area at risk) and more hemorrhage (percent of IA) after 240 minutes of occlusion than after 90 minutes of occlusion (54+/-17% versus 37+/-18% and 52+/-27% versus 29+/-27%, respectively; P<.01 for both comparisons), with no significant difference among treatments. Hemorrhage was not observed in the control group without reperfusion. LV angiography showed no differences in global and regional LV function between mechanical and pharmacological reperfusion. CONCLUSIONS: In this experimental model, hemorrhagic infarctions of similar extent were observed after both pharmacological and mechanical reperfusion. The extent of hemorrhage was increased by the delay in reperfusion but not by the presence of a lytic state.

Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs.

BACKGROUND: Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. METHODS AND RESULTS: Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5 x 10(9) pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30+/-0.42 to 0.33+/-0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82+/-0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59+/-0.14 versus 0.80+/-0.19 mm, P=0.02; 0.75+/-0.21 versus 1.04+/-0.25 mm, P=0.019; and 53+/-15% versus 75+/-11%, P=0.006, respectively). Lumen area was significantly larger (0.70+/-0.35 mm2 in AdCMVceNOS versus 0.32+/-0.18 mm2 in AdRR5, P=0.007). CONCLUSIONS: Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.

Noninvasive measurements of infarct size after thrombolysis with a necrosis-avid MRI contrast agent.

BACKGROUND: Gadophrin-2 is a new MRI contrast agent with high affinity for necrotic myocardium. The aim of the study was to evaluate whether noninvasive measurements of infarct size after thrombolysis are possible with gadophrin-2-enhanced MRI. METHODS AND RESULTS: Coronary artery thrombosis was induced in 3 groups of dogs by the copper-coil technique. Thrombolytic therapy together with aspirin and heparin was initiated after 90 minutes of occlusion. One day (group A), 2 days (group B), or 6 days (group C) after infarction, gadophrin-2 was injected intravenously (50 micromol. kg-1). In vivo T1-weighted segmented turbo-FLASH, in vivo T2-weighted segmented half-Fourier turbo spin echo (HASTE), and T1- and T2-weighted spin-echo MRI of the excised heart were performed 24 hours after gadophrin-2 injection. Regions of strong enhancement were observed on T1-weighted images. Planimetry of short-axis MR images and of corresponding triphenyltetrazolium chloride (TTC)-stained left ventricular (LV) slices showed a close correlation between the enhanced areas and TTC-negative areas for both in vivo (r2=0.98, P<0.0001; mean difference, 0.9+/-2.0% [SD] of the LV volume [LVV]) and postmortem (r2=0.99, P<0.0001; mean difference, 0.9+/-1.4% of LVV) measurements. T2-weighted images overestimated the infarct size by 8.1+/-5.4% of LVV. The mean infarct size was 10.8+/-11.6% of LVV (group A), 22.4+/-11.7% (group B), and 5.1+/-9.3% (group C). CONCLUSIONS: In this animal model, in vivo gadophrin-2-enhanced MRI could precisely determine infarct size after thrombolytic therapy. This technique may be very useful for the noninvasive evaluation of infarct size after reperfusion for AMI.

High frame rate myocardial integrated backscatter. Does this change our understanding of this acoustic parameter?

AIMS: Integrated backscatter (IB) and its cyclic variation (CV) derived from radio-frequency (RF) data have been used as parameters to attempt myocardial tissue characterization. Prior imaging systems used to measure IB and its CV typically acquired data at frame rates of 20-30 Hz and at a resolution of 6-8 bits. If changes in IB levels are in part related to specific short-lived events, occurring within the cardiac cycle, this frame rate and resolution could have been too low to resolve adequately what might be a more complex data set. METHODS AND RESULTS: To investigate this possibility, we acquired real time two-dimensional (2D) myocardial IQ data (the 'in-phase quadrature' sampled RF data) at high frame rate (> 100 Hz), high dynamic resolution (theoretical 19-bit) and a sector angle of 20 degrees. Several consecutive heart cycles of myocardial data were acquired from individual cardiac walls in five closed chest dogs and 10 healthy, young volunteers at normal heart rates. On the reconstructed RF data regions of interest were indicated, and IB and its CV were calculated. The extracted high frame rate curves showed that the CV of IB is not a smooth sinusoidal-like curve, but is made up of multiple reproducible peaks and troughs with local minima and maxima which are temporally related to active or passive mechanical events, i.e. systolic contraction, early ventricular relaxation and ventricular filling due to atrial contraction. CONCLUSIONS: This study shows that increasing the rate of real-time RF data acquisition results in a more complex, reproducible IB curve. The resolved maxima and minima in IB levels are related to specific phases of the myocardial contraction. Furthermore, spectral analysis showed that IB curves acquired at normal heart rates contain information up to 40 Hz. Hence, cardiac imaging data sets used to analyse regional myocardial function obtained at frequencies lower than 80 frames per second can contain aliased information.

Intracoronary delivery of Gd-DTPA and Gadophrin-2 for determination of myocardial viability with MR imaging.

The aim of this study was to compare intracoronary (i.c.) administration of Gadophrin-2, a necrosis-avid contrast agent (NACA), and nonspecific agent Gd-DTPA for determination of myocardial viability (MV) in acute myocardial infarction (AMI) with MRI. Reperfused AMI was induced in 12 dogs by transcatheter balloon occlusion of coronary artery. In 6 dogs each, Gd-DTPA at 0.1 mmol/kg or Gadophrin-2 at 0.005 mmol/kg was administered into coronary artery by fast bolus (n = 3) or slow infusion (n = 3). Serial ECG-triggered cardiac MRI of T1-weighted segmented turbo fast low-angle shot (FLASH) sequence was conducted and compared with triphenyltetrazolium chloride (TTC) histochemical staining. The contrast ratio and infarct size were quantified and analysed statistically. No cardiovascular side effects were found with local delivery of both agents. After i.c. administration, Gadophrin-2 induced a strong (CR > or = 1.78) and persistent (> or = 10 h) contrast enhancement of infarcted region. The infarct size defined with Gadophrin-2 was almost identical to that with TTC staining throughout the postcontrast period. With a dose 20 times higher, Gd-DTPA also strongly enhanced infarct-to-normal contrast; however, the enhancement diminished with time, i.e. from early strong to later faint enhancement and eventual loss of contrast. The delineated infarct size was also unstable, i.e. from early overestimation to later underestimation and eventual disappearance of the enhanced infarct. In combination with PTCA procedure, i.c. administration of MRI contrast agents may prove useful for post-procedure verification of diagnosis. The NACA-enhanced MRI may serve as an in vivo surrogate of postmortem histochemical staining for determination of MV. Although applicable in clinical setting, cardiac MRI with nonspecific Gd-DTPA is less reliable and should be performed within less than 1 h after contrast.