C. Chawantanpipat

Development and validation of a time-dependent risk model for predicting mortality in infective endocarditis

AIMS Existing risk models in infective endocarditis (IE) have not investigated whether the prognostic value of clinical parameters is time-dependent. We have explored the potential of time-dependent risk stratification to predict outcome in IE. METHODS AND RESULTS We studied 273 patients admitted with IE to two centres (derivation cohort n=192, validation cohort n=81). The derivation cohort was used to identify independent predictors of 6 months mortality at days 1, 8, and 15 (multivariable Cox regression, P<0.05). There were six predictors at day 1, five at day 8, and only three at day 15. Whereas heart failure, thrombocytopenia, and severe comorbidity predicted mortality at all three time-points, other predictors were time-dependent (age, tachycardia, renal impairment at day 1; severe embolic events, renal impairment at day 8). These predictors were incorporated into a time-dependent model. The model was validated in an independent cohort with concordance indices of 0.79 (95% CI 0.68-0.91) at day 1, 0.79 (95% CI 0.65-0.93) at day 8, and 0.84 (95% CI 0.73-0.95) at day 15. Six months mortality was 2.4% in patients deemed as low-risk at all time-points, compared with 78.2% in patients classified as high-risk at any evaluation. CONCLUSION Prognostic factors in IE are time-dependent. Time-dependent risk stratification accurately predicts outcome in IE.

The Index of Microcirculatory Resistance Predicts Myocardial Infarction Related to Percutaneous Coronary Intervention

Background— Periprocedural myocardial infarction (MI) occurs in a significant proportion of patients undergoing percutaneous coronary intervention (PCI) and portends poor outcomes. Currently, no clinically applicable method predicts periprocedural MI in the cardiac catheterization laboratory before it occurs. We hypothesized that impaired baseline coronary microcirculatory reserve, which reduces the ability to tolerate ischemic insults, is a risk for periprocedural MI and that the index of microcirculatory resistance (IMR) measured during PCI can predict occurrence of periprocedural MI. Methods and Results— Consecutive patients undergoing elective PCI of a single lesion in the left anterior descending coronary artery were recruited. A pressure-temperature sensor wire was used to measure IMR before PCI. Of the 50 patients studied, 10 had periprocedural MI. From binary logistic regression analyses of all clinical, procedural, and physiological parameters, univariable predictors of periprocedural MI were pre-PCI IMR (P=0.003) and the number of stents used (P=0.039). Pre-PCI IMR was the only independent predictor in bivariable regression analyses performed by adjusting for each available covariate one at a time (all P⩽0.02). Pre-PCI IMR ≥27 U had 80.0% sensitivity and 85.0% specificity for predicting periprocedural MI (C statistic, 0.80; P=0.003). Pre-PCI IMR ≥27 U was independently associated with a 23-fold risk of developing periprocedural MI (odds ratio, 22.7; 95% CI, 3.8–133.9). Conclusions— These data suggest that the status of the coronary microcirculation plays a role in determining susceptibility toward periprocedural MI at the time of elective PCI. The IMR can predict subsequent risk of developing myocardial necrosis and may guide adjunctive prevention strategies.

The relationship between coronary stenosis severity and compression type coronary artery movement in acute myocardial infarction.

