Continuous thermodilution to assess absolute flow and microvascular resistance: validation in humans using [15O]H2O positron emission tomography.

AIMS: Continuous thermodilution is a novel technique to quantify absolute coronary flow and microvascular resistance (MVR). Notably, intracoronary infusion of saline elicits maximal hyperaemia, obviating the need for adenosine. The primary aim of this study was to validate continuous thermodilution in humans by comparing invasive measurements to [15O]H2O positron emission tomography (PET). As a secondary goal, absolute flow and MVR were compared between invasive measurements obtained with and without adenosine. METHODS AND RESULTS: Twenty-five patients underwent coronary computed tomography angiography (CCTA), [15O]H2O PET, and invasive assessment. Absolute coronary flow and MVR were measured in the left anterior descending and left circumflex artery using a dedicated infusion catheter and a temperature/pressure sensor-tipped guidewire. Invasive measurements were performed with and without adenosine. In order to compare invasive flow measurements with PET perfusion, subtending myocardial mass of the investigated vessels was derived from CCTA using the Voronoi algorithm. Invasive and non-invasive measurements of adenosine-induced hyperaemic flow and MVR showed strong correlation (r = 0.91; P < 0.001 for flow and r = 0.85; P < 0.001 for MVR) and good agreement [intraclass correlation coefficient (ICC) = 0.90; P < 0.001 for flow and ICC = 0.79; P < 0.001 for MVR]. Absolute flow and MVR also correlated well between measurements with and without adenosine (r = 0.97; P < 0.001 for flow and r = 0.98; P < 0.001 for MVR) and showed good agreement (ICC = 0.96; P < 0.001 for flow and ICC = 0.98; P < 0.001 for MVR). CONCLUSIONS: Continuous thermodilution is an accurate method to measure absolute coronary flow and MVR, which is evidenced by strong agreement with [15O]H2O PET derived flow and resistance. Absolute flow and MVR correlate highly between invasive measurements obtained with and without adenosine, which confirms that intracoronary infusion of room temperature saline elicits steady-state maximal hyperaemia.

Timing of revascularization in patients with transient ST-segment elevation myocardial infarction: a randomized clinical trial.

Aims: Patients with acute coronary syndrome who present initially with ST-elevation on the electrocardiogram but, subsequently, show complete normalization of the ST-segment and relief of symptoms before reperfusion therapy are referred to as transient ST-segment elevation myocardial infarction (STEMI) and pose a therapeutic challenge. It is unclear what the optimal timing of revascularization is for these patients and whether they should be treated with a STEMI-like or a non-ST-segment elevation myocardial infarction (NSTEMI)-like invasive approach. The aim of the study is to determine the effect of an immediate vs. a delayed invasive strategy on infarct size measured by cardiac magnetic resonance imaging (CMR). Methods and results: In a randomized clinical trial, 142 patients with transient STEMI with symptoms of any duration were randomized to an immediate (STEMI-like) [0.3 h; interquartile range (IQR) 0.2-0.7 h] or a delayed (NSTEMI-like) invasive strategy (22.7 h; IQR 18.2-27.3 h). Infarct size as percentage of the left ventricular myocardial mass measured by CMR at day four was generally small and not different between the immediate and the delayed invasive group (1.3%; IQR 0.0-3.5% vs. 1.5% IQR 0.0-4.1%, P = 0.48). By intention to treat, there was no difference in major adverse cardiac events (MACE), defined as death, reinfarction, or target vessel revascularization at 30 days (2.9% vs. 2.8%, P = 1.00). However, four additional patients (5.6%) in the delayed invasive strategy required urgent intervention due to signs and symptoms of reinfarction while awaiting angiography. Conclusion: Overall, infarct size in transient STEMI is small and is not influenced by an immediate or delayed invasive strategy. In addition, short-term MACE was low and not different between the treatment groups.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Post-spastic flow recovery time to document vasospasm induced ischemia during acetylcholine provocation testing.

