Niall A. Herity

Adjunctive Platelet Glycoprotein IIb/IIIa Receptor Inhibition With Tirofiban Before Primary Angioplasty Improves Angiographic Outcomes

Background—Previous work has suggested that platelet glycoprotein IIb/IIIa receptor blockade may confer benefit in the treatment of acute myocardial infarction. The TIGER-PA pilot trial was a single-center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction. Methods and Results—A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion (“blush”). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrate a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early administration may be beneficial. Conclusions—This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

Coronary artery compliance and adaptive vessel remodelling in patients with stable and unstable coronary artery disease

OBJECTIVE To test the hypothesis that patients with unstable coronary syndromes show accentuated compensatory vessel enlargement compared with patients with stable angina, and that this may in part be related to increased coronary artery distensibility. DESIGN AND PATIENTS In 23 patients with unstable coronary syndromes (10 with non-Q wave myocardial infarction and 13 with unstable angina), the culprit lesion was investigated by intravascular ultrasound before intervention. The vessel cross sectional area (VA), lumen area (LA), and plaque area (VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Similar measurements were made in 23 patients with stable angina admitted during the same period and matched for age, sex, and target vessel. Calculations were made of remodelling index (VA at lesion site ÷ VA at reference site), distensibility index ([(ΔA/A)/ΔP] × 103, where ΔA is the luminal area change in systole and diastole and ΔP the difference in systolic and diastolic blood pressure measured at the tip of the guiding catheter during a cardiac cycle), and stiffness index β ([ln(Psys/Pdias)]/(ΔD/D), where Psys is systolic pressure, Pdias is diastolic pressure, and ΔD is the difference between systolic and diastolic lumen diameters). Positive remodelling was defined as when the VA at the lesion was > 1.05 times larger than at the proximal reference site, and negative remodelling when the VA at the lesion was < 0.95 of the reference site. RESULTS Mean (SD) LA at the lesion site was similar in both groups (4.03 (1.8) v4.01 (1.93) mm2), while plaque area was larger in the unstable group (13.29 (4.04) v 8.34 (3.6) mm2, p < 0.001). Remodelling index was greater in the unstable group (1.14 (0.18) v 0.83 (0.15), p < 0.001). Positive remodelling was observed in 15 patients in the unstable group (65%) but in only two (9%) in the stable group (p < 0.001). Negative remodelling occurred only in two patients with unstable symptoms (9%) but in 17 (74%) with stable symptoms. At the proximal reference segment, the difference in LA between systole and diastole was 0.99 (0.66) mm2 in the unstable group and 0.39 (0.3) mm2 in the stable group (p < 0.001), and the calculated coronary artery distensibility was 3.09 (2.69) and 0.94 (0.83) per mm Hg in unstable and stable patients, respectively (p < 0.001). The stiffness index β was lower in patients with unstable angina (1.95 (0.94) v 3.1 (0.96), p < 0.001). CONCLUSIONS Compensatory vessel enlargement occurs to a greater degree in patients with unstable than with stable coronary syndromes, and is associated with increased coronary artery distensibility.

Review: Clinical aspects of vascular remodeling.

Clinical Aspects of Vascular Remodeling. Vascular remodeling represents a spectrum of structural changes whereby the vascular wall responds to changes in its hemodynamic environment. Such changes may be classified as vessel enlargement (outward remodeling), diminution (inward remodeling), alternatively as adaptive (compensatory, appropriate to the hemodynamic stimulus), or maladaptive (dysfunctional, inappropriate). The direction and scale of remodeling are coordinated by endothelial production of growth factors, proteases, and cellular adhesion molecules in response to sensed changes in blood flow. In early atherosclerosis, outward remodeling preserves lumen size. Although protective in the long‐term, the matrix degradation involved in this process may predispose atherosclerotic plaques to rupture, hence increasing the risks of acute coronary syndromes. Inward remodeling also occurs in advanced atherosclerotic lesions, whereby the vessel shrinks rather than enlarging, exacerbating rather than ameliorating stenosis. In transplant coronary artery disease, early inward remodeling may he a more important component of vessel stenosis than intimal thickening, while inappropriate inward remodeling appears to he as least as important as excessive intimal growth in the development of restenosis after angioplasty. Increased awareness of vascular remodeling, and in particular its malaptive forms, may provide new therapeutic insights for the future.