BACKGROUND Acute myocardial infarction is thought to occur at sites of minor coronary stenosis. Recent data challenge this and also propose a role for coronary artery movement (CAM) in plaque instability. We examined the relationship between coronary stenosis severity, CAM pattern, and infarct-related lesions (IRLs) in acute myocardial infarction. METHODS We investigated 203 consecutive patients with ST-segment elevation myocardial infarction after successful fibrinolysis. Quantitative coronary angiography, CAM pattern, and extent score (atheroma burden) analysis was performed for each coronary artery segment. RESULTS The IRL stenosis was at least moderate (>50%) and severe (>70%) in 78% and 31% of patients, respectively. Culprit arteries were associated with higher atheroma extent scores (25.2 vs 21.6, P < .001). Analysis of 2,228 coronary segments showed that stenosis severity and IRLs were highly correlated, such that the likelihood of being a culprit segment progressively increased with worsening stenosis (odds ratio [OR] 30.0, 95% confidence interval [CI] 19.0-47.6, P < .001, for >70% vs <30% stenosis). Compression CAM was also strongly associated with culprit segments (OR 3.4, 95% CI 2.6-4.5, P < .001). In addition, compression CAM and stenosis severity were strongly correlated, with the likelihood of a coronary segment having compression CAM progressively increasing with worsening stenosis (OR 56.4, 95% CI 37.9-83.8, P < .001, for >70% vs <30% stenosis). CONCLUSIONS In patients with ST-segment elevation myocardial infarction, there is a strong relationship between stenosis severity and IRLs. Our study also raises the hypothesis that compression CAM may accelerate atherosclerosis and predispose to plaque vulnerability.

Thrombocytopenia and Mortality in Infective Endocarditis

To the Editor: Infective endocarditis remains a life-threatening disease. Platelets have an important role in the pathogenesis of endocarditis ([1][1]) and are sensitive monitors of the systemic host response to sepsis. We have investigated the platelet response in infective endocarditis and its

Measurement of pulmonary flow reserve and pulmonary index of microcirculatory resistance for detection of pulmonary microvascular obstruction

Background The pulmonary microcirculation is the chief regulatory site for resistance in the pulmonary circuit. Despite pulmonary microvascular dysfunction being implicated in the pathogenesis of several pulmonary vascular conditions, there are currently no techniques for the specific assessment of pulmonary microvascular integrity in humans. Peak hyperemic flow assessment using thermodilution-derived mean transit-time (Tmn) facilitate accurate coronary microcirculatory evaluation, but remain unvalidated in the lung circulation. Using a high primate model, we aimed to explore the use of Tmn as a surrogate of pulmonary blood flow for the purpose of measuring the novel indices Pulmonary Flow Reserve [PFR = (maximum hyperemic)/(basal flow)] and Pulmonary Index of Microcirculatory Resistance [PIMR = (maximum hyperemic distal pulmonary artery pressure)×(maximum hyperemic Tmn)]. Ultimately, we aimed to investigate the effect of progressive pulmonary microvascular obstruction on PFR and PIMR. Methods and Results Temperature- and pressure-sensor guidewires (TPSG) were placed in segmental pulmonary arteries (SPA) of 13 baboons and intravascular temperature measured. Tmn and hemodynamics were recorded at rest and following intra-SPA administration of the vasodilator agents adenosine (10–400 µg/kg/min) and papaverine (3–24 mg). Temperature did not vary with intra-SPA sensor position (0.010±0.009 v 0.010±0.009°C; distal v proximal; p = 0.1), supporting Tmn use in lung for the purpose of hemodynamic indices derivation. Adenosine (to 200 µg/kg/min) & papaverine (to 24 mg) induced dose-dependent flow augmentations (40±7% & 35±13% Tmn reductions v baseline, respectively; p<0.0001). PFR and PIMR were then calculated before and after progressive administration of ceramic microspheres into the SPA. Cumulative microsphere doses progressively reduced PFR (1.41±0.06, 1.26±0.19, 1.17±0.07 & 1.01±0.03; for 0, 104, 105 & 106 microspheres; p = 0.009) and increased PIMR (5.7±0.6, 6.3±1.0, 6.8±0.6 & 7.6±0.6 mmHg.sec; p = 0.0048). Conclusions Thermodilution-derived mean transit time can be accurately and reproducibly measured in the pulmonary circulation using TPSG. Mean transit time-derived PFR and PIMR can be assessed using a TPSG and adenosine or papaverine as hyperemic agents. These novel indices detect progressive pulmonary microvascular obstruction and thus have with a potential role for pulmonary microcirculatory assessment in humans.

