Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.

BACKGROUND: Regulators and clinical experts increasingly recognize the importance of incorporating patient-reported outcomes (PROs) in clinical studies of therapies for pulmonary arterial hypertension (PAH). No PAH-specific instruments have been developed to date in accordance with the 2009 FDA guidance for the development of PROs as endpoints in clinical trials. A qualitative research study was conducted to develop a new instrument assessing PAH symptoms and their impacts following the FDA PRO guidance. METHODS: A cross-sectional study was conducted at 5 centers in the US in symptomatic PAH patients aged 18-80 years. Concept elicitation was based on 5 focus group discussions, after which saturation of emergent concepts was reached. A PRO instrument for PAH symptoms and their impacts was drafted. To assess the appropriateness of items, instructions, response options, and recall periods, 2 rounds of one-on-one cognitive interviews were conducted, with instrument revisions following each round. Additional interviews tested the usability of an electronic version (ePRO). PRO development considered input from an international Steering Committee, and translatability and lexibility assessments. RESULTS: Focus groups comprised 25 patients (5 per group); 20 additional patients participated in cognitive interviews (10 per round); and 10 participated in usability interviews. Participants had a mean ± SD age of 53.1 ± 15.8 years, were predominantly female (93 %), and were diverse in race/ethnicity, WHO functional class (FC I/II: 56 %, III/IV: 44 %), and PAH etiology (idiopathic: 56 %, familial: 2 %, associated: 42 %). The draft PRO instrument (PAH-SYMPACT®) was found to be clear, comprehensive, and relevant to PAH patients in cognitive interviews. Items were organized in a draft conceptual framework with 16 symptom items in 4 domains (respiratory symptoms, tiredness, cardiovascular symptoms, other symptoms) and 25 impact items in 5 domains (physical activities, daily activities, social impact, cognition, emotional impact). The recall period is the past 24 h for symptoms, and the past 7 days for impacts. CONCLUSIONS: The PAH-SYMPACT® was shown to capture symptoms and their impacts relevant to PAH patients, demonstrating content saturation, concept validity, and ePRO usability. Final content and psychometric validation of the instrument will be based on the results of an ongoing Phase IIIb clinical trial in PAH patients.

High-sensitive troponin T: a novel biomarker for prognosis and disease severity in patients with pulmonary arterial hypertension.

PAH (pulmonary arterial hypertension) is the leading cause of fatal right ventricular failure. However, rarely detectable, cTnT [cardiac TnT (troponin T)] is a significant prognostic marker. Therefore the aim of the present study was to evaluate the usefulness of a novel high-sensitive cTnT (hsTnT) assay as a parameter for functional and prognostic evaluation of PAH patients. In 55 PAH patients (idiopathic, n=20; chronic thromboembolic, n=30; and interstitial lung disease, n=5) with a mean pulmonary artery pressure of 45+/-18 mmHg, cTnT was measured by a fourth-generation conventional assay and a novel hsTnT assay with a lower detection limit at 2 pg/ml [total imprecision <10% at the 99th percentile value (13.4 pg/ml)]. In 90.9% of patients, cTnT was detectable using the hsTnT assay and in 30.9% using the fourth-generation assay. Concentrations >99th percentile were observed in 27.3% using hsTnT compared with 10.9% using the fourth-generation assay. A total of five out of six patients with cTnT values >30 pg/ml (fourth-generation assay) or >29.5 pg/ml (hsTnT assay) died during the 12-month follow-up. There was a correlation between hsTnT and 6-min walk distance (r=-0.92, P=0.0014), right ventricular systolic strain (r=0.95, P=0.0018) and strain rate (r=0.82, P=0.0021). In AUC (area under the curve) analysis, hsTnT predicted death at least as effectively as hFABP (heart-type fatty-acid-binding protein) or NT-proBNP (N-terminal pro-brain natriuretic protein). Moreover, hsTnT predicted a WHO (World Health Organization) functional class >II better than NT-proBNP or hFABP. In conclusion, in PAH patients, the novel biomarker hsTnT is associated with death and advanced WHO functional class, and is related to systolic right ventricular dysfunction and an impaired 6-min walk distance.

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension.

