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Management of stable coronary artery disease (CAD) has been based on the assumption that flow-limiting atherosclerotic obstructions are the proximate cause of angina and myocardial ischemia in most patients and represent an important target for revascularization. However, the role of revascularization in reducing long-term cardiac events in these patients has been limited mainly to those with left main disease, 3-vessel disease with diabetes, or decreased ejection fraction. Mounting evidence indicates that nonepicardial coronary causes of angina and ischemia, including coronary microvascular dysfunction, vasospastic disorders, and derangements of myocardial metabolism, are more prevalent than flow-limiting stenoses, raising concerns that many important causes other than epicardial CAD are neither considered nor probed diagnostically. There is a need for a more inclusive management paradigm that uncouples the singular association between epicardial CAD and revascularization and better aligns diagnostic approaches that tailor treatment to the underlying mechanisms and precipitants of angina and ischemia in contemporary clinical practice., Competing Interests: Funding Support and Author Disclosures This publication was supported by an educational grant from Servier, Suresnes Cedex, France. Support in the development of the manuscript was also provided by Liberum IME, London, United Kingdom. Dr Boden receives research grant support from AbbVie, Amarin Pharmaceuticals, Amgen, AstraZeneca, Sanofi, Massachusetts Veterans Epidemiology Research and Information Center, VA New England Healthcare System’s Clinical Trials Network, and the National Heart, Lung, and Blood Institute (NHLBI), where he served as national co-principal investigator for the ISCHEMIA trial; is on the Board of Directors for the Boston VA Research Institute; receives consulting fees from Amarin Pharmaceuticals, Amgen, Janssen Pharmaceuticals, Metuchen Pharmaceuticals, and Servier; is on the VA Cooperative Studies Program data monitoring committee; and has received speaking honoraria from Amarin, Amgen, Janssen Pharmaceuticals, Pfizer, and Servier. Dr Marzilli lectures for Servier, Menarini, Degussa Pharma Group, Baldacci, Abbott, and AstraZeneca. Dr Crea has received personal speaker fees from Amgen, AstraZeneca, Servier, and BMS; and is a member of the advisory board for GlyCardial Diagnostics. Dr Mancini has received grants, advisory board appointments, and honoraria for educational lectures from Amgen, Sanofi, NovoNordisk, Lilly/Boehringer Ingelheim, and HLI Therapeutics; is on the advisory board for Esperion; and receives reports on grants from the National Institutes of Health (NIH) for the COURAGE and ISCHEMIA trials. Dr Weintraub has received research support from Amarin Corporation, NIH, and Centers for Disease Control and Prevention; and has served as a consultant for Amarin Corporation, AstraZeneca, Pfizer, Janssen, SC Pharma, Lexicon, Faraday, and The Medicines Company. Dr Taqueti is supported by NIH grant K23HL135438. Dr Pepine receives research grant support from NIH/NHLBI (R21AG063143, K08 HL130945, K01 HL138172, R01 HL146158, AG065141, R01 HL152162, R21 HL152264, R01 HL132448, UM1 HL087366, UM1 HL087318), NIH/National Center for Advancing Translational Sciences (UL1 TR001427), U.S. Department of Defense (W81XWH-17-2-0030, WARRIOR), Biocardia, Brigham and Women’s Hospital, CSL Behring, Cytori Therapeutics, DCRI, GE Healthcare, Mesoblast, and Pfizer; receives consultant fees/honoraria from Caladrius Biosciences, Slack, and Xylocor; and receives grant support from the Gatorade Foundation through the University of Florida Department of Medicine and from the McJunkin Family Foundation, Plantation, Florida. Dr Escaned has received speaker and advisory board honoraria from Abbott Laboratories and Philips. Dr Al-Lamee has received speaker honoraria from Philips Volcano, Abbott Vascular, and Menarini Pharmaceuticals. Dr Gowdak has received congress-related travel expenses from Servier; has participated in clinical trials sponsored by Servier and Angion Biomedica; has been a speaker for Servier, Boehringer-Lilly, and Abbott; is an advisory board member for Servier; and has prepared written scientific material for Servier and Abbott. Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GSK, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health; and receives research funding from the British Heart Foundation (grant RE/18/6134217), Chief Scientist Office, Engineering and Physical Sciences Research Council (EP/R511705/1, EP/S030875/1), European Union (754946-2), Medical Research Council (MR/S018905/1), and UKRI (MC/PC/20014). Dr Kaski has received speaker honoraria from A. Menarini Farmaceutica lnternazionale, Servier, and Bayer UK. Dr Escaned has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the current pathophysiological model of chronic ischemic heart disease (IHD), myocardial ischemia and exertional angina are caused by obstructive atherosclerotic plaque, and the clinical management of IHD is centered on the identification and removal of the stenosis. Although this approach has been in place for years, several lines of evidence, including poor prognostic impact, suggest that this direct relationship may present an oversimplified view of IHD. Indeed, a large number of studies have found that IHD can occur in the presence or absence of obstructive coronary artery disease and that atherosclerosis is just 1 element in a complex multifactorial pathophysiological process that includes inflammation, microvascular coronary dysfunction, endothelial dysfunction, thrombosis, and angiogenesis. Furthermore, the high recurrence rates underscore the fact that removing stenosis in patients with stable IHD does not address the underlying pathological mechanisms that lead to the progression of nonculprit lesions. The model proposed herein shifts the focus away from obstructive epicardial coronary atherosclerosis and centers it on the microvasculature and myocardial cell where the ischemia is taking place. If the myocardial cell is placed at the center of the model, all the potential pathological inputs can be considered, and strategies that protect the cardiomyocytes from ischemic damage, regardless of the causative mechanism, can be developed., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the rate of progression of fibrosis by 2 consecutive cardiac magnetic resonance (CMR) examinations and its relation with clinical variables., Background: In hypertrophic cardiomyopathy (HCM) myocardial fibrosis, detected by late gadolinium enhancement (LGE), is associated to a progressive ventricular dysfunction and worse prognosis., Methods: A total of 55 HCM patients (37 males; mean age 43 ± 18 years) underwent 2 CMR examinations (CMR-1 and CMR-2) separated by an interval of 719 ± 410 days. Extent of LGE was measured, and the rate of progression of LGE (LGE-rate) was calculated as the ratio between the increment of LGE (in grams) and the time (months) between the CMR examinations., Results: At CMR-1, LGE was detected in 45 subjects, with an extent of 13.3 ± 15.2 g. At CMR-2, 53 (96.4%) patients had LGE, with an extent of 24.6 ± 27.5 g. In 44 patients, LGE extent increased significantly (≥1 g). Patients with apical HCM had higher increments of LGE (p = 0.004) and LGE-rate (p < 0.001) than those with other patterns of hypertrophy. The extent of LGE at CMR-1 and the apical pattern of hypertrophy were independent predictors of the increment of LGE. Patients with worsened New York Heart Association functional class presented higher increase of LGE (p = 0.031) and LGE-rate (p < 0.05) than those with preserved functional status., Conclusions: Myocardial fibrosis in HCM is a progressive and fast phenomenon. LGE increment, related to a worse clinical status, is more extensive in apical hypertrophy than in other patterns., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature., Background: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined., Methods: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty., Results: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration., Conclusions: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.

Objective: To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA)., Background: In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies., Methods: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion., Results: Adenosine did not affect stenosis resistance, while it decreased (p < 0.05) microvascular resistance to 52 +/- 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 +/- 15 vs. 46 +/- 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% +/- 1,298% and 671% +/- 652% of baseline, respectively, p < 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 +/- 7 mm Hg, p < 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation., Conclusions: In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation.