The relationship between endothelial progenitor cell populations and epicardial and microvascular coronary disease-a cellular, angiographic and physiologic study.

Background Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease. Methods Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo. Results There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r = 0.371, p = 0.04; r = -0.358, p = 0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r = 0.59, p = 0.005; r = 0.589, p = 0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function. Conclusions EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.

MEASUREMENT OF PULMONARY FLOW RESERVE IN HIGHER PRIMATES

1 There are currently limited diagnostic methods for assessing the integrity of the pulmonary microvasculature. We hypothesized that a novel, invasively determined physiological index of ‘pulmonary flow reserve’ (PFR = maximal hyperaemic pulmonary blood flow divided by basal pulmonary flow) may facilitate microvascular assessment in the lung. Therefore, we developed a baboon model in which to: (i) validate the use of Doppler flow velocity for PFR assessment; (ii) define the optimal drug and dose regimen for attainment of maximal pulmonary hyperaemia; and (iii) demonstrate the feasibility of measuring PFR in healthy higher primates. 2 Doppler sensor guidewires were placed in segmental pulmonary arteries of 11 ketamine‐anaesthetized baboons. Vessel diameter, flow velocity and haemodynamics were recorded before and after direct intrapulmonary artery administration of saline, adenosine (50–500 µg/kg per min) and papaverine (3–60 mg), enabling calculation of PFR. 3 Saline (either bolus injection or infusion) did not alter vessel diameter or flow velocity (P > 0.1), validating local drug administration. Both adenosine and papaverine induced dose‐dependent increases in flow velocity from baseline (from 22.5 ± 2.3 to 32.7 ± 4.8 cm/s for 400–500 µg/kg per min adenosine; and from 23.9 ± 1.1 to 34.6 ± 4.0 cm/s for 24 mg papaverine; both P < 0.0001), without affecting pulmonary artery pressure or vessel diameter (P > 0.3). Healthy primate PFR values were 1.35 ± 0.10 and 1.39 ± 0.10 using 200 µg/kg per min adenosine and 24 mg papaverine, respectively (P > 0.8). 4 In conclusion, pulmonary flow reserve in higher primates can be assessed using Doppler sensor guidewire and either adenosine or papaverine as microvascular hyperaemic agents. Measurements of PFR may facilitate pulmonary microvascular assessments.

Doppler-derived Pulmonary Flow Reserve Detects Pulmonary Microvascular Obstruction in High Primates

BACKGROUND Despite increasing evidence implicating the pulmonary microcirculation in the pathogenesis of lung conditions such as pulmonary vascular disease, there remain few methods for its evaluation in vivo. We recently demonstrated that the novel index of Doppler-derived pulmonary flow reserve (PFR(dopp)=maximal hyperaemic/basal pulmonary flow) could be reliably measured in high primates. Noting that the microvasculature is the chief regulator of pulmonary blood flow, we hypothesised that PFR(dopp) may detect microcirculatory loss. We therefore studied the relationship between PFR(dopp) and experimentally induced pulmonary microvascular obstruction using microspheres in higher primates. METHODS Under ketamine anaesthesia, Doppler sensor-guidewires were placed in the segmental pulmonary artery of three adult baboons. Doppler flow velocity and haemodynamics were recorded at rest and during hyperaemia [as induced by intrapulmonary artery adenosine (200 μg/kg/min)]. Serial PFR(dopp) evaluations were made after cumulative intrapulmonary artery ceramic microspheres administration. RESULTS Cumulative microsphere administration progressively reduced PFR(dopp) (1.54 ± 0.26, 1.48 ± 0.20, 1.12 ± 0.04 and 1.18 ± 0.09; baseline, 10(4), 10(5) and 10(6) microspheres boluses; p<0.02) without affecting pulmonary artery pressure, systemic artery pressure or heart rate. CONCLUSIONS Doppler-derived PFR can detect partial, progressive pulmonary microvascular obstruction in higher primates. PFR(dopp) may thus have a potential role in the assessment of the pulmonary microcirculation in vivo.