Background: Intracoronary acetylcholine (ACh) provocation is an established method for diagnosing epicardial and microvascular vasospasm in contemporary clinical practice. We hypothesize that ACh-induced vasospasm is followed by post-spastic reactive hyperemia (PSRH), which is measured as an increased flow-recovery time. Objectives: To assess flow-recovery time, indicative of ischemia, among the diagnostic endotypes that follow ACh provocation testing. Methods: Patients with angina and non-obstructive coronary artery disease on angiography who underwent ACh provocation testing were included in this analysis. Doppler flow was continuously measured during the procedure and used to determine the flow-recovery time, which was calculated as time between cessation of ACh infusion and the point of flow recovery. Results: Conventional provocation testing according to the COVADIS criteria diagnosed vasospasm in 63%(77/123), an equivocal result in 22%(27/123) and a negative result in 15%(19/123) of patients. In reaction to the highest-dose of ACh, flow-recovery time was significantly extended and similar in the epicardial, microvascular and equivocal test results compared to the negative result (all p < 0.001) indicative of PSRH. Conclusion: Flow-recovery time in patients with an equivocal result is similar to patients with vasospasm, which indicates the occurrence of myocardial ischemia and therefore, these patients may benefit from medical treatment.

Presence of Coronary Endothelial Dysfunction, Coronary Vasospasm, and Adenosine-Mediated Vasodilatory Disorders in Patients With Ischemia and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary function testing in patients with ischemia and nonobstructive coronary arteries (INOCA) commonly includes assessment of adenosine-mediated vasodilation and acetylcholine spasm provocation. The purpose of this study was to evaluate the diagnostic value of additional endothelial function testing for the diagnosis of vasomotor dysfunction in patients with INOCA. METHODS: In this retrospective cohort study, we included patients with INOCA who underwent clinically indicated comprehensive coronary function testing. Endothelial dysfunction was defined as a <50% increase in coronary blood flow, determined by Doppler flow, and/or epicardial vasoconstriction compared to baseline, in response to low-dose acetylcholine. Coronary artery spasm (CAS) was defined as vasospastic angina or microvascular angina in response to coronary high-dose acetylcholine. An impaired adenosine-mediated vasodilation was defined as a coronary flow reserve <2.5 and/or hyperemic microvascular resistance ≥2.5. RESULTS: Among all 110 patients, 79% had endothelial dysfunction, 62% had CAS, and 29% had an impaired adenosine-mediated vasodilation. Endothelial dysfunction was present in 80% of patients who tested positively for CAS and/or an impaired adenosine-mediated vasodilation. Endothelial function testing increases the diagnostic yield of coronary function testing that only incorporates adenosine testing and spasm provocation by 17% to 92%. Of patients with normal adenosine-mediated vasodilation and no inducible CAS, 68% had endothelial dysfunction. CONCLUSIONS: Concomitant endothelial dysfunction was prevalent in the vast majority of patients with INOCA with inducible CAS and/or an impaired adenosine-mediated vasodilation. In patients with INOCA without inducible CAS and normal adenosine-mediated vasodilation, two-thirds had endothelial dysfunction. These results indicate the relevance to perform endothelial function testing in patients with INOCA in view of its therapeutic implication.

Haemodynamic characterisation of different endotypes in coronary artery vasospasm in reaction to acetylcholine.

