Koen M. Marques

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension

AIMS Pulmonary arterial compliance (C) is increasingly being recognized as an important contributor to right ventricular afterload, but for monitoring of treatment of pulmonary hypertension (PH) most often still only pulmonary vascular resistance (R) is used. We aimed at testing the hypothesis that R and C are coupled during treatment of PH and that substantial changes in both R and C would result in more haemodynamic improvement than changes in R alone. METHODS AND RESULTS Data were analysed of two right-heart catheterizations of 52 patients with pulmonary arterial hypertension and 10 with chronic-thromboembolic PH. The product of R and C (= stroke volume over pulse pressure) did not change during therapy (P = 0.320), implying an inverse relationship. Changes in cardiac index correlated significantly (P < 0.001) with changes in R (R(2) = 0.37), better with changes in C (R(2) = 0.66), and best with changes in both (R(2) = 0.74). CONCLUSION During therapy for PH, R and C remain inversely related. Therefore, changes in both R and C better explain changes in cardiac index than either of them alone. Not only resistance but also compliance plays a prominent role in PH especially in an early stage of the disease.

Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study.

OBJECTIVES This study sought to examine the diagnostic accuracy of the instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) with respect to hyperemic fractional flow reserve (FFR) in a core laboratory-based multicenter collaborative study. BACKGROUND FFR is an index of the severity of coronary stenosis that has been clinically validated in 3 prospective randomized trials. iFR and Pd/Pa are nonhyperemic pressure-derived indices of the severity of stenosis with discordant reports regarding their accuracy with respect to FFR. METHODS iFR, resting Pd/Pa, and FFR were measured in 1,768 patients from 15 clinical sites. An independent physiology core laboratory performed blinded off-line analysis of all raw data. The primary objectives were to determine specific iFR and Pd/Pa thresholds with ≥90% accuracy in predicting ischemic versus nonischemic FFR (on the basis of an FFR cut point of 0.80) and the proportion of patients falling beyond those thresholds. RESULTS Of 1,974 submitted lesions, 381 (19.3%) were excluded because of suboptimal acquisition, leaving 1,593 for final analysis. On receiver-operating characteristic analysis, the optimal iFR cut point for FFR ≤0.80 was 0.90 (C statistic: 0.81 [95% confidence interval: 0.79 to 0.83]; overall accuracy: 80.4%) and for Pd/Pa was 0.92 (C statistic: 0.82 [95% confidence interval: 0.80 to 0.84]; overall accuracy: 81.5%), with no significant difference between these resting measures. iFR and Pd/Pa had ≥90% accuracy to predict a positive or negative FFR in 64.9% (62.6% to 67.3%) and 48.3% (45.6% to 50.5%) of lesions, respectively. CONCLUSIONS This comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients.

A comparison of noninvasive MRI-based methods of estimating pulmonary artery pressure in pulmonary hypertension.

To assess the accuracy of several noninvasive MRI‐based estimators of pulmonary artery pressure by comparing them with invasive pressure measurement.

High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study

Objectives: This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST‐segment elevation after primary percutaneous coronary intervention (PCI). Background: After successful PCI for acute myocardial infarction 40–50% of patients show persistent ST‐segment elevation indicating suboptimal myocardial reperfusion. Adenosine has been studied to ameliorate reperfusion and is frequently used in a variety of doses, but there are no prospective studies to support its use for treatment of suboptimal reperfusion. Methods: We conducted a blinded, randomized, and placebo‐controlled study with high dose intracoronary adenosine in 51 patients with <70% ST‐segment resolution (STRes) after successful primary PCI. All patients were treated with stents and abciximab. Results: Immediately after adenosine, significantly more patients showed optimal (>70%) STRes compared with placebo (33% versus 9%, P < 0.05). Mean STRes was higher after adenosine (35.4% versus 23.0%, P < 0.05). In addition, TIMI frame count was significant lower (15.7 versus 30.2, P < 0.005), Myocardial Blush Grade was higher (2.7 versus 2.0, P < 0.05) and resistance index was lower in the adenosine group (0.70 versus 1.31 mm Hg per ml/min, P < 0.005). Conclusions: Intracoronary adenosine accelerates recovery of microvascular perfusion in case of persistent ST segment elevation after primary PCI.

Coronary microvascular resistance: methods for its quantification in humans

Coronary microvascular dysfunction is a topic that has recently gained considerable interest in the medical community owing to the growing awareness that microvascular dysfunction occurs in a number of myocardial disease states and has important prognostic implications. With this growing awareness, comes the desire to accurately assess the functional capacity of the coronary microcirculation for diagnostic purposes as well as to monitor the effects of therapeutic interventions that are targeted at reversing the extent of coronary microvascular dysfunction. Measurements of coronary microvascular resistance play a pivotal role in achieving that goal and several invasive and noninvasive methods have been developed for its quantification. This review is intended to provide an update pertaining to the methodology of these different imaging techniques, including the discussion of their strengths and weaknesses.