BACKGROUND: In idiopathic pulmonary arterial hypertension (IPAH), peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1), to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist) improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. METHODS: In 32 IPAH-patients (19 female, WHO functional class II (n = 10), III (n = 22); (data presented as mean +/- standard deviation) pulmonary vascular resistance (11 +/- 5 Wood units), lung function, 6 minute walk test (6-MWT; 364 +/- 363.7 (range 179.0-627.0) m), systolic pulmonary artery pressure, sPAP, 79 +/- 19 mmHg), and NT-proBNP serum levels (1427 +/- 2162.7 (range 59.3-10342.0) ng/L) were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day). RESULTS AND DISCUSSION: At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 +/- 25 and 45 +/- 24% predicted. Total lung capacity was 95.6 +/- 12.5% predicted and residual volume was 109 +/- 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 +/- 19 and 53 +/- 69 m, respectively; p < 0.01; whereas sPAP decreased by 7 +/- 14 and 10 +/- 19 mmHg, respectively; p < 0.05. NT-proBNP serum levels tended to be reduced by 123 +/- 327 and by 529 +/- 1942 ng/L; p = 0.11). There was no difference in expiratory flows or lung volumes during 3 and 12 months. CONCLUSION: This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

Evaluation cardioprotective effects of atorvastatin in rats by real time myocardial contrast echocardiography.

BACKGROUND: The ability to assess myocardial perfusion in small animals is important, especially to investigate models of myocardial ischemia. Myocardial perfusion is usually assessed by postmortem techniques, eliminating the possibility of follow-up in intervention studies. The purpose of the study was to examine the feasibility of real time myocardial contrast echocardiography (MCE) to evaluate cardioprotective effects of atorvastatin in a rat model of acute ischemia-reperfusion injury. METHODS: The rats (n=15) underwent 20 minutes of mechanical left descending coronary artery (LAD) occlusion followed by 180 minutes of reperfusion. The animals received either atorvastatin (10 mg/kg), atorvastatin and the nitric oxide synthase (NOS)-inhibitor N-Nitro-L-Argininemethylester (L-NAME) (15 mg/kg), or vehicle. MCE was performed to assess the size of the perfusion defect and the myocardial signal intensities (A(max)) at the baseline, during occlusion, and during reperfusion. For comparison, the infarct size, risk area, and regional myocardial blood flow (MBF) were determined by the standard techniques as well. RESULTS: The dynamics of ischemia-reperfusion injury could be visualized serially by MCE. The infarct size-to-risk area ratio progressively increased during reperfusion and was markedly reduced in the atorvastatin group. Triphenyltetrazolium chloride (TTC) staining confirmed a 23% reduction in the infarct size by atorvastatin. The infarct size by MCE correlated well with the histological methods (r=0.86, P < 0.001). A(max) was reduced in the anterior segments during LAD occlusion (0.08 +/- 0.01 dB) compared to the baseline (2.9 +/- 0.4 dB), approached higher levels post revascularization of LAD (3.22 +/- 0.50 dB), but decreased during 180 minutes of reperfusion (2.32 +/- 0.40 dB). After 180 minutes of reperfusion, A(max) in the risk area was significantly higher in the atorvastain-treated group compared to the vehicle-treated group (2.32 +/- 0.40 dB vs 1.3 +/- 0.4 dB, P

Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension.

Dyspnea and exercise limitation are common in patients with idiopathic pulmonary arterial hypertension (IPAH). Recently, a reduction in inspiratory and expiratory muscle strength has been observed in IPAH. However, it has not been investigated whether this respiratory muscle weakness might be part of a general muscle dysfunction as observed in congestive left heart failure. Therefore, in 24 consecutive IPAH patients (16 female; age 58.7+/-16.2; WHO class II-III; systolic pulmonary artery pressure during echocardiography at rest (sPAP) 65.0+/-20.6 mmHg, and 6-min-walk test (6-MWT) 473.6+/-127.7 m), the maximal isometric forearm muscle strength (best of three hand grip manoeuvres), maximal inspiratory and expiratory mouth occlusion pressures (Pimax, Pemax) were prospectively evaluated. The isometric forearm muscle strength was significantly lower in IPAH patients (281.7+/-102.6N) than in matched 24 healthy controls (397.1+/-116.8 N; p=0.03). In IPAH patients, there was a correlation between maximal isometric forearm muscle strength and 6-MWT (r=0.67; p=0.0007) and both, Pimax (r=0.69; p=0.0003) and Pemax (r=0.63; p=0.01), respectively. There was no correlation between forearm muscle strength and sPAP (r=0.30; p=0.16). The present skeletal muscle dysfunction is a novel finding in patients with IPAH. The correlation with respiratory muscle dysfunction and severity of disease might indicate a generalised "myopathy" in IPAH.