Effect of a change in gender on coronary arterial size: a longitudinal intravascular ultrasound study in transplanted hearts.

OBJECTIVES We sought to document whether a physiologic change in gender has any effect on coronary arterial size. BACKGROUND The coronary arteries are smaller in women, even after correction for body surface area (BSA). These differences may contribute to adverse clinical outcomes after coronary artery bypass graft surgery and myocardial infarction in women. In male and female transsexuals, pharmacologic doses of estrogens and androgens significantly influence vascular diameter. Thus, gender differences in the coronary vasculature may be a reflection of the hormonal environment. METHODS In 86 patients who had undergone orthotopic heart transplantation, serial intravascular ultrasound studies of the proximal left anterior descending coronary artery (LAD) were analyzed. Changes in vessel area (VA) over the first or second post-transplant year were recorded, and comparisons were made between donor hearts that were transplanted in a patient of the same gender and those that were transplanted in a patient of the opposite gender. RESULTS Vessel area of the proximal LAD increased over time in all patient groups. In hearts transplanted within the same gender and in male donor hearts transplanted to female recipients, the change was small and not significant. However, in hearts transplanted from female donors to male recipients, there was a substantial and highly significant increase in LAD VA (median 16.13 to 17.88 mm(2); p = 0.01). This increase was not explained by confounding due to changes in BSA or left ventricular wall thickness. CONCLUSIONS This pattern of arterial remodeling early after heart transplantation supports a link between host gender and coronary arterial size.

Selective regional myocardial infiltration by the percutaneous coronary venous route: A novel technique for local drug delivery

Recent advances in the treatment of heart disease, in particular cardiovascular gene therapy and therapeutic angiogenesis, highlight the need for efficient and practical local delivery methods for the heart. We assessed the feasibility of percutaneous selective coronary venous cannulation and injection as a novel approach to local myocardial drug delivery. In anesthetized swine, the coronary sinus was cannulated percutaneously and a balloon‐tipped catheter advanced to the anterior interventricular vein (AIV) or middle cardiac vein (MCV). During balloon occlusion, venous injection of radiographic contrast caused regional infiltration of targeted myocardial regions. Complete AIV occlusion had no impact on LAD flow parameters. Videodensitometric analysis following venous injection showed that radiographic contrast persisted for at least 30 min. Selective regional myocardial infiltration is feasible by this approach, targeting selected myocardial beds, including the apex, anterior wall, septum, and inferoposterior wall. This novel technique has potential application for local myocardial drug or growth factor delivery. Cathet. Cardiovasc. Intervent. 51:358–363, 2000.

Coronary artery distensibility and compensatory vessel enlargement – a novel parameter influencing vascular remodeling?

Abstract Vascular remodeling implies the concept of compensatory vessel enlargement to preserve luminal dimensions during atheromatous plaque development. However, negative remodeling, i.e. vessel shrinkage in response to plaque accumulation has also been described. So far, the factors influencing positive or negative remodeling are uncertain. We hypothesized that vascular distensibility, a measure of vessel compliance, is related to compensatory enlargement.In 58 patients undergoing intravascular ultrasound interrogation of a de novo lesion prior to coronary intervention, the cross-sectional vessel area (VA), lumen area (LA) and plaque area (PA = VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Positive remodeling was defined to be present when the VA at the lesion was > 1.05 times larger than that at the proximal reference (group A), negative remodeling when the VA at the lesion was < 0.95 of the reference site (group C) and in-between was considered to be intermediate (group B). Vessel compliance was measured by calculating vascular distensibility.Results showed a similar LA at the lesion site in all groups (4.18 ± 2.18 vs. 4.36 ± 1.19 vs. 3.74 ± 1.81 mm2, NS) while VA and PA were significantly larger in group A (17.19 ± 5.08 vs. 14.22 ± 3.66 and 12.45 ± 4.82 mm2, p = 0.005 and 13 ± 4.55 vs. 9.95 ± 3.58 and 8.7 ± 3.83, p = 0.003, respectively). Vascular distensibility at the proximal reference segment was significantly greater in group A (3.55 ± 2.67 vs. 1.25 ± 1.03 and 0.85 ± 0.73 mmHg−1, p < 0.001) with a positive correlation between remodeling and distensibility (R = 0.52, p < 0.001). In a multiple regression model including clinical and lesional factors, distensibility was the only predictor of remodeling.In conclusion, these results suggest that compensatory vessel enlargement occurs to a greater degree in patients with increased coronary artery distensibility, which appears to be a predictor for positive remodeling.

