Comparison of three-dimensional proximal isovelocity surface area to cardiac magnetic resonance imaging for quantifying mitral regurgitation.

The aim of our study was to evaluate 3-dimensional (3D) color Doppler proximal isovelocity surface area (PISA) as a tool for quantitative assessment of mitral regurgitation (MR) against in vitro and in vivo reference methods. A customized 3D PISA software was validated in vitro against a flowmeter MR phantom. Sixty consecutive patients, with ≥mild MR of any cause, were recruited and the regurgitant volume (RVol) was measured by 2D PISA, 3D peak PISA, and 3D integrated PISA, using transthoracic (TTE) and transesophageal echocardiography (TEE). Cardiac magnetic resonance imaging (CMR) was used as reference method. Flowmeter RVol was associated with 3D integrated PISA as follows: y = 0.64x + 4.7, r(2) = 0.97, p <0.0001 for TEE and y = 0.88x + 4.07, r(2) = 0.96, p <0.0001 for TTE. The bias and limit of agreement in the Bland-Altman analysis were 6.8 ml [-3.5 to 17.1] for TEE and -0.059 ml [-6.2 to 6.1] for TTE. In vivo, TEE-derived 3D integrated PISA was the most accurate method for MR quantification compared to CMR: r(2) = 0.76, y = 0.95x - 3.95, p <0.0001; 5.1 ml (-14.7 to 26.5). It was superior to TEE 3D peak PISA (r(2) = 0.67, y = 1.00x + 6.20, p <0.0001; -6.3 ml [-33.4 to 21.0]), TEE 2D PISA (r(2) = 0.54, y = 0.76x + 0.18, p <0.0001; 8.4 ml [-20.4 to 37.2]), and TTE-derived measurements. It was also most accurate by receiver operating characteristic analysis (area under the curve 0.99) for the detection of severe MR, RVol cutoff = 48 ml, sensibility 100%, and specificity 96%. RVol and the cutoff to define severe MR were underestimated using the most accurate method. In conclusion, quantitative 3D color Doppler echocardiography of the PISA permits a more accurate MR assessment than conventional techniques and, consequently, should enable an optimized management of patients suffering from MR.

Effect of lifetime endurance training on left atrial mechanical function and on the risk of atrial fibrillation.

BACKGROUND: Left atrium (LA) dilation and P-wave duration are linked to the amount of endurance training and are risk factors for atrial fibrillation (AF). The aim of this study was to evaluate the impact of LA anatomical and electrical remodeling on its conduit and pump function measured by two-dimensional speckle tracking echocardiography (STE). METHOD: Amateur male runners >30 years were recruited. Study participants (n=95) were stratified in 3 groups according to lifetime training hours: low (<1500 h, n=33), intermediate (1500 to 4500 h, n=32) and high training group (>4500 h, n=30). RESULTS: No differences were found, between the groups, in terms of age, blood pressure, and diastolic function. LA maximal volume (30±5, 33±5 vs. 37±6 ml/m(2), p<0.001), and conduit volume index (9±3, 11±3 vs. 12±3 ml/m(2), p<0.001) increased significantly from the low to the high training group, unlike the STE parameters: pump strain -15.0±2.8, -14.7±2.7 vs. -14.9±2.6%, p=0.927; conduit strain 23.3±3.9, 22.1±5.3 vs. 23.7±5.7%, p=0.455. Independent predictors of LA strain conduit function were age, maximal early diastolic velocity of the mitral annulus, heart rate and peak early diastolic filling velocity. The signal-averaged P-wave (135±11, 139±10 vs. 148±14 ms, p<0.001) increased from the low to the high training group. Four episodes of non-sustained AF were recorded in one runner of the high training group. CONCLUSION: The LA anatomical and electrical remodeling does not have a negative impact on atrial mechanical function. Hence, a possible link between these risk factors for AF and its actual, rare occurrence in this athlete population, could not be uncovered in the present study.

The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease.

OBJECTIVE: To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). METHODS: This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. RESULTS: During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by -8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to -0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). CONCLUSIONS: Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD. CLINICALTRIALSGOV IDENTIFIER: NCT01039389.

Prognostic relevance of coronary collateral function: confounded or causal relationship?