Evidence of left ventricular contractile asynchrony by echocardiographic phase imaging in patients with type 2 diabetes mellitus and without clinically evident heart disease.

Left ventricular electromechanical asynchrony has been shown to predict cardiac events in patients with heart failure. This study investigated whether left ventricular asynchrony is present in patients with type 2 diabetes mellitus (DM) with no clinically evident heart disease and normal QRS durations. Asynchrony was evaluated in 24 patients with DM, 15 nondiabetic control subjects, and 20 patients with left bundle branch block (LBBB) due to cardiomyopathy serving as positive controls by conventional tissue Doppler imaging and by a novel method, echocardiographic phase imaging. Asynchrony was significantly higher in patients with DM than in controls and significantly lower than in patients with LBBB. This was shown by tissue Doppler imaging: the SD of time to peak myocardial velocity was 13 +/- 10 ms in controls, compared with 30 +/- 19 ms in patients with DM (p <0.01) and 68 +/- 28 ms in those with LBBB (p <0.001). Similar data were obtained using echocardiographic phase imaging: the SD of phase degrees was 25 degrees +/- 8 degrees in controls, compared with 44 degrees +/- 21 degrees in patients with DM (p = 0.02) and 76 degrees +/- 25 degrees in those with LBBB (p <0.001). Tissue Doppler imaging correlated with echocardiographic phase imaging (r = 0.79, p <0.0001) but was more time consuming (15.5 +/- 4.5 vs 4.5 +/- 2.2 min/patient, p <0.05) and showed higher intraobserver variability (5.6% vs 3.2%, p <0.05). In conclusion, this is the first study showing increased left ventricular asynchrony in patients with DM and no clinical evidence of heart disease.

Evaluation of cardioprotective effects of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in myocardial ischemia-reperfusion injury by real-time myocardial contrast echocardiography.

OBJECTIVES: The purpose was to examine the cardioprotective effects of recombinant P-selectin glycoprotein ligand-immunoglobulin (rPSGL-Ig) in ischemia-reperfusion injury by real-time myocardial contrast echocardiography (MCE). BACKGROUND: P-selectin mediates leukocyte recruitment into areas of inflammation. METHODS: Sixteen pigs underwent 45 min of left anterior descending coronary artery occlusion followed by reperfusion and received rPSGL-Ig or vehicle. To assess changes in myocardial perfusion (A x beta), MCE was performed. RESULTS: After 120 min of reperfusion, A x beta in the risk area was higher (0.84 +/- 0.15 dB/s vs. 0.28 +/- 0.1 dB/s, p < 0.0001), and the infarct size was lower (30.3 +/- 12% vs. 57 +/- 14%, p = 0.002) in the rPSGL-Ig group compared with the vehicle group. CONCLUSIONS: Recombinant PSGL-Ig improved postischemic reflow accurately detected by real-time MCE.

Cyclic variation of myocardial signal intensity in real-time myocardial perfusion imaging.

BACKGROUND: The presence of cyclic intensity variation during real-time myocardial perfusion imaging (RTPI) has been controversially discussed. We investigated whether cyclic intensity variation is systematically found during RTPI and whether such variations are related to regional functional parameters. METHODS: Intraoperative RTPI were obtained in 12 pigs before, during, and after left descending coronary artery occlusion with 60 mL/h SonoVue infusion. Furthermore, RTPI was performed in 14 patients after slow bolus injection of 0.7 mL of Optison. Instantaneous regional systolic to diastolic (S/D) myocardial intensity ratios were calculated after high mechanical index bubble destruction. S/D ratios were correlated with A- and beta-values, and fractional area shortening. RESULTS: Systematic cyclic S/D changes were present in both experimental settings showing significantly higher systolic values (animals, S/D 1.28 +/- 0.44; patients, S/D 1.25 +/- 0.7). Cyclic S/D variation was not related to fractional area shortening, or A- or beta-values (all r < 0.3, not significant). CONCLUSION: Consistent cyclic changes in myocardial contrast intensity can be measured both in intraoperative animals and in patients, showing higher systolic values. S/D ratios are not related to regional functional parameters.

Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUND: Originally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions. METHODS: Prospective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18-65 years) and elderly (>65 years) patients with newly diagnosed IPAH (incident cases only) were compared. RESULTS: A total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n=209; median age, 54 [16] years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n=378; median age, 75 [8] years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance>400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p=0.006 by log-rank analysis). CONCLUSIONS: In countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required. CLINICAL TRIALS REGISTRATION: NCT01347216.

Soluble TWEAK predicts hemodynamic impairment and functional capacity in patients with pulmonary arterial hypertension.

Soluble TWEAK is a member of the TNF-alpha family of cytokines that has been shown to predict mortality in patients with heart failure. Pulmonary artery hypertension is a devastating disease, in which right ventricular function has been shown to be the major determinant of prognosis. In this hypothesis-generating study, we sought to evaluate the potential usefulness of sTWEAK in the prediction of disease severity in patients with pulmonary artery hypertension. We therefore conducted a retrospective analysis of sTWEAK serum levels in 95 stable patients with PAH. For all patients data on hemodynamic parameters, biomarkers and functional exercise tests were available. Compared to controls, patients with PAH showed significantly decreased levels of sTWEAK [median 314 pg/ml (interquartile range 217-473 pg/ml) vs. 405 (321-496 pg/ml); PAH vs. controls; P < 0.0001]. Soluble TWEAK levels were inversely correlated with NYHA class, pulmonary artery pressure, pulmonary vascular resistance, NT-proBNP, and troponin T levels and directly correlated with cardiac index, reduced 6-min walk test distances, and peak oxygen consumption. ROC curve analysis of sTWEAK levels in PAH patients revealed a cutoff value of 306 pg/ml for sTWEAK to be predictive of a reduced exercise capacity (6-min walk test <300 m) in patients with PAH with a similar predictive value compared to NT-proBNP. Intraindividual serial evaluation of sTWEAK revealed the potential of sTWEAK as follow-up marker in patients with PAH. In our hypothesis-generating study, sTWEAK was closely correlated to hemodynamic, functional, and serological indices of outcome in patients with PAH. Further prospective studies are needed to determine the role of sTWEAK as potential biomarker in patients with PAH.

Respiratory muscle dysfunction in congestive heart failure--the role of pulmonary hypertension.

BACKGROUND: Inspiratory muscle weakness has been described in patients with congestive heart failure (CHF), and only recently in patients with idiopathic pulmonary arterial hypertension. However, the relationship between pulmonary hemodynamics and respiratory muscle function has not been investigated in patients with CHF. METHODS AND RESULTS: In two tertial referral centers for CHF patients, 532 consecutive CHF patients (159 female, age 59 ± 12 years, NYHA I-IV) were studied by right heart catheterization, maximal inspiratory mouth occlusion pressure (Pi(max)) and pressure 0.1s after beginning of inspiration during tidal breathing at rest (P(0.1)). There was a significant correlation between Pi(max) and mean pulmonary artery pressure (PAPm) (r=-0.65, p=0.0023), mean pulmonary capillary wedge pressure (PCWPm) (r=-0.56; p=0.0018), PVR (r=-0.73; p=0.0031), and cardiac output (r=0.51; p=0.0022). Moreover, the ratio P(0.1)/Pi(max) showed a linear correlation with PAPm (r=0.54; p=0.0019), and with TPG (r=0.64; p=0.0014) respectively. Vital capacity was reduced in relation to increased PAPm (r=-0.54; p=0.0029). Pi(max) and P(0.1)/Pi(max) were independent from VC. CONCLUSIONS: This study provides the first evidence of a close relation between inspiratory muscle dysfunction, increased ventilatory drive and pulmonary hypertension in a large patient cohort with CHF. Pi(max) and P(0.1) can easily be measured in clinical routine and might become an additional parameter for the non-invasive monitoring of the hemodynamic severity of disease.

Strain and strain rate echocardiography for evaluation of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension.

