Paolo G. Camici

Guidelines on the management of stable angina pectoris: executive summary

We thank the authors for raising the interesting discussion regarding the treatment of hypertension in patients with concomitant coronary disease. The J-shaped association between on-treatment blood pressure and risk has been described in longitudinal cohorts of patients with treated hypertension as well as in clinical trial populations, both in on-treatment and control arms. However, it is not absolutely clear that the association is treatmentrelated; in fact, one meta-analysis of seven randomized controlled trials including data on more than 40 000 patients has shown that the J-shaped relationship between blood pressure and mortality was not related to antihypertensive treatment. In this meta-analysis, noncardiovascular death was inversely related to blood pressure (both systolic and diastolic) in contrast to the J-shaped relationships for cardiovascular and total mortality, leading the authors to hypothesize that poor health conditions leading to low blood pressure and an increased risk of death might in part explain the J-shaped curve. Secondly, as discussed in the full-text version of the guidelines, there is accumulating evidence that blood pressure lowering in the ‘normal’ range is associated with improved cardiovascular outcomes in the population with known coronary disease. In the CAMELOT study, patients with coronary disease and mean blood pressure of 129/78 were randomized to enalapril, amlodipine, or placebo. Blood pressure reductions were similar (5/2 mm) in both treatment groups and associated with similar relative reductions in the composite endpoint of cardiovascular death, MI, and stroke, although not statistically significant in either group because of the small sample size. An intravascular ultrasound substudy demonstrated a significant inverse correlation between progression of atherosclerosis and blood pressure reduction even in this normal blood pressure range, with the greatest benefit observed in patients whose blood pressure fell below 120/80. Thus, the task force has felt it important, in the absence of unequivocal evidence to the contrary, to preserve consistency between guidelines on prevention and angina with regard to targets for institution of therapy for hypertension in the presence of coronary disease. No lower limit has yet been identified as a definite cutoff beyond which blood pressure should not be lowered further, although, clearly, symptomatic hypotension or postural hypotension will limit aggressive blood pressure lowering in the lower range.

Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: A study with nitrogen-13 ammonia and positron emission tomography

To assess regional coronary reserve in hypertrophic cardiomyopathy, regional myocardial blood flow was measured in 23 patients with hypertrophic cardiomyopathy and 12 control subjects by means of nitrogen-13 ammonia and dynamic positron emission tomography. In patients with hypertrophic cardiomyopathy at baseline study, regional myocardial blood flow was 1.14 +/- 0.43 ml/min per g in the hypertrophied (20 +/- 3 mm) interventricular septum and 0.90 +/- 0.35 ml/min per g (p less than 0.05 versus septal flow) in the nonhypertrophied (10 +/- 2 mm) left ventricular free wall. These were not statistically different from the corresponding values in control subjects (1.04 +/- 0.25 and 0.91 +/- 0.21 ml/min per g, respectively, p = NS). After pharmacologically induced coronary vasodilation (dipyridamole, 0.56 mg/kg intravenously over 4 min), regional myocardial blood flow in patients with hypertrophic cardiomyopathy increased significantly less than in control subjects both in the septum (1.63 +/- 0.58 versus 2.99 +/- 1.06 ml/min per g, p less than 0.001) and in the free wall (1.47 +/- 0.58 versus 2.44 +/- 0.82 ml/min per g, p less than 0.001). In addition, patients with hypertrophic cardiomyopathy who had a history of chest pain had more pronounced impairment of coronary vasodilator reserve than did those without a history of chest pain. After dipyridamole, coronary resistance in the septum decreased by 38% in patients without a history of chest pain, but decreased by only 14% in those with such a history (p less than 0.05). Coronary resistance in the free wall decreased by 45% in patients without and by 27% in those with a history of chest pain (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Stunning, Hibernation, and Assessment of Myocardial Viability