BACKGROUND: Vasoreactivity testing with high-dose acetylcholine is considered vasospasm provocation and low-dose as endothelial function testing. AIMS: To assess the changes in reaction to low- and high-dose acetylcholine in the endotypes of CAS as defined by the Coronary Vasomotor Disorders International Study Group (COVADIS) working group. METHODS: Changes in coronary epicardial diameter, coronary blood flow (CBF) and vascular resistance were determined at low-dose acetylcholine. RESULTS: A total of 88 ANOCA patients were included in this analysis. In the negative group (n = 14) incremental infusion of acetylcholine produced a progressive increase in CBF (p = 0.008). In reaction to low-dose acetylcholine, the epicardial vasospasm group (n = 30) is characterised by epicardial vasoconstriction that is significantly more severe compared to the microvascular vasospasm group (p = 0.004)(n = 23). The equivocal group (n = 21) is characterised by an increase in CBF and reduction in vascular resistance that are both significantly different compared to the epicardial vasospasm group (p = 0.036 and p = 0.007, respectively). High-dose acetylcholine decreased epicardial diameter and CBF significantly in the epicardial vasospasm, microvascular vasospasm and in the equivocal group (all p < 0.05. Vascular resistance increased significantly in the epicardial vasospasm group (p < 0.001) and equivocal group (p = 0.009). CONCLUSION: In reaction to low-dose acetylcholine the negative and equivocal endotype has haemodynamic changes that suggest intact endothelium. In reaction to high-dose acetylcholine the epicardial vasospasm, microvascular vasospasm and equivocal endotype have hemodynamic changes that suggest VSMC-hyperreactivity. These results suggest that the equivocal endotype is a positive test comparable to microvascular vasospasm in the presence of normal endothelial function.

Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine With Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment.

BACKGROUND: Intravenous infusion of adenosine is considered standard practice for fractional flow reserve (FFR) assessment but is associated with adverse side-effects and is time-consuming. Intracoronary bolus injection of adenosine is better tolerated by patients, cheaper, and less time-consuming. However, current literature remains fragmented and modestly sized regarding the equivalence of intracoronary versus intravenous adenosine. We aim to investigate the relationship between intracoronary adenosine and intravenous adenosine to determine FFR. METHODS: We performed a lesion-level meta-analysis to compare intracoronary adenosine with intravenous adenosine (140 µg/kg per minute) for FFR assessment. The search was conducted in accordance to the Preferred Reporting for Systematic Reviews and Meta-Analysis statement. Lesion-level data were obtained by contacting the respective authors or by digitization of scatterplots using custom-made software. Intracoronary adenosine dose was defined as; low: <40 µg, intermediate: 40 to 99 µg, and high: ≥100 µg. RESULTS: We collected 1972 FFR measurements (1413 lesions) comparing intracoronary with intravenous adenosine from 16 studies. There was a strong correlation (correlation coefficient =0.915; P<0.001) between intracoronary-FFR and intravenous-FFR. Mean FFR was 0.81±0.11 for intracoronary adenosine and 0.81±0.11 for intravenous adenosine (P<0.001). We documented a nonclinically relevant mean difference of 0.006 (limits of agreement: -0.066 to 0.078) between the methods. When stratified by the intracoronary adenosine dose, mean differences between intracoronary and intravenous-FFR amounted to 0.004, 0.011, or 0.000 FFR units for low-dose, intermediate-dose, and high-dose intracoronary adenosine, respectively. CONCLUSIONS: The present study documents clinically irrelevant differences in FFR values obtained with intracoronary versus intravenous adenosine. Intracoronary adenosine hence confers a practical and patient-friendly alternative for intravenous adenosine for FFR assessment.