OBJECTIVE: To expand the limited information on the prognostic impact of quantitatively obtained collateral function in patients with coronary artery disease (CAD) and to estimate causality of such a relation. DESIGN: Prospective cohort study with long-term observation of clinical outcome. SETTING: University Hospital. PATIENTS: One thousand one hundred and eighty-one patients with chronic stable CAD undergoing 1771 quantitative, coronary pressure-derived collateral flow index measurements, as obtained during a 1-min coronary balloon occlusion (CFI is the ratio between mean distal coronary occlusive pressure and mean aortic pressure both subtracted by central venous pressure). Subgroup of 152 patients included in randomised trials on the longitudinal effect of different arteriogenic protocols on CFI. INTERVENTIONS: Collection of long-term follow-up information on clinical outcome. MAIN OUTCOME MEASURES: All-cause mortality and major adverse cardiac events. RESULTS: Cumulative 15-year survival rate was 48% in patients with CFI<0.25 and 65% in the group with CFI≥0.25 (p=0.0057). Cumulative 10-year survival rate was 75% in patients without arteriogenic therapy and 88% (p=0.0482) in the group with arteriogenic therapy and showing a significant increase in CFI at follow-up. By proportional hazard analysis, the following variables predicted increased all-cause mortality: age, low CFI, left ventricular end-diastolic pressure and number of vessels with CAD. CONCLUSIONS: A well-functioning coronary collateral circulation independently predicts lowered mortality in patients with chronic CAD. This relation appears to be causal, because augmented collateral function by arteriogenic therapy is associated with prolonged survival.

Quantitative myocardial contrast echocardiography: a new method for the non-invasive detection of chronic heart transplant rejection.

BACKGROUND: Chronic heart transplant rejection, i.e. cardiac allograft vasculopathy (CAV) is a major adverse prognostic factor after heart transplantation (HTx). This study tested the hypothesis that the relative myocardial blood volume (rBV) as quantified by myocardial contrast echocardiography accurately detects severe CAV as defined by coronary intravascular ultrasound (IVUS). METHODS AND RESULTS: Forty-five HTx patients underwent a total of 50 quantitative IVUS measurements for intima thickness assessment (>1 mm = severe CAV; the reference method). Simultaneously, the two factors constituting myocardial perfusion (mL/min/g) were obtained by transthoracic contrast echocardiography at rest: rBV (the test method), a measure of microvascular density (mL/mL), and its exchange rate ß (1/s; a measure of coronary conductance) after mechanical contrast bubble disruption.Sixty-nine per cent (31 of 45) of the HTx patients showed severe CAV. rBV at rest was equal to 0.17 ± 0.05 in the group without severe CAV, and it was equal to 0.12 ± 0.07 in the group with severe CAV (P = 0.0157). Conversely, ß amounted to 6.4 ± 4.5 in the former and to 10.3 ± 6.2 in the latter group (P = 0.0410), thus, maintaining normal resting myocardial perfusion at 1 mL/min/g. IVUS determined intima thickness correlated significantly and inversely with rBV at rest. An rBV value at rest <0.14 accurately detected severe CAV (intima thickness >1 mm): area under the receiver operating characteristics curve = 0.844, P = 0.004, sensitivity = 0.90, specificity = 0.75. CONCLUSION: Severe CAV can be detected using the non-invasive method of quantitative myocardial contrast echocardiography. rBV at rest amounting to <14% of the surrounding tissue accurately detects coronary intima thickness >1 mm as determined invasively by IVUS. CLINICAL TRIAL NUMBER: NCT00414895.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function.

OBJECTIVE: This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN: Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING: University Hospital. PATIENTS: 35 patients with chronic stable coronary artery disease. INTERVENTION: 2-min iCSO. MAIN OUTCOME MEASURES: Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS: I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS: ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.

Determinants of prognostically relevant intracoronary electrocardiogram ST-segment shift during coronary balloon occlusion.