Objectives: The aim of the study was to evaluate whether adenosine infusion can induce production of active renin and angiotensin II in human coronary circulation., Background: Adenosine can activate angiotensin production in the forearm vessels of essential hypertensive patients., Methods: In six normotensive subjects and 12 essential hypertensive patients adenosine was infused into the left anterior descending coronary artery (1, 10, 100 and 1,000 microg/min x 5 min each) while active renin (radioimmunometric assay) and angiotensin II (radioimmunoassay after high performance liquid chromatography purification) were measured in venous (great cardiac vein) and coronary arterial blood samples. In five out of 12 hypertensive patients adenosine infusion and plasma samples were repeated during intracoronary angiotensin-converting enzyme inhibitor benazeprilat (25 microg/min) administration. Finally, in adjunctive hypertensive patients, the same procedure was applied during intracoronary sodium nitroprusside (n = 4) or acetylcholine (n = 4)., Results: In hypertensive patients, but not in control subjects, despite a similar increment in coronary blood flow, a significant (p < 0.05) transient increase of venous active renin (from 10.7 +/- 1.4 [95% confidence interval 9.4 to 11.8] to a maximum of 13.8 +/- 2.1 [12.2 to 15.5] with a consequent drop to 10.9 +/- 1.8 [9.7 to 12.1] pg/ml), and angiotensin II (from 14.6 +/- 2.0 [12.7 to 16.5] to a maximum of 20.4 +/- 2.7 [18.7 to 22.2] with a consequent drop to 16.3 +/- 1.8 [13.9 to 18.7] pg/ml) was observed under adenosine infusion, whereas arterial values did not change. Calculated venous-arterial active renin and angiotensin II release showed a strong correlation (r = 0.78 and r = 0.71, respectively; p < 0.001) with circulating active renin. This adenosine-induced venous angiotensin II increase was significantly blunted by benazeprilat. Finally, both sodium nitroprusside and acetylcholine did not affect arterial and venous values of active renin and angiotensin II., Conclusions: These data indicate that exogenous adenosine stimulates the release of active renin and angiotensin II in the coronary arteries of essential hypertensive patients, and suggest that this phenomenon is probably due to renin release from tissue stores of renally derived renin.

Objectives: This study sought to compare, head to head, the two most popular pharmacologic stress echocardiographic tests--dipyridamole and dobutamine--with state of the art protocols in a large multicenter prospective study., Background: In the continuing quest for ideal diagnostic accuracy, pharmacologic stress echocardiography has quickly moved over the years from low to high dose regimens and is currently performed with atropine coadministration., Methods: Dobutamine (up to 40 microgram/kg body weight per min) plus atropine (up to 1 mg over 4 h) and dipyridamole (up to 0.84 mg/kg per min over 10 h) plus atropine (up to 1 mg over 4 h) stress echocardiography was performed on different days, in random order and within 1 week in 360 patients with chest pain syndrome. Thirteen different echocardiographic laboratories, all fulfilling quality control criteria for stress echocardiographic reading, contributed to the study., Results: No major complications occurred during either test. The test was interrupted before achievement of predetermined end points for limiting side effects in 37 dobutamine-atropine and 7 dipyridamole-atropine stress echocardiographic studies (feasibility 90% vs. 98%, p < 0.01). Diagnostic accuracy was assessed in a subset of 110 patients with no obvious rest dyssynergy (akinesia or dyskinesia) who underwent coronary angiography independently of test results and within 1 week of testing. Significant coronary artery disease (> or = 50% diameter reduction in at least one major coronary vessel by quantitative coronary angiography) was found in 92 patients. Sensitivity for detection of coronary artery disease was 84% (77 of 92) for dobutamine-atropine and 82% (75 of 92) for dipyridamole-atropine stress echocardiography (p = NS), with a specificity of 89% (16 of 18) for dobutamine-atropine and 94% (17 of 18) for dipyridamole-atropine stress echocardiography (p = NS). A significant correlation was present between peak wall motion score index during dipyridamole-atropine and dobutamine-atropine stress echocardiography (r = 0.83, p < 0.0001)., Conclusions: Dobutamine-atropine and dipyridamole-atropine stress echocardiography are safe and feasible, although submaximal studies are more frequent with dobutamine. The two stresses have comparable accuracy in the detection of angiographically assessed coronary artery disease, although dobutamine is marginally more sensitive and dipyridamole marginally more specific. Stratification of the ischemic response in the space domain is also comparable with the two stresses.