1-Year Outcomes of Delayed Versus Immediate Intervention in Patients With Transient ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: The aim of the present study was to determine the effect of a delayed versus an immediate invasive approach on final infarct size and clinical outcome up to 1 year. BACKGROUND: Up to 24% of patients with acute coronary syndromes present with ST-segment elevation myocardial infarction (STEMI) but show complete resolution of ST-segment elevation and symptoms before revascularization. Current guidelines do not clearly state whether these patients with transient STEMI should be treated with a STEMI-like or non-ST-segment elevation acute coronary syndrome-like intervention strategy. METHODS: In this multicenter trial, 142 patients with transient STEMI were randomized 1:1 to either delayed or immediate coronary intervention. Cardiac magnetic resonance imaging was performed at 4 days and at 4-month follow-up to assess infarct size and myocardial function. Clinical follow-up was performed at 4 and 12 months. RESULTS: In the delayed (22.7 h) and the immediate (0.4 h) invasive groups, final infarct size as a percentage of the left ventricle was very small (0.4% [interquartile range: 0.0% to 2.5%] vs. 0.4% [interquartile range: 0.0% to 3.5%]; p = 0.79), and left ventricular function was good (mean ejection fraction 59.3 ± 6.5% vs. 59.9 ± 5.4%; p = 0.63). In addition, the overall occurrence of major adverse cardiac events, consisting of death, recurrent infarction, and target lesion revascularization, up to 1 year was low and not different between both groups (5.7% vs. 4.4%, respectively; p = 1.00). CONCLUSIONS: At follow-up, patients with transient STEMI have limited infarction and well-preserved myocardial function in general, and delayed or immediate revascularization has no effect on functional outcome and clinical events up to 1 year.

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.

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 x 10(6) MBMC were infused, of which 3.9 +/- 2.3 x 10(6) 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.

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.

Effects of epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension.

OBJECTIVES: To gain more knowledge of changes in main pulmonary artery flow and right ventricular mass and volumes in patients with pulmonary hypertension during epoprostenol therapy. METHODS: Eleven patients (9 women) were evaluated before the start of therapy and every 4 months thereafter. Right and left ventricular volumes and masses were measured by cine MRI. Flow was measured with MRI velocity quantification. At the same times, 6-min walking tests were performed. Right-heart catheterizations were performed at baseline and after 1 year. RESULTS: Right ventricular mass in the patient group was significantly higher from that in a control group of healthy volunteers (95 +/- 26 g vs 42 +/- 10 g, p < 0.05 [mean +/- SD]), whereas the stroke volume was lower (34 +/- 11 mL vs 81 +/- 11 mL, p < 0.05). The greatest improvement in right ventricular stroke volume (to 41 +/- 11 mL, p < 0.05) took place in the first 4 months. During the 1-year follow-up, right ventricular end-diastolic volume and mass did not change, and mean pulmonary artery pressure remained nearly stable at 55 mm Hg at baseline and 53 mm Hg after 1 year. Pulmonary vascular resistance decreased by 12.5% (p = 0.06). CONCLUSIONS: From these data we conclude that epoprostenol lowers pulmonary vascular resistance, leading to an increase in pulmonary artery flow. This increase in pulmonary artery flow corresponds well with the increase in 6-min walking distance and can be noninvasively monitored by MRI (flow quantification). Right ventricular dilatation and hypertrophy are not reversed by epoprostenol therapy, but do not progress either.

[Diagnosis and treatment of pulmonary hypertension]. / Diagnostiek en behandeling van pulmonale hypertensie.

Pulmonary hypertension is defined as a mean pulmonary artery pressure of more than 25 mmHg. There are many possible causes of pulmonary hypertension; pulmonary hypertension has a poor prognosis, irrespective of the underlying cause. The most frequent causes of pulmonary hypertension are left heart failure and lung disease. The diagnostic work up of pulmonary hypertension starts with investigations into left heart failure and lung disease. If these reveal no cause, ventilation perfusion scintigraphy should be carried out so that chronic thrombo-embolic pulmonary hypertension can be demonstrated or excluded. In most cases, chronic thrombo-embolic pulmonary hypertension can be treated curatively by means of pulmonary endarterectomy. If chronic thrombo-embolic pulmonary hypertension is also ruled out, then we speak of pulmonary arterial hypertension. Prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylyl cyclase stimulators have been shown to be effective in patients with pulmonary arterial hypertension. This condition should be treated at specialist centres.

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.

Recovery of microcirculation after intracoronary infusion of bone marrow mononuclear cells or peripheral blood mononuclear cells in patients treated by primary percutaneous coronary intervention the Doppler substudy of the Hebe trial.