The last 3 decades have witnessed an unprecedented improvement in the outcome of patients with acute coronary syndromes. The widespread use of thrombolytic therapy and percutaneous coronary interventions, in association with increasingly potent antithrombotic agents, has contributed to significant reductions in mortality and morbidity in these patients. Although overall survival has improved, a downside of this success has been the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure. This problem is compounded by the rising age of our population and the higher prevalence of comorbidities such as diabetes mellitus that confer an increased risk of coronary artery disease (CAD) and congestive heart failure. Patients with CAD represent by far the most numerous cohort among those with congestive heart failure, and their treatment remains a partial success.1 Typically, these patients have multivessel disease, increased LV volumes, and variable degrees of regional and/or global systolic dysfunction, although more cases of isolated diastolic dysfunction have been reported recently.2–4 In these patients, coronary revascularization may lead to symptomatic and prognostic improvement, and these clinical benefits are accompanied by evidence of reverse LV remodeling. In this context, the concept of myocardial viability was developed and a number of different techniques have been used to demonstrate the presence of viable tissue before coronary revascularization. The aim of this review article is to summarize our current understanding of the concept of myocardial viability and its clinical implications in patients with CAD and chronic LV dysfunction. Throughout this review, we use the term viability to describe dysfunctional myocardium subtended by diseased coronary arteries with limited or absent scarring that therefore has the potential for functional recovery. Viability is a prospective definition, but it does not imply evidence of functional recovery after interventions. The term hibernation, which …

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans.

OBJECTIVE Absolute myocardial blood flow (MBF) is not well-defined in large normal populations, and appears to be heterogeneous in both humans and animals. These factors contribute to the difficulties in defining resting MBF to hibernating myocardium. We therefore assessed absolute baseline and hyperemic MBF in a large population of normal humans. METHODS MBF was quantified by positron emission tomography with oxygen-15-labeled water at baseline and during hyperemia induced by either adenosine or dipyridamole in 131 men and 38 women, aged 21-86 (mean 46+/-12) years. MBF was corrected for workload using the rate-pressure product (RPP). RESULTS Uncorrected baseline MBF ranged from 0.590 to 2.050 (mean 0.985+/-0.230) ml/min/g (coefficient of variation=27%), and corrected MBF from 0.736 to 2.428 (mean 1.330+/-0.316) ml/min/g (coefficient of variation=24%). MBF in the inferior region was significantly (P<0.0001) lower than either the anterior or lateral regions. Baseline MBF in females was significantly (P<0.001) higher than in males. CONCLUSIONS These results confirm the heterogeneity of MBF in normals and highlight the difficulty in establishing the lower limit of normal MBF.

Hemodialysis-Induced Cardiac Dysfunction Is Associated with an Acute Reduction in Global and Segmental Myocardial Blood Flow

BACKGROUND AND OBJECTIVES Hemodialysis is associated with hemodynamic instability, acute cardiac ischemia, and the development of regional wall motion abnormalities (RWMAs). This study used serial intradialytic H(2)(15)O positron emission tomography scanning to confirm that the development of dialysis-induced RWMAs was associated with reduction in myocardial blood flow (MBF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Four prevalent hemodialysis patients without angiographically significant coronary artery disease had measurements of MBF during standard hemodialysis and biofeedback dialysis. All patients underwent serial measurements of MBF using positron emission tomography. Concurrent echocardiography was used to assess left ventricular function and the development of RWMAs. Hemodynamic variables were measured using continuous pulse wave analysis. RESULTS Mean prehemodialysis MBF was within the normal range. Global MBF was acutely reduced during hemodialysis. Segmental MBF was reduced to a significantly greater extent in areas that developed RWMAs compared with those that did not. Not all regions with reduced MBF were functionally affected, but a reduction in myocardial blood flow of >30% from baseline was significantly associated with the development of RWMAs. No significant differences in hemodynamic tolerability, RWMA development, or MBF between dialysis modalities were observed. CONCLUSIONS Hemodialysis is associated with repetitive myocardial ischemia, which, in the absence of coronary artery disease, may be due to coronary microvascular dysfunction. Stress-induced segmental left ventricular dysfunction correlates with matched reduction in MBF. Functional poststress recovery is consistent with myocardial stunning induced by hemodialysis. This process may be important in the development of heart failure in long-term hemodialysis patients.

Myocardial metabolism in ischemic heart disease: basic principles and application to imaging by positron emission tomography.