Optimizing the non-invasive imaging of right ventricular (RV) function is of increasing interest for therapy monitoring and risk stratification in patients with idiopathic pulmonary hypertension (IPAH). Therefore, this study evaluated strain and strain rate echocardiography as a tool for comprehensive assessment of RV function and disease severity in IPAH patients. In 30 IPAH patients [WHO functional classes II-IV; mean pulmonary artery pressure (mPAP) 48.8 +/- 12.5 mmHg; pulmonary vascular resistance (PVR) 7.9 +/- 5.3 Wood units] and in 10 matched healthy control subjects' two-dimensional echocardiography, 6-MWD and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were obtained. In IPAH patients when compared with controls, RV systolic strain (-18.8 +/- 4.3 vs. -34.5 +/- 3.8%, p = 0.0016) and strain rate (-1.6 +/- 0.6 vs. -2.7 +/- 0.5 s(-1), p = 0.018) were significantly altered and correlated significantly with elevated NT-proBNP levels (r = 0.73 and r = 0.62; p < 0.001, respectively) and reduced 6-MWD (r = -0.76 and r = -0.81; p < 0.001). In IPAH patients, reduced strain correlated with both mPAP (r = 0.61, p = 0.01 for strain; and r = 0.55, p = 0.04 for strain rate, respectively), and PVR (r = 0.84, p < 0.001 for strain; and r = 0.67, p < 0.001 for strain rate, respectively). This study gives first comprehensive evidence that strain echocardiography allows accurate non-invasive assessment of RV function and disease severity in patients with IPAH.

Echocardiographic phase imaging to predict reverse remodeling after cardiac resynchronization therapy.

OBJECTIVES: The aim of our study was to investigate whether echocardiographic phase imaging (EPI) can predict response in patients who are considered for cardiac resynchronization therapy (CRT). BACKGROUND: CRT improves quality of life, exercise capacity, and outcome in patients with bundle-branch block and advanced heart failure. Previous studies used QRS duration to select patients for CRT; the accuracy of this parameter to predict functional recovery, however, is controversial. METHODS: We examined 42 patients with advanced heart failure (New York Heart Association [NYHA] functional class III to IV, QRS duration >130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of Delta ESV >or=15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. RESULTS: The Ts-SD and the mean EPI-Index were related to Delta ESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index

Immediate and chronic effects of AV-delay optimization in patients with cardiac resynchronization therapy.

BACKGROUND: Acute changes of the AV-delay in CRT patients have a significant impact on hemodynamics. However, the chronic functional effects of AV-delay optimization have not been systematically examined despite of their potential role for chronic functional improvement. METHODS: Therefore, in this study we investigated whether optimization of AV-delay in CRT patients as assessed by echocardiographic measurement of the velocity time integral of the left ventricular outflow tract (LVOT-VTI) chronically changes (1) echocardiographic parameters of systolic and diastolic left ventricular function, (2) walking distance in the 6-min walk test, (3) levels of NT-proBNP and (4) quality of life as assessed by a standard questionnaire. 33 patients underwent optimization of AV-delay 31+/-8 weeks after initiation of CRT. Follow up (FU) was conducted 43+/-5 days later. RESULTS: E/Ea, the ratio of peak E-wave of mitral inflow and of TDI of the mitral annulus, significantly decreased immediately post-optimization (11+/-1 vs. 14+/-1 at baseline, p<0.05) and further decreased at FU (8+/-1, p<0.05 vs. immediately post-optimization) indicating improvement of diastolic function, while traditional parameters of diastolic function derived from pulse wave Doppler remained unchanged. There was a slight increase of LV-ejection fraction as assessed by echocardiography acutely after optimization (baseline: 25+/-2%, optimized: 28+/-1%, p<0.05), while LV-ejection fraction at FU did not differ from baseline. 6-min walk test improved from 449+/-17 m (baseline) to 475+/-17 m at FU (p<0.05). During this period NT-proBNP significantly decreased from 3193+/-765 ng/l to 2593+/-675 ng/l (p<0.05). Quality of life was unchanged at FU. CONCLUSION: This study demonstrates for the first time chronic functional improvement due to AV-delay optimization in patients with CRT.

Cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 in ischemia-reperfusion injury.