The prognostic relevance of quantitative an intracoronary occlusive electrocardiographic (ECG) ST-segment shift and its determinants have not been investigated in humans. In 765 patients with chronic stable coronary artery disease, the following simultaneous quantitative measurements were obtained during a 1-minute coronary balloon occlusion: intracoronary ECG ST-segment shift (recorded by angioplasty guidewire), mean aortic pressure, mean distal coronary pressure, and mean central venous pressure (CVP). Collateral flow index (CFI) was calculated as follows: (mean distal coronary pressure minus CVP)/(mean aortic pressure minus CVP). During an average follow-up duration of 50 ± 34 months, the cumulative mortality rate from all causes was significantly lower in the group with an ST-segment shift <0.1 mV (n = 89) than in the group with an ST-segment shift ≥0.1 mV (n = 676, p = 0.0211). Factors independently related to intracoronary occlusive ECG ST-segment shift <0.1 mV (r(2) = 0.189, p <0.0001) were high CFI (p <0.0001), intracoronary occlusive RR interval (p = 0.0467), right coronary artery as the ischemic region (p <0.0001), and absence of arterial hypertension (p = 0.0132). "High" CFI according to receiver operating characteristics analysis was ≥0.217 (area under receiver operating characteristics curve 0.647, p <0.0001). In conclusion, absence of ECG ST-segment shift during brief coronary occlusion in patients with chronic coronary artery disease conveys a decreased mortality and is directly influenced by a well-developed collateral supply to the right versus left coronary ischemic region and by the absence of systemic hypertension in a patient's history.

Right ventricular systolic function assessment: rank of echocardiographic methods vs. cardiac magnetic resonance imaging.

AIMS: Right ventricular (RV) systolic function is prognostically important, but its assessment by echocardiography remains challenging, in part because of the multitude of available measurement methods. The purpose of this prospective study was to rank these methods against the reference of RV ejection fraction (EF) as obtained in a broad clinical population by magnetic resonance imaging (MRI). METHODS AND RESULTS: Two hundred and twenty-three individuals were included in the study. The following seven Doppler echocardiographic parameters were tested using receiver operating characteristic (ROC) analysis for their accuracy to distinguish between normal and moderately impaired RVEF by MRI (RVEF cut-off 50%), respectively, between moderately and severely reduced RVEF (cut-off 30%): RV fractional area and fractional long-axis change (FLC), RV myocardial performance index (MPI), tricuspid annular peak systolic excursion, Doppler tissue imaging-derived isovolumic acceleration and peak systolic velocity (S') at the lateral tricuspid annulus, and strain at the lateral free wall as obtained by speckle-tracking echocardiography. Survival analysis was performed. All seven Doppler echocardiographic parameters correlated significantly with RVEF by MRI (range between 5 and 85%). RVEF <50% was best detected by S' < 11 cm/s: area under the ROC curve 0.779 (95% confidence interval 0.716-0.843), sensitivity 0.740, and specificity 0.753. RVEF ≤30% was best detected by MPI > 0.50: area under the ROC curve 0.948 (95% confidence interval 0.906-0.991), sensitivity 0.947, and specificity 0.852. The Kaplan-Meier analysis revealed reduced cumulative survival among patients with RVEF ≤30% (P = 0.0003). CONCLUSION: A systolic long-axis peak velocity of <11 cm/s at the lateral tricuspid annulus most accurately detects moderately impaired RVEF as obtained by MRI; severely reduced RVEF ≤30% is best detected by RV MPI at a value of >0.50.

Determinants of preformed collateral vessels in the human heart without coronary artery disease.

BACKGROUND: Coronary collaterals protect myocardium jeopardized by coronary artery disease (CAD). Promotion of collateral circulation is desirable before myocardial damage occurs. Therefore, determinants of collateral preformation in patients without CAD should be elucidated. METHODS: In 106 patients undergoing coronary angiography who were free of coronary stenoses, a total of 39 clinical test variables were collected. The coronary collateral flow index (CFI) was measured. Stepwise multiple linear regression analysis was performed after choosing a restricted number of candidates emerging from univariate testing. Separate multiple regression analyses were performed in patients with and without beta-blocker therapy. RESULTS: Nine parameters were found to be possible determinants of CFI by univariate analysis: arterial hypertension (aHT), dyslipidemia, statins, diuretics, age, height, heart rate (HR), pulse pressure amplitude, and left ventricular end-diastolic pressure (LVEDP). After multiple regression analysis, a low HR, absence of aHT, and elevated LVEDP were significantly related to CFI (F = 5.31, p = 0.002, adjusted r(2) = 0.12). In patients without beta-blockers, a low HR and absence of aHT were independent predictors of CFI (F = 8.03, p < 0.001, n = 50, adjusted r(2) = 0.30). CONCLUSIONS: A low HR and absence of aHT are both related to collateral preformation in humans. We suppose that bradycardia favors fluid shear stress in coronary arteries, thus triggering collateral growth.