Acute Myocardial Infarction and Vascular Remodeling

We used intravascular ultrasound to show that outward remodeling predominates in lesions responsible for acute myocardial infarction, whereas negative remodeling is far more prevalent in lesions responsible for chronic stable angina. The total cholesterol:high-density lipoprotein ratio was also strongly correlated with outward remodeling.

Evaluation of high‐pressure retrograde coronary venous delivery of FGF‐2 protein

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor‐2 (FGF‐2) protein via high‐pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF‐2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere‐derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF‐2 protein (6 μg/kg) was delivered via high‐pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF‐2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 μg; P < 0.04) and in the LAD region (1.2 vs. 0.64 μg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32–1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32–1.23; P = 0.02) and the control arms (1.32–1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30–1.23; P < 0.05), but did not change significantly in the other three arms. High‐pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium. Catheter Cardiovasc Interv 2004;61:422–428.

The influence of plaque orientation (pericardial or myocardial) on coronary arterial remodeling.

BACKGROUND Many systemic, regional and lesion factors have been identified which may influence arterial remodeling, but little is known about the importance of extravascular resistance to vessel enlargement. As myocardial systolic splinting may significantly affect vessel expansion the effect of plaque orientation on arterial remodeling in eccentric coronary atherosclerotic lesions was examined. METHODS Using intravascular ultrasound imaging to obtain cross-sectional vessel area (VA), plaque area (PA) and lumen area (LA), remodeling in eccentric left anterior descending coronary artery lesions was compared which predominantly involved the pericardial or free arc (P, n=25) and the myocardial side (M, n=40) of the vessel wall. Normalized vessel area (NVA, VA(lesion)/VA(reference)) was compared as a continuous and categorical variable (positive>1.05, intermediate 0.95-1.05, negative<0.95) as well as remodeling index (RI, VA(lesion)-VA(reference)/PA(lesion)-PA(reference)). RESULTS The two groups were well matched for clinical and lesion characteristics known to affect remodeling. Reference segments areas were similar in the two groups; while lesion LA was also similar, in the pericardial group there was significantly greater lesion PA (P 12.78+/-0.72, M 10.26+/-0.50 mm(2), P<0.05) and VA (P 15.71+/-0.90, M 12.82+/-0.57 mm(2), P<0.05) demonstrating enhanced compensatory remodeling. Outward remodeling was significantly greater in P than in M by both NVA (P 1.03+/-0.03, M 0.86+/-0.03, P<0.01) and RI (P 0.02+/-0.07, M -1.10+/-0.32, P<0.01). Positive, intermediate and negative remodeling occurred in nine, nine and seven lesions in P and in four, ten and 26 lesions in M (P<0.01). CONCLUSIONS Remodeling compensates more for plaque growth in eccentric coronary lesions which are surrounded by the pericardium than those surrounded by the myocardium. Extravascular resistance appears to influence arterial remodeling.

Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease

Background: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease. 
Methods: Forty‐three non‐smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months. 
Results: For all patients, the average fasting plasma homocysteine level was 17.0±SD 6.6 μmol/L with a range from 6.0 to 36.9 μmol/L. Twenty‐six patients (60%) had fasting plasma homocysteine levels above 15.0 μmol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2±SD 7.0 μmol/L) to those with abnormal (16.8±SD 6.2 μmol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=−0.56, p<0.0001). 
Conclusions: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.