Objectives: The aim of this study was to evaluate myocardial blood flow regulation in collateral-dependent myocardium of patients with coronary artery disease., Background: Despite great clinical relevance, perfusion correlates of collateral circulation in humans have rarely been estimated by quantitative methods at rest and during stress., Methods: Nineteen patients with angina and isolated occlusion of the left anterior descending (n = 14) or left circumflex (n = 5) coronary artery were evaluated. Using positron emission tomography and nitrogen-13 ammonia, we obtained flow measurements at baseline, during atrial pacing-induced tachycardia and after intravenous administration of dipyridamole (0.56 mg/kg body weight over 4 min). Flow values in collateral-dependent and remote areas were compared with values in 13 normal subjects., Results: Flow at rest was similar in collateralized and remote myocardium (0.61 +/- 0.11 vs. 0.63 +/- 0.17 ml/min per g, mean +/- 1 SD), and both values were lower than normal (1.00 +/- 0.20 ml/min per g, p < 0.01). During pacing, blood flow increased to 0.83 +/- 0.25 and 1.11 +/- 0.39 ml/min per g in collateral-dependent and remote areas, respectively (p < 0.05 vs. baseline); both values were lower than normal (1.86 +/- 0.61 ml/min per g, p < 0.01). Dipyridamole induced a further increase in perfusion in remote areas (1.36 +/- 0.57 ml/min per g, p < 0.01 vs. pacing) but not in collateral-dependent regions (0.93 +/- 0.37 ml/min per g, p = NS vs. pacing); again, both values were lower (p < 0.01) than normal (3.46 +/- 0.78 ml/min per g). Dipyridamole flow in collateral-dependent myocardium was slightly lower in patients with poorly developed than in those with well developed collateral channels (0.75 +/- 0.29 vs. 1.06 +/- 0.38 ml/min per g, respectively, p = 0.06); however, the former showed higher flow inhomogeneity (collateral/control flow ratio 0.58 +/- 0.10 vs. 0.81 +/- 0.22, respectively, p < 0.02). A linear direct correlation was observed between flow reserve of collateral-dependent and remote regions (r = 0.83, p < 0.01)., Conclusions: Despite rest hypoperfusion, collateral-dependent myocardium maintains a vasodilator reserve that is almost fully utilized during increases in oxygen consumption. A global microvascular disorder might hamper adaptation to chronic coronary occlusion.

Coronary hemodynamics, myocardial metabolism and left ventricular function at rest and after incremental atrial pacing were evaluated in 12 patients with stress-induced angina and ST segment depression, angiographically normal coronary arteries and no evidence of spasm, generally labeled as syndrome X, and in 10 normal subjects. At baseline study, great cardiac vein flow was comparable in patients and control subjects. During pacing, an equivalent rate-pressure product was reached in the two groups, but the slope of the relation between rate-pressure product and great cardiac vein flow was significantly less steep in patients than in normal subjects (0.0027 vs. 0.0054 ml/mm Hg.beat, p less than 0.001). Nevertheless, the left ventricular ejection fraction was comparable in both groups at rest (66 +/- 6% vs. 71 +/- 7%, p = NS) and during pacing (71 +/- 7% vs. 66 +/- 5%, p = NS). At baseline study, myocardial glucose extraction was more efficient in patients with syndrome X (p less than 0.05), but net myocardial exchange of pyruvate and alanine was, respectively, smaller and greater than in control subjects. Lactate was extracted to a similar extent in the two groups and in no instance was net lactate release observed during pacing or recovery. During pacing and recovery, patients with syndrome X showed net pyruvate release, unlike the control subjects in whom net pyruvate exchange was positive. In addition, patients with syndrome X continued to show net myocardial extraction of alanine during spacing and recovery, whereas normal subjects produced alanine throughout the study. Myocardial carbohydrate oxidation increased significantly during maximal pacing in normal subjects but not in patients, in whom it always remained below (p less than 0.01) the concurrent rate of myocardial uptake of carbohydrate equivalents (glucose, lactate, pyruvate, alanine). Myocardial energy expenditure was significantly lower in patients than in control subjects at maximal rate-pressure product levels (p less than 0.01). The metabolic pattern in patients with syndrome X therefore is not consistent with classic ischemia, although differences in the net exchange of circulating substrates (glucose, pyruvate, alanine) can be demonstrated. Thus, in patients with syndrome X, the symptoms, electrocardiographic signs and impairment in the increase in great cardiac vein flow during pacing coexist with preserved global and regional left ventricular function and myocardial energy efficiency.