Microvascular response to metabolic and pressure challenge in the human coronary circulation.

In vivo observations of microcirculatory behavior during autoregulation and adaptation to varying myocardial oxygen demand are scarce in the human coronary system. This study assessed microvascular reactions to controlled metabolic and pressure provocation [bicycle exercise and external counterpulsation (ECP)]. In 20 healthy subjects, quantitative myocardial contrast echocardiography and arterial applanation tonometry were performed during increasing ECP levels, as well as before and during bicycle exercise. Myocardial blood flow (MBF; ml·min(-1)·g(-1)), the relative blood volume (rBV; ml/ml), the coronary vascular resistance index (CVRI; dyn·s·cm(-5)/g), the pressure-work index (PWI), and the pressure-rate product (mmHg/min) were assessed. MBF remained unchanged during ECP (1.08 ± 0.44 at baseline to 0.92 ± 0.38 at high-level ECP). Bicycle exercise led to an increase in MBF from 1.03 ± 0.39 to 3.42 ± 1.11 (P < 0.001). The rBV remained unchanged during ECP, whereas it increased under exercise from 0.13 ± 0.033 to 0.22 ± 0.07 (P < 0.001). The CVRI showed a marked increase under ECP from 7.40 ± 3.38 to 11.05 ± 5.43 and significantly dropped under exercise from 7.40 ± 2.78 to 2.21 ± 0.87 (both P < 0.001). There was a significant correlation between PWI and MBF in the pooled exercise data (slope: +0.162). During ECP, the relationship remained similar (slope: +0.153). Whereas physical exercise decreases coronary vascular resistance and induces considerable functional capillary recruitment, diastolic pressure transients up to 140 mmHg trigger arteriolar vasoconstriction, keeping MBF and functional capillary density constant. Demand-supply matching was maintained over the entire ECP pressure range.

Instantaneous coronary collateral function during supine bicycle exercise.

AIMS: The instantaneous response of the collateral circulation to isometric physical exercise in patients with non-occlusive coronary artery disease (CAD) is not known. METHODS AND RESULTS: Thirty patients (age 59 +/- 9 years) undergoing percutaneous coronary intervention because of stable CAD were included in the study. Collateral function was determined before and during the last minute of a 6 min protocol of supine bicycle exercise during radial artery access coronary angiography. Collateral flow index (CFI, no unit) was determined as the ratio of mean distal coronary occlusive to mean aortic pressure both subtracted by central venous pressure. To avoid confounding due to recruitment of coronary collaterals by repetitive balloon occlusions, patients were randomly assigned to a group 'rest first' with CFI measurement during rest followed by CFI during exercise, and to a group 'exercise first' with antecedent CFI measurement during exercise before CFI at rest. Simultaneously, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography in the last 10 consecutive patients. Overall, CFI increased from 0.168 +/- 0.118 at rest to 0.262 +/- 0.166 during exercise (P = 0.0002). The exercise-induced change in CFI did not differ statistically in the two study groups. Exercise-induced CFI reserve (CFI during exercise divided by CFI at rest) was 2.2 +/- 1.8. Overall, rest to peak bicycle exercise change of coronary collateral conductance was from 0.010 +/- 0.010 to 1.109 +/- 0.139 mL/min/100 mmHg (P < 0.0001); the respective change was similar in both groups. CONCLUSION: In patients with non-occlusive CAD, collateral flow instantaneously doubles during supine bicycle exercise as compared with the resting state. ClinicalTrials.gov Identifier: NCT00947050.

Safety of diagnostic balloon occlusion in normal coronary arteries.

