Stanislas U. Sys

Personality as independent predictor of long-term mortality in patients with coronary heart disease

BACKGROUND Emotional distress has been related to mortality in patients with coronary heart disease (CHD), but little is known about the role of personality in long-term prognosis. We postulated that type-D personality (the tendency to suppress emotional distress) was a predictor of long-term mortality in CHD, independently of established biomedical risk factors. METHODS We studied 268 men and 35 women with angiographically documented CHD, aged 31-79 years, who were taking part in an outpatient rehabilitation programme. All patients completed personality questionnaire at entry to the programme. We contacted them 6-10 years later (mean 7-9) to find out survival status. The main endpoint was death from all causes. FINDINGS At follow-up, 38 patients had died; there were 24 cardiac deaths. The rate of death was higher for type-D patients than for those without type-D (23 [27%]/85 vs 15 [7%]/218; p < 0.00001). The association between type-D personality and mortality was still evident more than 5 years after the coronary event and was found in both men and women. Mortality was also associated with impaired left ventricular function, three-vessel disease, low exercise tolerance, and the lack of thrombolytic therapy after myocardial infarction. When we controlled for these biomedical predictors in multiple logistic regression analysis, the impact of type-D remained significant (odds ratio 4.1 [95% CI 1.9-8.8]; p = 0.0004). In this group of CHD patients, type-D was an independent predictor of both cardiac and non-cardiac mortality. Social alienation and depression were also related to mortality, but did not add to the predictive power of type-D. INTERPRETATION We found that type-D personality was a significant predictor of long-term mortality in patients with established CHD, independently of biomedical risk factors. Personality traits should be taken into account in the association between emotional distress and mortality in CHD.

Simultaneous Coronary Pressure and Flow Velocity Measurements in Humans Feasibility, Reproducibility, and Hemodynamic Dependence of Coronary Flow Velocity Reserve, Hyperemic Flow Versus Pressure Slope Index, and Fractional Flow Reserve

BACKGROUND To assess coronary lesion severity in the catheterization laboratory, several guide wire-based methods have been proposed. The purpose of the present study was to compare the feasibility and the reproducibility of coronary flow velocity reserve (CFVR), instantaneous hyperemic diastolic velocity-pressure slope index (IHDVPS), and pressure-derived myocardial fractional flow reserve (FFRmyo). METHODS AND RESULTS From distal coronary pressure and flow velocity signals (0.014-in guide wires), CFVR, IHDVPS, and FFRmyo were computed in 15 stenoses (13 patients) under the four following pairs of conditions: (1) twice under baseline conditions; (2) during atrial pacing at 80 and 110 bpm; (3) before and during intravenous infusion of nitroprusside; and (4) before and during intravenous infusion of dobutamine. A total of 104 measurements were obtained. Both CFVR and FFRmyo could be calculated in all cases. IHDVPS could be calculated in only 79% of cases. The mean value of CFVR did not change between the two baseline measurements and during infusion of nitroprusside but decreased from 1.85 +/- 0.41 to 1.66 +/- 0.45 (P < .05) during atrial pacing and from 1.90 +/- 0.50 to 1.41 +/- 0.28 (P < .05) during dobutamine infusion. The mean values of IHDVPS and FFRmyo remained similar, whichever the changes in hemodynamic conditions. The coefficient of variation between two consecutive measurements was significantly lower for FFRmyo (4.2%) than for CFVR (17.7%) and for IHDVPS (24.7%). CONCLUSIONS CFVR is easy to measure but sensitive to hemodynamic changes. IHDVPS can be measured only in < 80% of cases and is highly variable even without changes in hemodynamic conditions. FFRmyo is easy to measure and almost independent of hemodynamic changes.

Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography.