The human heart in the fasting state extracts FFA, glucose, lactate, pyruvate, and ketone bodies from the systemic circulation. Of these substrates, FFA utilization accounts for the greater part of oxygen consumption and energy production. The oxidative use of lipid (FFA) and carbohydrate (glucose and lactate) fuels is reciprocally regulated through the operation of Randles cycle. Feeding, by increasing both insulin and glucose concentration, shifts myocardial metabolism towards preferential carbohydrate usage, both for oxidative energy generation and for glycogen synthesis. During conditions of reduced oxygen supply, the oxidation of all substrates is decreased while anaerobic metabolism is activated. In patients with coronary artery disease and stable angina pectoris, lactate release in the CS can be demonstrated during pacing stress. However, this occurs in only 50% of patients, and no relationship can be demonstrated between lactate production and the severity of ischemia. In patients with chronic angina, a significant release of alanine in the CS and an increased myocardial uptake of glutamate could be demonstrated at rest and following pacing. These two phenomena result from increased transamination of excess pyruvate to alanine with glutamate serving as NH2 donor. In addition, release of citrate (a known inhibitor of glycolysis) in the CS can be demonstrated following pacing in patients with stable angina. The introduction of PET has made it possible to study regional myocardial perfusion and metabolism in humans noninvasively. Two basically different patterns of myocardial glucose utilization have been observed in patients with coronary artery disease studied at rest using 18F-flurodeoxyglucose. In patients with stable angina on exercise but studied at rest, regional myocar- dial glucose utilization was homogeneously low and comparable with that of a group of normals. In contrast, in patients with unstable angina, myocardial glucose utilization at rest was increased even in the absence of symptoms and ECG signs of acute ischemia. In patients with stable angina, a prolonged increase in glucose uptake could be demonstrated in the post-ischemic myocardium in the absence of perfusion abnormalities, and a state of chronic metabolic ischemia is proposed. PET imaging has also allowed prospective differentiation between viable and nonviable segmental function in patients with recent myocardial infarction and in those undergoing coronary artery surgery; in both cases viable segments have relatively maintained glucose uptakes, whereas nonviable segments have depressed glucose uptakes.

Central nervous pathways mediating angina pectoris

The central nervous pathways of angina pectoris have never been identified in vivo in man. We used positron emission tomography to examine the changes in regional cerebral blood flow associated with angina pectoris. Dynamic positron emission tomography with 15O-labelled water was used in 12 patients with angina and angiographically proven coronary artery disease to measure regional cerebral blood flow changes during angina induced by intravenous dobutamine. All subjects had typical retrosternal chest pain accompanied by ischaemic electrocardiographic changes during dobutamine infusion. Compared to the resting state, angina was associated with increased regional cerebral blood flow in the hypothalamus (percentage change in regional cerebral blood flow +6.5 and Z score 7.2) periaquaductal grey (+2.6 and 4.0), bilaterally in the thalamus (left: +2.7 and 4.3; right +3.7 and 4.7) and lateral prefrontal cortex (left +11.5 and 7.6; right +8.5 and 7.8) and left inferior anterocaudal cingulate cortex (+9.4 and 6.6). In contrast, it was reduced bilaterally in the mid-rostrocaudal cingulate cortex (left -3.7 and 6.3; right -4.7 and 4.6) and fusiform gyrus (left -3.2 and 4.0; right -3.3 and 3.7), right posterior cingulate (-3.9 and 5.8) and left parietal cortices (-4.8 and 6.3). Several minutes after stopping dobutamine infusion, when the patients no longer experienced angina and the electrocardiographic changes had resolved, thalamic, but not cortical activation could be seen. We propose that the central structures activated constitute the pathways for perception of anginal pain and that the thalamus may act as a gate to afferent pain signals, with cortical activation being necessary for the sensation of pain. This method of investigation may form a basis for research into anomalies of visceral pain perception such as silent myocardial ischaemia.

Coronary Heart Disease in Smokers Vitamin C Restores Coronary Microcirculatory Function

BackgroundCoronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. Methods and ResultsWe used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (P <0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. ConclusionsThe present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Increased uptake of 18F-fluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina.

Regional myocardial perfusion and exogenous glucose uptake were assessed with rubidium-82 (82Rb) and 18F-2-fluoro-2-deoxyglucose (FDG) in 10 normal volunteers and 12 patients with coronary artery disease and stable angina pectoris by means of positron emission tomography. In patients at rest, the myocardial uptake of 82Rb and FDG did not differ significantly from that measured in normal subjects. The exercise test performed within the positron camera in eight patients produced typical chest pain and ischemic electrocardiographic changes in all. In each of the eight patients a region of reduced cation uptake was demonstrated in the 82Rb scan recorded at peak exercise, after which uptake of 82Rb returned to the control value 5 to 14 min after the end of the exercise. In these patients, FDG was injected in the recovery phase when all the variables that were altered during exercise, including regional myocardial 82Rb uptake, had returned to control values. In all but one patient, FDG accumulation in the regions of reduced 82Rb uptake during exercise was significantly higher than that in the nonischemic regions, i.e., the ones with a normal increment of 82Rb uptake on exercise. In the nonischemic areas, FDG uptake was not significantly different from that found in normal subjects after exercise. In conclusion, myocardial glucose transport and phosphorylation seem to be enhanced in the postischemic myocardium of patients with exercise-induced ischemia.