Arthur Filusch

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.

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.

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.

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 <or=59%) showed significant improvement in NYHA functional class and in 6-min walk test (409 +/- 88 m at follow-up vs. 312 +/- 86 m initially, p < 0.001). CONCLUSION Echocardiographic phase imaging can predict functional recovery, reverse LV remodeling, and clinical outcomes in patients who undergo CRT. EPI is a method that objectively and accurately quantifies LV dyssynchrony and seems to be noninferior to TDI for the prediction of reverse LV remodeling and functional recovery.

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 (Amax) 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). Amax 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, Amax 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 ≤ 0.05), indicating preserved MBF. The L‐NAME‐treated group showed no significant difference compared to the vehicle‐treated group (Amax 1.12 ± 0.60 dB vs 1.3 ± 0.4 dB). The regional blood flow ratio (ischemic‐to‐nonischemic wall) measured by the microspheres was significantly higher in the atorvastatin group compared to the control and the L‐NAME groups, respectively (0.92 ± 0.13 vs 0.45 ± 0.23 vs 0.51 ± 0.16, P ≤ 0.05). Conclusions: Atorvastatin has cardioprotective effects in acute reperfusion injury. Contrast echocardiography allows visual and quantitative evaluation of the dynamics of myocardial ischemia‐reperfusion injury and can be used to monitor cardioprotective effects during pharmacological interventions even in small animals.

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°) and heterogeneous distribution of phase angles (SD 66 ± 17°), correctly identifying 13/14 perfusion defects. The in vitro validation yielded increasing phase angles with increasing β-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.

Usefulness of myocardial parametric imaging to evaluate myocardial viability in experimental and in clinical studies

Objective: To evaluate whether myocardial parametric imaging (MPI) is superior to visual assessment for the evaluation of myocardial viability. Methods and results: Myocardial contrast echocardiography (MCE) was assessed in 11 pigs before, during, and after left anterior descending coronary artery occlusion and in 32 patients with ischaemic heart disease by using intravenous SonoVue administration. In experimental studies perfusion defect area assessment by MPI was compared with visually guided perfusion defect planimetry. Histological assessment of necrotic tissue was the standard reference. In clinical studies viability was assessed on a segmental level by (1) visual analysis of myocardial opacification; (2) quantitative estimation of myocardial blood flow in regions of interest; and (3) MPI. Functional recovery between three and six months after revascularisation was the standard reference. In experimental studies, compared with visually guided perfusion defect planimetry, planimetric assessment of infarct size by MPI correlated more significantly with histology (r2  =  0.92 versus r2  =  0.56) and had a lower intraobserver variability (4% v 15%, p < 0.05). In clinical studies, MPI had higher specificity (66% v 43%, p < 0.05) than visual MCE and good accuracy (81%) for viability detection. It was less time consuming (3.4 (1.6) v 9.2 (2.4) minutes per image, p < 0.05) than quantitative blood flow estimation by regions of interest and increased the agreement between observers interpreting myocardial perfusion (κ  =  0.87 v κ  =  0.75, p < 0.05). Conclusion: MPI is useful for the evaluation of myocardial viability both in animals and in patients. It is less time consuming than quantification analysis by regions of interest and less observer dependent than visual analysis. Thus, strategies incorporating this technique may be valuable for the evaluation of myocardial viability in clinical routine.

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 μg/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 ≤ 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°. PD rose in mild ischemic segments (CFR>1.5) to 28.9 ± 10° (p = 0.003) and to 89.6 ± 25° (p = 0.0002) in severely ischemic segments (CFR ≤ 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° (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.

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension.

BackgroundIn 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.MethodsIn 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 DiscussionAt 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.ConclusionThis 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.

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×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×b= 0.02 ± 0.01) compared to baseline (1.2 ± 0.34, p < 0.01) defining risk areas and approached higher levels postrecanalization (A×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°± 15°. PD decreased during coronary occlusion to −108°± 38°, increased to 29°± 19° postrecanalization but decreased to −61°± 35° 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.