Stefano F. de Marchi

Beneficial Effect of Recruitable Collaterals A 10-Year Follow-Up Study in Patients With Stable Coronary Artery Disease Undergoing Quantitative Collateral Measurements

Background— The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up. Methods and Results— Eight-hundred forty-five individuals (age, 62±11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure–derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: where Poccl is mean coronary occlusive pressure, Pao is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI <0.25) or well-grown collateral vessels (CFI ≥0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI (P=0.0395, P=0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking. Conclusions— A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.

Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies

Background— Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individuals susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. Methods and Results— We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. Conclusions— Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

Assessment of the Human Coronary Collateral Circulation

Cardiovascular disease is the leading cause of death in industrialized countries and may become the most important reason for mortality worldwide.1 In patients suffering from coronary artery disease (CAD), the size of myocardial infarction mainly determines outcome.2 Accordingly, the primary strategy to reduce cardiovascular mortality is by shrinking infarct size (IS) (Figure 1A).3 In the clinical setting of acute myocardial infarction, Antoniucci et al4,5 documented in 1164 patients undergoing primary percutaneous coronary intervention (PCI) that the presence of angiographic collaterals before PCI purported a survival benefit compared with the situation without them (Figure 2). As a surrogate for IS, studies on the effect of myocardial salvage procedures have employed the magnitude of ECG ST-segment elevation during coronary balloon occlusion (Figure 3).6,7 IS, measured as the degree of ECG ST-segment elevation during a 1-minute coronary occlusion, is influenced by the following factors: duration of occlusion, ischemic area at risk for myocardial infarction (AR), collateral blood supply to the ischemic zone, ischemic preconditioning, and myocardial oxygen consumption.8 In the context of a single brief artificial coronary occlusion of uniform duration without preceding bouts of ischemia (Figure 3),6 ECG signs of ischemia are influenced predominantly by the AR and by collateral supply to this region. Furthermore, Figure 1B3 illustrates that AR and collateral supply are inversely related to each other (ie, AR tends to shrink toward zero in the presence of well-functioning collaterals). They are termed sufficient if they prevent an ECG ST-segment elevation of ≥0.1 mV during a 1-minute coronary balloon occlusion; otherwise, they are termed insufficient collaterals. Figure 1. Schematic drawing of the coronary artery circulation without (A) and with interarterial anastomoses (B) between the right coronary artery and the occluded left anterior descending artery (occluded downstream …

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 ≥1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 &mgr;g/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.

An indicator of sudden cardiac death during brief coronary occlusion: electrocardiogram QT time and the role of collaterals.

AIMS The coronary collateral circulation has a beneficial role regarding all-cause and cardiac mortality. Hitherto, the underlying mechanism has not been clarified. The aim of this prospective study was to assess the effect of the coronary collateral circulation on electrocardiogram (ECG) QTc time change during short-term myocardial ischaemia. METHODS AND RESULTS A total of 150 patients (mean age 63 +/- 11 years, 38 women) were prospectively included in this study. An ECG was recorded at baseline and during a standardized 1 min coronary balloon occlusion. QT interval was measured before, during, and after balloon occlusion and was corrected for heart rate (QTc). Simultaneously obtained collateral flow index (CFI), expressing collateral flow relative to normal anterograde flow, was determined based on intracoronary pressure measurements. During occlusion of the left anterior descending coronary artery mean QTc interval increased from 422 +/- 33 to 439 +/- 36 ms (P < 0.001), left circumflex occlusion led to an increase from 414 +/- 32 to 427 +/- 27 ms (P < 0.001). QTc was not influenced by occlusion of the right coronary artery (RCA) (417 +/- 35 and 415 +/- 34 ms, respectively; P = 0.863). QTc change during occlusion of the left coronary artery was inversely correlated with CFI (R(2) = 0.122, P = 0.0002). CONCLUSION Myocardial ischaemia leads to QT prolongation during a controlled 1 min occlusion of the left, but not the RCA. QT prolongation is inversely related to collateral function indicating a protective mechanism of human coronary collaterals against cardiac death.

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 r2 = 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 r2 = 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.

Right ventricular absolute myocardial blood flow in complex congenital heart disease

Objective A consequence in patients with d-transposition of the great arteries (d-TGA) and tetralogy of Fallot (TOF) is right ventricular hypertrophy (RVH) and right ventricular failure. Myocardial contrast echocardiography (MCE) permits the determination of the myocardial microvascular density reflected by the relative myocardial blood volume (rBV; ml/ml). This study was conducted to elucidate the relationship between RVH and myocardial microvascular changes by quantitative MCE in patients with d-TGA and TOF. Methods Three groups of individuals were included in the study: 22 patients with d-TGA, 18 patients with TOF and 22 healthy individuals (controls). MCE was performed at rest and during adenosine-induced hyperaemia. rBV and myocardial blood flow (MBF; ml/min per gram) were derived from steady state and refill sequences of ultrasound contrast agent. Results Hyperaemic septal rBV differed significantly between the groups and was highest in controls: d-TGA 0.141±0.060 ml/ml, TOF 0.134±0.080 ml/ml, controls 0.189±0.074 ml/ml, p=0.005. Myocardial blood flow reserve (MBFR), that is the ratio of hyperaemic to baseline MBF, differed significantly between the groups and was lowest in d-TGA (2.68±1.13) versus TOF (3.37±1.57) and controls (4.22±1.17, p=0.001). Hyperaemic septal rBV, MBF and MBFR showed a significant correlation with right ventricular systolic function as determined by tricuspid annular plane systolic excursion. Conclusions Right ventricular myocardial microvascular density of the septal wall in d-TGA and TOF patients with RVH due to pressure and/or volume overload is reduced. This appears to be related to a reduced myocardial perfusion reserve and impaired right ventricular systolic function.

Plasma homocysteine and cardiovascular risk in heart failure with and without cardiorenal syndrome.

INTRODUCTION Plasma homocysteine (Hcy) has been associated with an increased cardiovascular (CV) risk in patients with chronic heart failure (CHF). Thus, we investigated whether Hcy has a prognostic impact on CV events in CHF-patients with and without cardiorenal syndrome (CRS). METHODS 161 patients with CHF were included in the present analysis. 94 patients had systolic (SD) (EF <40%) and 67 diastolic (DD) dysfunction (EF>or=40%). 60 had cardiorenal syndrome (CRS+ creatinine clearance<60 ml/min). Mean ejection fraction was 38+/-16% (n=153) and mean VO2 max 19+/-7 ml/min (n=87). RESULTS Homocysteine is significantly increased in patients with CHF (20+/-7 micromol/l). The increase correlates not only with the severity of the disease (NYHA, EF, VO2max), but also with various metabolic (BNP, uric acid) and nephrologic parameters (creatinine, creatinine clearance). During follow-up (23+/-37 months), patients with the highest homocysteine (>or=20 micromol/l) passed away more often (p<0.035) or decompensated more frequently (p<0.004) than those with a low Hcy. In patients with CRS the rate of decompensation was significantly higher than in those without CRS (p<0.0007). CONCLUSIONS Homocysteine is an important marker for an increased CV risk in patients with CHF. A homocysteine of >/=20 micromol/l is associated with a high risk to decompensate or to die (odds ratio 2.57). The presence of CRS is also associated with an increased CV risk (odds ratio 3.7) and predicts an adverse clinical outcome.

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.