OBJECTIVE: The aims of the study were to visualize the dynamics of ischemia-reperfusion injury by real-time myocardial contrast echocardiography and to investigate the cardioprotective effects of the novel endothelin-A receptor antagonist BSF 461314. BSF 461314 reduced infarct size by 47% and preserved microvascular integrity. Real-time myocardial contrast echocardiography allowed visualization of postischemic microvascular dysfunction and quantification of cardioprotective effects of selective endothelin antagonism. Blood flow index A x beta was reduced in anterior segments during ischemia compared with baseline (0.06 +/- 0.01 vs 0.98 +/- 0.2 dB/s) but was higher in the BSF 461314 group after 120 minutes of reperfusion (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015). Therefore, selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time myocardial contrast echocardiography accurately detected changes in microvascular reflow. BACKGROUND: Endothelin-1 is a potent vasoconstrictor and elevated in myocardial ischemia. The aims of the study were to examine cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 and to visualize changes in the microvasculature by real-time myocardial contrast echocardiography (MCE). METHODS: A total of 16 open-chest pigs underwent 45 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. A total of 1 mg/kg BSF 461314 or vehicle was given intravenously before reperfusion. Serial MCE was performed to assess changes in myocardial blood flow A x beta and perfusion defect size. Myocardial blood flow was measured by fluorescent microspheres and infarct size was measured by triphenyltetrazolium chloride tissue staining. RESULTS: Dynamics of infarct size expansion and tissue perfusion were correctly assessed by MCE. A x beta Was reduced in anterior segments during left anterior descending coronary artery occlusion (0.06 +/- 0.01 dB/s) compared with baseline (0.98 +/- 0.2 dB/s), approached higher levels postrecanalization (1.2 +/- 0.1 dB/s), but gradually decreased during reperfusion (0.3 +/- 0.05 dB/s, P < .01). After 120 minutes of reperfusion A (2.1 +/- 0.5 vs 1.0 +/- 0.6 dB, P < .03), beta (0.36 +/- 0.09/s vs 0.21 +/- 0.09/s, P = .01), and A x beta (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015) in the risk area were higher in the BSF 461314-treated group compared with vehicle indicating preserved myocardial perfusion. Triphenyltetrazolium chloride staining confirmed a 47% reduction in infarct size by BSF 461314. CONCLUSIONS: Selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time MCE allows visual and quantitative evaluation of dynamics of myocardial ischemia-reperfusion injury and monitoring of cardioprotective effects during pharmacologic interventions.

Fourier phase analysis can be used to objectively analyze real-time myocardial contrast echocardiograms.

BACKGROUND: Real-time myocardial contrast echocardiography (MCE) is increasingly used to assess myocardial perfusion. However, objective methods for evaluating MCE are not yet widely available. We sought to validate the ability of Fourier analysis applied to MCE to assess serial changes in microvascular perfusion during coronary occlusion and reperfusion. METHODS: Six pigs underwent 45 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Real time MCE was performed at baseline, during coronary occlusion, and at 5, 30, 60 and 120 min of reperfusion. Signal intensities from replenishment curves were fitted to an exponential function to obtain plateau SI (A) and the rate of SI rise (b). MCE images were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of myocardial intensity changes as phase angles in parametric images. The phase angle difference (PD) of posterior vs. anterior region was calculated as an index of myocardial opacification heterogeneity and compared to MCE index of myocardial blood flow A x b. RESULTS: After initial hyperemia, a progressive reduction in flow was observed during reperfusion. During LAD occlusion signal intensities were significantly reduced in anterior regions (A x b = 0.02+/-0.01) compared to baseline (1.2+/-0.34, p < 0.01) defining risk areas and approached higher levels postrecanalization (A x b = 1.48+/-0.6) but gradually decreased during 120 min of reperfusion (A = 0.51+/-0.3, p < 0.01). Similarly, profiles of phase angles in LAD perfusion territorities were consistently modified during reperfusion. The mean PD at baseline was 18 degrees+/-15 degrees. PD decreased during coronary occlusion to -108 degrees+/-38 degrees, increased to 29 degrees+/-19 degrees postrecanalization but decreased to -61 degrees+/-35 degrees after 120 min of reperfusion. PD significantly correlated with A (r = 0.8, p < 0.0001) and b (r = 0.73, p < 0.0001). CONCLUSIONS: The progressive reduction in post-ischemic microvascular perfusion was accurately detected by real-time MCE. Fourier phase imaging is feasible to quantify dynamics of myocardial opacification in a simple and objective format and is a promising approach for the interpretation of contrast echocardiograms.