Diagnostic coronary balloon occlusion (CBO) is mandatory for collateral function assessment, during angioscopy and optical coherence imaging, and when using certain coronary protection devices against emboli. Thus far, the safety of diagnostic CBO regarding procedural and long-term complications in normal coronary arteries has not been studied. In 316 patients, diagnostic CBO was performed for collateral function measurement in 426 angiographically normal vessels. The angioplasty balloon was inflated for 60 to 120 seconds using inflation pressures of 1 to 3 atm, followed by control angiography during and after CBO. Patients were divided into groups with entirely normal (n = 133) and partially normal (n = 183) vessels. Primary end points were procedural and long-term complications. De novo stenosis development was assessed by quantitative coronary angiography in 35% of the patients. Secondary end points were cardiac events at 5 years of follow-up. Procedural complications occurred in 1 patient (0.2%). In 150 repeat angiographic procedures in 92 patients (follow-up duration 10 +/- 15 months), quantitative coronary angiography revealed no difference in percentage diameter narrowing between baseline and follow-up (4.1% vs 3.9%, p = 0.69). During follow-up periods of 14 and 72 months, respectively, a new stenotic lesion was detected in 1 patient in each group (1.3%). Major cardiac events and percutaneous coronary intervention for stable angina were less frequent in the group with entirely normal than with partially normal vessels (0.8% vs 5.5%, p = 0.02, and 0.8% vs 18%, p <0.0001). In conclusion, low-inflation pressure diagnostic CBO in angiographically normal coronary arteries bears a minimal risk for procedural and long-term complications and can therefore be regarded as a safe procedure.

Coronary collateral growth by external counterpulsation: a randomised controlled trial.

BACKGROUND: The efficacy of external counterpulsation (ECP) on coronary collateral growth has not been investigated in a randomised controlled study. Objective To test the hypothesis that ECP augments collateral function during a 1 min coronary balloon occlusion. PATIENTS AND METHODS: Twenty patients with chronic stable coronary artery disease were studied. Before and after 30 h of randomly allocated ECP (20 90 min sessions over 4 weeks at 300 mm Hg inflation pressure) or sham ECP (same setting at 80 mm Hg inflation pressure), the invasive collateral flow index (CFI, no unit) was obtained in 34 vessels without coronary intervention. CFI was determined by the ratio of mean distal coronary occlusive pressure to mean aortic pressure with central venous pressure subtracted from both. Additionally, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography, and brachial artery flow-mediated dilatation was obtained. RESULTS: CFI changed from 0.125 (0.073; interquartile range) at baseline to 0.174 (0.104) at follow-up in the ECP group (p=0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (p=0.14). Baseline to follow-up change of coronary collateral conductance was from 0.365 (0.268) to 0.568 (0.585) ml/min/100 mm Hg in the ECP group (p=0.072), and from 0.229 (0.212) to 0.305 (0.422) ml/min/100 mm Hg in the sham ECP group (p=0.45). There was a correlation between the flow-mediated dilatation change from baseline to follow-up and the corresponding CFI change (r=0.584, p=0.027). CONCLUSIONS: ECP appears to be effective in promoting coronary collateral growth. The extent of collateral function improvement is related to the amount of improvement in the systemic endothelial function.

Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial.

BACKGROUND: The efficacy of granulocyte colony-stimulating factor (G-CSF) for coronary collateral growth promotion and thus impending myocardial salvage has not been studied so far, to our best knowledge. METHODS AND RESULTS: In 52 patients with chronic stable coronary artery disease, age 62+/-11 years, the effect on a marker of myocardial infarct size (ECG ST segment elevation) and on quantitative collateral function during a 1-minute coronary balloon occlusion was tested in a randomized, placebo-controlled, double-blind fashion. The study protocol before coronary intervention consisted of occlusive surface and intracoronary lead ECG recording as well as collateral flow index (CFI, no unit) measurement in a stenotic and a > or =1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 microg/kg; n=26) or placebo (n=26). The CFI was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure. The ECG ST segment elevation >0.1 mV disappeared significantly more often in response to G-CSF (11/53 vessels; 21%) than to placebo (0/55 vessels; P=0.0005), and simultaneously, CFI changed from 0.121+/-0.087 at baseline to 0.166+/-0.086 at follow-up in the G-CSF group, and from 0.152+/-0.082 to 0.131+/-0.071 in the placebo group (P<0.0001 for interaction of treatment and time). The absolute change in CFI from baseline to follow-up amounted to +0.049+/-0.062 in the G-CSF group and to -0.010+/-0.060 in the placebo group (P<0.0001). CONCLUSIONS: Subcutaneous G-CSF is efficacious during a short-term protocol in improving signs of myocardial salvage by coronary collateral growth promotion.