OBJECTIVES: In the present substudy of the Hebe trial, we investigated the effect of intracoronary bone marrow mononuclear cell (BMMC) and peripheral blood mononuclear cell (PBMC) therapy on the recovery of microcirculation in patients with reperfused ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Several studies have suggested that cell therapy enhances neovascularization after STEMI. METHODS: Paired Doppler flow measurements were available for 23 patients in the BMMC group, 18 in the PBMC group, and 19 in the control group. Coronary flow was assessed at 3 to 8 days after primary percutaneous coronary intervention (PCI) and repeated at 4-month follow-up, with intracoronary Doppler flow measurements. RESULTS: At baseline, the coronary flow velocity reserve was reduced in the infarct-related artery and improved over 4 months in all 3 groups. The increase of coronary flow velocity reserve did not significantly differ between the 2 treatment groups and the control group (BMMC group: 2.0 ± 0.5 to 3.1 ± 0.7; PBMC group: 2.2 ± 0.6 to 3.2 ± 0.8; control group: 2.0 ± 0.5 to 3.4 ± 0.9). Additionally, the decrease in hyperemic microvascular resistance index from baseline to 4-month follow-up was not statistically different between the 2 treatment groups and the control group. CONCLUSIONS: In STEMI patients treated with primary PCI in the Hebe trial, adjuvant therapy with BMMCs or PBMCs does not improve the recovery of microcirculation. Therefore, our data do not support the hypothesis of enhanced neovascularization after this mode of cell therapy. (Multicenter, randomised trial of intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention [PCI]; ISRCTN95796863).

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.

Right coronary artery flow impairment in patients with pulmonary hypertension.

AIMS: This study investigates whether increased right ventricular (RV) pressure in pulmonary hypertension (PH) impairs right coronary artery (RCA) flow and RV perfusion. METHODS: In 25 subjects, five patients with idiopathic pulmonary arterial hypertension, nine patients with chronic thromboembolic pulmonary arterial hypertension, and 11 healthy controls, flow of the RCA and left anterior descending (LAD) artery was measured with MR flow quantification. RESULTS: In PH, RCA peak systolic and mean systolic flow were lower, 1.02 +/- 0.62 mL/s and 0.42 +/- 0.30 mL/s, than peak and mean diastolic flow, 2.99 +/- 1.97 mL/s (P < 0.001) and 1.73 +/- 0.97 mL/s (P < 0.001); a pattern similar to the LAD. In contrast, in controls, RCA peak and mean flow in systole, 1.63 +/- 0.58 mL/s and 0.72 +/- 0.23 mL/s, were comparable to peak and mean flow in diastole, 1.72 +/- 0.48 mL/s and 0.93 +/- 0.28 mL/s (NS). The systolic-to-diastolic flow ratio in the RCA, and mean flow per gram RV tissue, were inversely related to RV mass, R = -0.61 (P = 0.009), and R = -0.73 (P < 0.001) and to RV pressure, R = -0.83 (P < 0.001), and R = -0.57 (P = 0.033). CONCLUSION: Although in controls, RCA flow is similar in systole and diastole, in PH there is systolic flow impediment, which is proportional to RV pressure and mass. In patients with severe RV hypertrophy total mean flow is reduced.

Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension.

AIMS: This study investigated the relationship between right ventricular (RV) structure and function and survival in idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: In 64 patients, cardiac magnetic resonance, right heart catheterization, and the six-minute walk test (6MWT) were performed at baseline and after 1-year follow-up. RV structure and function were analysed as predictors of mortality. During a mean follow-up of 32 months, 19 patients died. A low stroke volume (SV), RV dilatation, and impaired left ventricular (LV) filling independently predicted mortality. In addition, a further decrease in SV, progressive RV dilatation, and further decrease in LV end-diastolic volume (LVEDV) at 1-year follow-up were the strongest predictors of mortality. According to Kaplan-Meier survival curves, survival was lower in patients with an inframedian SV index or= 84 mL/m(2), and an inframedian LVEDV