BACKGROUND Experimental studies have shown that fractional flow reserve (defined as the ratio of maximal achievable flow in a stenotic area to normal maximal achievable flow) can be calculated from coronary pressure measurements only. The objectives of this study were to validate fractional flow reserve calculation in humans and to compare this information with that derived from quantitative coronary angiography. METHODS AND RESULTS Twenty-two patients with an isolated, discrete proximal or mid left anterior descending coronary artery stenosis and normal left ventricular function were studied. Relative myocardial flow reserve, defined as the ratio of absolute myocardial perfusion during maximal vasodilation in the stenotic area to the absolute myocardial perfusion during maximal vasodilation (adenosine 140 micrograms.kg-1 x min-1 intravenously during 4 minutes) in the contralateral normally perfused area, was assessed by 15O-labeled water and positron emission tomography (PET). Myocardial and coronary fractional flow reserve were calculated from mean aortic, distal coronary, and right atrial pressures recorded during maximal vasodilation. Distal coronary pressures were measured by an ultrathin, pressure-monitoring guide wire with minimal influence on the trans-stenotic pressure gradient. Minimal obstruction area, percent area stenosis, and calculated stenosis flow reserve were assessed by quantitative coronary angiography. There was no difference in heart rate, mean aortic pressure, or rate-pressure product during maximal vasodilation during PET and during catheterization. Percent area stenosis ranged from 40% to 94% (mean, 77 +/- 13%), myocardial fractional flow reserve from 0.36 to 0.98 (mean, 0.61 +/- 0.17), and relative flow reserve from 0.27 to 1.23 (mean, 0.60 +/- 0.26). A close correlation was found between relative flow reserve obtained by PET and both myocardial fractional flow reserve (r = .87) and coronary fractional flow reserve obtained by pressure recordings (r = .86). The correlations between relative flow reserve obtained by PET and stenosis measurements derived from quantitative coronary angiography were markedly weaker (minimal obstruction area, r = .66; percent area stenosis, r = -.70; and stenosis flow reserve, r = .68). CONCLUSIONS Fractional flow reserve derived from pressure measurements correlates more closely to relative flow reserve derived from PET than angiographic parameters. This validates in humans the use of fractional flow reserve as an index of the physiological consequences of a given coronary artery stenosis.

Diastolic failure: Pathophysiology and therapeutic implications

Primary diastolic dysfunction or failure is a distinct pathophysiologic entity. It results from increased resistance to ventricular filling, which leads to an inappropriate upward shift of the diastolic pressure-volume relation, particularly during exercise (exercise intolerance). The causes of diastolic failure are inappropriate tachycardia, decreased diastolic compliance and impaired systolic relaxation. Impaired (incomplete or slowed) systolic relaxation must be conceptually distinguished from compensatory prolonged systolic contraction (delayed or retarded relaxation). Optimal therapy will depend on the type of disease, the phase during the course of a given disease and the coexistence and relative contribution of various (de)compensatory processes. Treatment may consist of bradycardic, remodeling and lusitropic drugs.

Relation Between Myocardial Fractional Flow Reserve Calculated From Coronary Pressure Measurements and Exercise-Induced Myocardial Ischemia

BACKGROUND Myocardial fractional flow reserve (FFRmyo) is a functional index of stenosis severity that can be derived from intracoronary pressure measurements performed during maximal vasodilatation. It is defined as the maximal myocardial perfusion during hyperemia in the presence of a stenosis in the epicardial artery expressed as a fraction of its normal maximal expected value. To determine threshold values of FFRmyo, of hyperemic translesional pressure gradient (delta P(max)), and of resting translesional pressure gradient (delta P(rest)) that are uniformly associated with exercise-induced ischemia, we studied the relation between these pressure-derived indexes and the results of exercise ECG. METHODS AND RESULTS We studied 60 patients with an isolated lesion in one major epicardial coronary artery, normal left ventricular function, and no left ventricular hypertrophy. Maximal exercise ECG (off anti-ischemic medication) was performed within 6 hours before catheterization. Intracoronary pressure measurements were taken at rest and during hyperemia with a pressure monitoring guide wire. ST-segment depressions at peak exercise (considered abnormal when > or = 0.1 mV) were compared with FFRmyo, delta P(max), and delta P(rest). Thirty-seven patients had an abnormal and 23 patients a normal exercise ECG. A significant linear correlation was found between the magnitude of ST-segment depressions and both FFRmyo and delta P(max) (r = -.75, SEE = 0.53; r = .71, SEE = 0.56). A weaker correlation was noted between ST-segment depressions and delta P(rest) (r = .53, SEE = 0.67). Sensitivity and specificity curves were constructed for the prediction of an abnormal exercise ECG for the three pressure-derived indexes. The values that most accurately predicted an abnormal exercise ECG were 66% for FFRmyo, 31 mm Hg for delta P(max), and 12 mm Hg for delta P(rest). No patient with a FFRmyo value > 72% showed an abnormal exercise ECG. In addition, receiver operating characteristic curves demonstrated a greater accuracy of FFRmyo and of delta P(max) than of delta P(rest) for predicting the results of the exercise ECG. CONCLUSIONS In the present study, cutoff values of FFRmyo and translesional pressure gradients are established from the relation between intracoronary pressure-derived indexes and ECG signs of myocardial ischemia during maximal exercise. These values can be helpful for clinical decision making in cases with dubious angiographic results. Furthermore, our data support the concept that stenosis physiology is better reflected by hyperemic than by basal measurements.