Detection of acute myocardial ischemia during pharmacological stress in graded coronary artery stenosis: analysis of left ventricular asynchrony using Fourier phase imaging in pigs.

BACKGROUND: Stress echocardiography is increasingly used to identify coronary artery disease, but quantitative techniques are required to improve the accuracy of this method. Current algorithms used to analyze wall motion usually neglect motion asynchrony that is found in acute ischemia. Fourier phase imaging of echocardiographic images may offer the possibility to detect asynchrony, but its feasibility with dobutamine stress echocardiography (DSE) is undefined. The aim of this study was to investigate whether the extent of left ventricular asynergy can be used to quantify the severity of regional myocardial dysfunction and to detect functionally significant coronary artery stenoses during DSE. METHODS: Regional wall motion abnormalities were induced by graded coronary stenoses (mild and severe) of the left anterior descending coronary artery (LAD) in seven open-chest anesthetized pigs. DSE (10-40 microg/kg/min) was performed under control conditions and during sustained ischemia. Coronary flow was measured under resting conditions and during maximal hyperemic response due to intravenous infusion of adenosine. Functional significance of stenoses was defined as mild when coronary flow reserve (CFR) was reduced but > 1.5 and severe when CFR was < or = 1.5. Echocardiographic cine loops were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of wall motion as phase angles in parametric images and regional phase histograms. The phase difference (PD) of the first Fourier harmonic of posterior vs. anterior myocardial wall motion was calculated as an index of left ventricular asynchrony. Segmental fractional area shortening (FAS) and wall thickening (WT) as ratio of stress to rest served as a reference method of regional wall motion. RESULTS: The increase in FAS (1.62 +/- 0.6 vs. 0.42 +/- 0.2, p = 0.0002) and WT (1.92 +/- 0.5 to 0.3 +/- 1.1; p = 0.004) in anterior regions during DSE was significantly higher in the control group compared to severe ischemia but not compared to mild ischemia. During graded ischemia, profiles of phase angles were consistently modified, showing a delayed onset in regional contraction. The mean PD during DSE in the control group was 10.4 +/- 7 degrees. PD rose in mild ischemic segments (CFR > 1.5) to 28.9 +/- 10 degrees (p = 0.003) and to 89.6 +/- 25 degrees (p = 0.0002) in severely ischemic segments (CFR < or = 1.5). There was a significant inverse correlation between the PDs and WT (r = -0.87, p < 0.0001). Normal WT ratios yielded low phase angles while segmental phase angles increased with decreased WT. The intraobserver variability of phase analysis was 2.7 +/- 24 degrees (mean +/- 2SD). CONCLUSIONS: These results suggest that left ventricular asynchrony is an indicator of acute ischemia. Echocardiographic Fourier phase imaging is feasible to quantify wall motion displaying contraction sequence in a simple and objective format and is a promising approach for the clinical interpretation of stress echocardiograms.

Fourier phase and amplitude analysis for automated objective evaluation of myocardial contrast echocardiograms.

AIMS: Objective methods for evaluating myocardial contrast echocardiography (MCE) are not yet widely available. We applied a Fourier analysis to myocardial contrast echocardiograms to identify myocardial perfusion defects. METHODS: Harmonic power-Doppler contrast echocardiograms were performed in 21 patients undergoing Tl-201-SPECT imaging and in 13 controls. Images were transformed using Fourier analysis to obtain phase of the first harmonic sinusoidal curve displayed as color coded sequence of myocardial intensity changes. Means and standard deviations of regional phase angles were measured. The method was validated in an in vitro model. A contrast filled latex balloon was imaged at different gain settings mimicking defined time-intensity curves. An intraoperative porcine infarction model served to prove feasibility of Fourier transformation to analyze real-time pulse inversion contrast echocardiography. RESULTS: In patients, phase imaging and intensity analysis showed focal areas with marked phase shifts (106 +/- 90 degrees) and heterogeneous distribution of phase angles (SD 66 +/- 17 degrees), correctly identifying 13/14 perfusion defects. The in vitro validation yielded increasing phase angles with increasing beta-values. This method was successfully applied to real-time MCE, identifying all infarction areas during occlusion of the left anterior descending artery. CONCLUSION: Phase analysis can be used to display dynamics of myocardial opacification.