Regional coronary flow reserve and regional myocardial contractility were evaluated in 29 patients after maximal pharmacologic coronary vasodilation (intravenous dipyridamole, 0.56 mg/kg body weight, administered over 4 minutes). Nineteen patients had a severe (80 to 99%) proximal and isolated stenosis of the left anterior descending coronary artery and 10 patients had normal coronary arteries; all had normal ventricular function under rest conditions. Myocardial contractility was assessed by means of continuous two-dimensional echocardiographic monitoring; coronary reserve was evaluated by coronary sinus thermodilution. After dipyridamole infusion, 9 of the 19 patients with left anterior descending artery stenosis had transient myocardial asynergy involving the septum or apex, or both (Group IA), whereas 10 patients showed no asynergy (Group IB). No impairment of contractility was observed in the 10 patients with normal coronary arteries (Group II). Coronary blood flow was measured under basal conditions and up to 10 minutes after the end of dipyridamole infusion. In patients in Group II, dipyridamole induced an increase in great cardiac vein flow of 167 +/- 68% (mean +/- SD). The 10 patients in Group IB showed a response comparable with that of the control group (Group II) (136 +/- 45% increase in great cardiac vein flow; NS versus Group II), whereas the 9 patients in Group IA had an increase of 46 +/- 30% (p less than 0.01 versus both Group IB and Group II). No significant difference was found in the angiographic severity of the stenosis expressed in terms of minimal cross-sectional area (Group IA = 0.30 +/- 0.13 mm2, Group IB = 0.34 +/- 0.18 mm2; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The possible role of prostaglandins in mediating large coronary artery vasodilation by nitrates was investigated by quantitative magnification coronary angiography. The effects of aspirin (1 g systemically and 100 mg intracoronary) in preventing large coronary artery vasodilation induced by intracoronary isosorbide dinitrate was investigated in 16 patients. Of these, 5 received 0.3 mg (Group 1A) and 11 received 3 mg (Group 1B) intracoronary isosorbide dinitrate, before and 15 minutes after aspirin. Relative to control, 0.3 mg isosorbide dinitrate induced a 19 +/- 9% (mean +/- SD) (p less than 0.01) and 19.5 +/- 11% (p less than 0.01) increase in coronary diameter before and after aspirin, respectively (p = NS). Changes after 3 mg isosorbide were 23 +/- 12% (p less than 0.01) and 26.5 +/- 14% (p less than 0.01), respectively, before and after aspirin (p = NS). In 10 additional patients (Group 2), the effect of the same dose of aspirin on rest coronary artery tone was assessed: changes relative to control were 0.9 +/- 5.5% (p = NS) minutes after aspirin. The intracoronary administration of 3 mg isosorbide dinitrate produced a 24.7 +/- 11% increase in coronary diameter (p = NS versus pre- and postaspirin isosorbide in Group 1B). Urinary 6-ketoprostaglandin-F1 alpha values in urine samples collected in the 8 hours before and the 8 hours after the study in five patients in Group 1B and five patients of Group 2, revealed a 36 +/- 14% (mean +/- SD) reduction in excretion of prostacyclin (p less than 0.01). These data rule out a role for prostaglandins both in mediating dilation of large coronary arteries by nitrates and in affecting their vascular tone at rest.

The mechanism of electrocardiographic ST segment changes during acute coronary occlusion was evaluated in 28 consecutive patients with single vessel coronary artery disease undergoing coronary angioplasty. Patients were continuously monitored with a six lead electrocardiogram. Twenty-three patients showed ST changes in the primary zone of occlusion, and 13 of these had additional ST changes in a remote zone. Ten of these 13 had unusually extensive arteries supplying the remote zone. The balloon occluded two adjacent normal arteries in two patients, and no coronary anatomic explanation was evident in one patient. Ten patients with striking primary zone ST changes showed no remote change. Seven had nonextensive primary zone arteries, and three others had abundant collateral vessels. Five patients showed no electrocardiographic changes in primary or remote zones. Four had collateral vessels, and one had left ventricular hypertrophy on the baseline electrocardiogram. It was concluded that remote electrocardiographic changes are probably due to occlusion of unusually extensive coronary arteries and are not simply reciprocal.