Myocardial Contractile Response to Nitric Oxide and cGMP

BACKGROUND Cardiac endothelium releases a number of factors that may modulate performance of underlying cardiac muscle. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cGMP, may be involved in this cardiac modulation. METHODS AND RESULTS We examined the myocardial contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhibitor zaprinast in isolated cat papillary muscle. Modulation of these effects by endocardial endothelium (EE) and by cholinergic and adrenergic stimulation was also investigated. Concentration-response curves with addition of NO-releasing nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic inotropic response. Although administration of low concentrations induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. The response to high concentrations of 8-bromo-cGMP was shifted to the right in muscles with damaged EE, whereas cholinergic stimulation shifted the curve leftward. Zaprinast caused a monophasic concentration-dependent positive inotropic effect; damaging the EE shifted the terminal portion of the curve upward. Concomitant cholinergic or adrenergic stimulation modified the response to zaprinast into a negative inotropic response. CONCLUSIONS NO and cGMP induced a concentration-dependent biphasic contractile response. The myocardial contractile effects of NO and cGMP were modulated by the status of EE and by concomitant cholinergic or adrenergic stimulation.

Personality and mortality after myocardial infarction.

Previous research showed a) emotional distress is a risk factor for mortality after myocardial infarction (MI) and b) emotional distress is linked to stable personality traits. In this study, we examined the role of these personality traits in mortality after MI. Subjects were 105 men, 45 to 60 years of age, who survived a recent MI. Baseline assessment included biomedical and psychosocial risk factors, as well as each patients personality type. After 2 to 5 (mean, 3.8) years of follow-up, 15 patients (14%) had died. Rate of death for patients with a distressed personality type (11/28 = 39%) was significantly greater than that for patients with other personality types (4/77 = 5%) (p <.0001). Patients with this personality type tend simultaneously to experience distress and inhibit expression of emotions. Low exercise tolerance, previous MI (p <.005), anterior MI, smoking, and age (p <.05) were also associated with mortality. A logistic regression model including these biomedical factors had a sensitivity for mortality of only 27%. The addition of distressed personality type in this model more than doubled its sensitivity. Of note, among patients with poor physical health, those with a distressed personality type had a five-fold mortality risk (p <.005). Consistent with the findings of other investigators, depression (p <.005), life stress, use of benzodiazepines (p <.01), and somatization (p <.05) were also related to post-MI mortality. These psychosocial risk factors were more prevalent in the distressed personality type than in the other personality types (p <.001-.05). Multiple logistic regression indicated that these psychosocial factors did not add to the predictive value of the distressed personality type. Hence, an important personality effect was observed despite the low power. This suggests that personality traits may play a role in the detrimental effect of emotional distress in MI patients.

Effects of damaging the endocardial surface on the mechanical performance of isolated cardiac muscle.

The mechanical properties of mammalian ventricular cardiac muscle have been studied in the presence and in the absence of an intact endocardial surface. Isotonic and isometric twitch contractions were obtained from papillary muscles of the right ventricle of cat at 29° and 37° C, at different extracellular calcium concentrations ([Ca2+]o), and at different initial muscle lengths. The endocardial surface was damaged by gentle abrasion of the muscle surface with a plastic blade or by brief immersion for 1 second with 1 % Triton X-100. Although there was no evidence of damage to myocardial cells, damaging the endocardial surface resulted in an immediate and irreversible abbreviation of the twitch contractions with, except at the highest [Ca2+]., a decrease in peak isometric twitch tension. These changes induced 1) an asymmetrical shift of the tension-[Ca2+] relation towards increasing [Ca2+] but with no effect at the highest [Ca2+]o, and 2) a rightward and downward shift of the length-tension relation. Both shifts were significantly more pronounced at 37° C than at 29° C; they were not accompanied by significant changes in Vmax. The asymmetrical shift of the tension-[Ca2+]o relation suggests that the endocardium-mediated chain of events may be mediated by changes in the sensitivity of the contractile proteins to Ca2+. This hypothesis is also supported by the similar pattern of changes (i.e., modulation of the onset of early tension decline) induced by decreasing length at each [Ca2+]. and by the removal of a functional endocardium. Accordingly, the endocardium may help to control the performance of the heart by modulating peak contractile performance and relaxation of the underlying myocardium.