Does the instantaneous wave-free ratio approximate the fractional flow reserve?

OBJECTIVES This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR). BACKGROUND Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance. METHODS Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables. RESULTS We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model. CONCLUSIONS iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics.

Clinically Significant Change in Stroke Volume in Pulmonary Hypertension

BACKGROUND Stroke volume is probably the best hemodynamic parameter because it reflects therapeutic changes and contains prognostic information in pulmonary hypertension (PH). Stroke volume directly reflects right ventricular function in response to its load, without the correction of compensatory increased heart rate as is the case for cardiac output. For this reason, stroke volume, which can be measured noninvasively, is an important hemodynamic parameter to monitor during treatment. However, the extent of change in stroke volume that constitutes a clinically significant change is unknown. The aim of this study was to determine the minimal important difference (MID) in stroke volume in PH. METHODS One hundred eleven patients were evaluated at baseline and after 1 year of follow-up with a 6-min walk test (6MWT) and cardiac MRI. Using the anchor-based method with 6MWT as the anchor, and the distribution-based method, the MID of stroke volume change could be determined. RESULTS After 1 year of treatment, there was, on average, a significant increase in stroke volume and 6MWT. The change in stroke volume was related to the change in 6MWT. Using the anchor-based method, an MID of 10 mL in stroke volume was calculated. The distribution-based method resulted in an MID of 8 to 12 mL. CONCLUSIONS Both methods showed that a 10-mL change in stroke volume during follow-up should be considered as clinically relevant. This value can be used to interpret changes in stroke volume during clinical follow-up in PH.

The diastolic flow-pressure gradient relation in coronary stenoses in humans.

OBJECTIVES We assessed the feasibility and reproducibility of the instantaneous diastolic coronary flow velocity-pressure gradient relation to characterize different degrees of coronary stenoses. BACKGROUND Assessment of the hemodynamic significance of coronary stenoses can be difficult. Using sensor-tipped guidewires, various physiologic indexes can be determined in the catheterization laboratory. Each of the current methods, however, has limitations. METHODS After positioning a Doppler flow wire and a pressure wire distal of a coronary stenosis, the flow velocity signals and the proximal and distal pressure were sampled simultaneously, at baseline and after intracoronary administration of adenosine. The instantaneous diastolic flow velocity and pressure gradient of single cardiac cycles at baseline, at maximal and intermediate hyperemia were plotted. Data were fitted with a regression line using the equation: Delta P = 0 +kv+Sv(2). Measurements were performed in 11 normal coronary arteries, 20 intermediate stenoses and in 7 severe stenoses before and after percutaneous transluminal coronary angioplasty plus stenting. RESULTS We found significant differences between normal coronary arteries, intermediate and severe stenoses. Percutaneous transluminal coronary angioplasty nearly normalized the highly abnormal flow-pressure gradient relation in the severe stenoses. A high degree of reproducibility was observed. In 3% of the measurements, analysis was not possible due to the occurrence of pressure drift or bad flow velocity signals. CONCLUSIONS It is feasible to assess the diastolic flow velocity-pressure gradient relation over a wide range of stenoses. It characterizes the hemodynamics of epicardial coronary stenoses and allows discrimination between normal coronary arteries, intermediate and severe stenoses.

Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute myocardial infarction treated with primary PCI: Pilot study of the multicenter HEBE trial

Objective: This study was a pilot trial to determine safety and feasibility of intracoronary infusion of mononuclear bone marrow cells (MBMC) in patients with acute myocardial infarction (MI). Background: Studies reporting the effect of MBMC therapy on improvement of left ventricular (LV) function have shown variable results. The HEBE trial is a large multicenter, randomized trial that currently enrolls patients. Prior to this trial we performed a pilot study. Methods: Twenty‐six patients with a first acute MI were prospectively enrolled in eight centers. Bone marrow aspiration was performed at a median of 6 days after primary PCI (interquartile range, 5–7 days). MBMC were isolated by gradient centrifugation and were infused intracoronary the same day. All patients underwent magnetic resonance imaging before cell infusion and after 4 months. Clinical events were assessed up to 12 months. Results: Within 10 hr after bone marrow aspiration, 246 ± 133 × 106 MBMC were infused, of which 3.9 ± 2.3 × 106 cells were CD34+. In one patient, this procedure was complicated by local dissection. LV ejection fraction significantly increased from 45.0 ± 6.3% to 47.2 ± 6.5% (P = 0.03). Systolic wall thickening in dysfunctional segments at baseline improved with 0.9 ± 0.7 mm (P < 0.001). Infarct size decreased 37% from 17.8 ± 8.2 to 11.2 ± 4.2 gram (P < 0.001). During 12‐month follow‐up, 3 additional revascularizations were performed and an ICD was implanted in one patient, 3 weeks after PCI. Conclusion: In patients with acute MI, intracoronary infusion of MBMC is safe in a multicenter setting. At 4‐month follow‐up, a modest increase in global and regional LV function was observed, with a concomitant decrease in infarct size.