Transstenotic coronary pressure gradient measurement in humans : in vitro and in vivo evaluation of a new pressure monitoring angioplasty guide wire

OBJECTIVES The present study was designed to investigate 1) the feasibility and accuracy of coronary pressure measurements with a novel 0.015-in. (0.038 cm) fluid-filled guide wire, and 2) the effect of the guide wire itself on stenosis hemodynamics. BACKGROUND To assess the functional results of coronary angioplasty, measurements of the transstenotic pressure gradient have been advocated. However, this gradient is no longer routinely measured because it is not reliable when determined with the angioplasty catheter. METHODS A fluid-filled 0.015-in. guide wire to be connected to a conventional pressure transducer was developed. Five wires were tested for their frequency response characteristics and for their accuracy in measuring hydrostatic pressure. In an in vitro model of stenosis (reference diameter 4 mm), the pressure gradient was determined at incremental flow levels for varying stenosis severity with and without a 0.015-in. guide wire through the narrowing. In 37 patients, the transstenotic pressure gradient was measured before and after angioplasty and compared with obstruction area and percent area stenosis as determined by quantitative coronary angiography. RESULTS The correlation between the actual pressure and the pressure recorded by the guide wire was excellent (r = 0.98) despite a slight underestimation (-3 +/- 5%). Phasic pressure recordings were precluded by a long time constant of 16 +/- 4 s. The presence of the guide wire produced a significant overestimation (> 20%) of the pressure decrease only in cases of tight stenosis (> 90% area reduction). Furthermore, a theoretic model based on the fluid dynamic equation predicted that this overestimation was inversely proportional to the reference diameter of the vessel, yet was only slightly influenced by the flow. The lesion was crossed in all but one patient (97%) and pressure gradient was recorded throughout the study in 34 (94%) of 36 patients. The mean pressure gradient decreased from 30 +/- 19 before to 3 +/- 5 mm Hg after angioplasty (p < 0.01). A curvilinear relation was found between the pressure gradient and both percent area stenosis (r2 = 0.67) and obstruction area (r2 = 0.72). A sharp increase in pressure gradient was noted once the stenosis exceeded 75% area reduction. CONCLUSIONS Mean transstenotic pressure gradients can be easily and reliably recorded with a 0.015-in. fluid-filled guide wire. This ability should facilitate the functional assessment of coronary stenoses of intermediate severity and of immediate postangioplasty results.

Analysis of relaxation in the evaluation of ventricular function of the heart

T HE MANAGEMENT of cardiac diseases has evolved from one of expectant observation to current medical and surgical interventions aimed at preserving or restoring myocardial function. This has led to a search for thorough understanding and evaluation of global and regional left ventricular function during systole and diastole. In the past, major research emphasis had been placed on the analysis of the contraction phase of systole. Only recently, our attention has been drawn also to the relaxation phase of systole and to diastole. In this respect, early detection of impaired relaxation has been emphasized for the evaluation of both global and regional ventricular function in patients with heart disease. Although early relaxation abnormalities have been found in various cardiac diseases that eventually lead to cardiac failure, such as hypertrophic and ischemic cardiomyopathy, the underlying mechanisms are as yet not fully understood.’ Given the recent progress in our understanding of the physiology and pathophysiology of the relaxation phase of systole of the heart as a muscle and pump,* these mechanisms can now be more easily appreciated. In this review, we will first summarize our present knowledge of relaxation of cardiac muscle. More specifically, we will describe how relaxation is controlled by three interacting determinants: (1) load, (2) (in)activation, and (3) nonuniform distribution of load and (in)activation in space and in time, and how this triple control constitutes a logical extension of a similar triple control of performance during contraction (Fig 1). Second, we will examine how this triple control applies to the intact in situ heart as a pump. Third, we will discuss how various factors, acting either alone or in concert, underlie relaxation abnormalities that occur early on in heart disease. Finally, we will critically review various measurements and indices of ventricular relaxation in view of these new concepts.