Sensitivity, specificity, and predictive accuracies of non-invasive tests, singly and in combination, for diagnosis of hibernating myocardium.

OBJECTIVE: To determine the best test(s) for predicting functional recovery of hibernating myocardium after reperfusion. METHODS: A prospective study to compare echocardiographic left ventricular diastolic wall thickness (> or =5 mm), low-dose dobutamine echocardiography and rest-redistribution thallium-201 scintigraphy, alone and in combination, for predicting recovery of left ventricular akinesis after surgical revascularization. RESULTS: Twenty-eight consecutive patients aged 58+/-9 years were studied. Of the 448 left ventricular segments, 263 were akinetic at rest; 230/263 (87%) had wall thickness > or =5 mm, 135 (51%) had a positive response and 175 (66.5%) were graded viable on thallium. Of akinetic segments 61% improved after surgery. Left ventricular score decreased from 2.3+/-0.4 to 1.8+/-0.4 (P<0.01) and ejection fraction increased from 27+/-10 to 37+/-14% (P<0.01). For predicting results at 1 year, diastolic wall thickness had a sensitivity and a predictive accuracy of a negative test of 100% but a specificity of 28% and predictive accuracy of a positive test of 61%. The addition of dobutamine echocardiography or thallium-201 improved the predictive accuracy of a positive test to 76% and 69%, respectively; the addition of both tests was not of greater benefit than that of a single test. CONCLUSIONS: Diastolic wall thickness <5 mm on echocardiography was the best simple and single predictor of non-recovery of left ventricular dysfunction. The addition of dobutamine echocardiography or thallium-201, but not both, was the best solution for predicting recovery of left ventricular dysfunction. In times of limited resources, these findings are important from a clinical point of view.

[A hyperhomocysteinemia study in a population with a familial factor for acute myocardial infarct and sudden cardiac death at a young age]. / Studio dell'iperomocisteinemia in una popolazione con pesante familiarità per infarto miocardico acuto e morte improvvisa cardiaca in giovane età.

The alterations of the metabolism of methionine determining an accumulation of homocysteine in blood (hyperhomocysteinemia) recognize a multifactorial etiology, hereditary as well as acquired. To date several case-control studies have documented that the condition of hyperhomocysteinemia can be considered an independent risk factor of coronary disease and its noxious effects are dose-dependent. It exerts its effect by different mechanisms both prothrombotic and endothelial. In our study we started from an initial cohort of 2227 subjects (1210 males, 1017 females) aged between 45 and 64 years among which we selected 22 persons with at least 2 first-degree relatives below age 50 who had had either a major cardiovascular event (acute myocardial infarction or sudden death) or angiographically documented cardiac disease. We reconstructed the proper pedigrees obtaining 22 families in whom we identified four main subgroups to carry out analyses and comparisons: case-control, composed respectively of all the subjects who survived a major cardiovascular event or a coronary disease documented angiographically and clinically healthy subjects; affected line and non affected line, composed respectively of members belonging to the family line of the proband and members of collateral family line. Each of the subjects involved in the study underwent a complete history regarding job and sports activities, a standardized physical examination, 12-lead digital ECG according to the European Standard Communication Protocol. A blood sample was taken in fasting conditions to determine total cholesterol, HDL and LDL cholesterol, triglycerides, glycemia, fibrinogen, plasma homocysteine. The results indicate how among the cases there were more subjects with homocysteine higher than the 95 degrees percentile in males alone (p = 0.03), the estimated odds ratio calculated from Fisher's test was 8.34 (95% confidence interval 1.32-52.7). Despite the fact that mean age was significantly lower (p = 0.01) in males of the affected line compared to those of the non affected line, the results show much higher homocysteine values in the affected family line in both males and females: a difference quite evident in the distribution especially as regards the 95 degrees percentile. These results obtained in the subjects belonging to the same families emphasize that familial aggregation, which influences the sharing of the genetic patrimony, socio-cultural environment and food habits can induce a differential risk for homocysteinemia. The study of mutations of genes coding for the key enzymes of the metabolism of homocysteine, methylenetetrahydrofolate reductase and cystathionine beta-synthase, which we prepared, will enable use to evaluate the relative influence feeding habits and genetic factors have in the development of hyperhomocysteinemia.

Hibernating myocardium: its pathophysiology and clinical role.

Myocardial hibernation, as first defined by Rahimtoola, is a state of chronic contractile dysfunction in patients with coronary artery disease which is fully reversible upon reperfusion. Clinical conditions consistent with the existence of myocardial hibernation include unstable and stable angina, myocardial infarction heart failure, and anomalous origin of coronary arteries. The mechanisms of hibernation are not known. Morphological alterations have been described in the hibernating area of patients, but these information are strongly affected by the diagnostic criteria utilized to screen patients. It has been postulated that hibernation is an adaptive phenomenon occurring during ischemia. In this context, downregulation of contraction is not regarded as a consequence of energetic deficit, but as a regulatory event aimed at reducing energy expenditure, thereby maintaining integrity and viability. Thus, hibernation might bear a relationship to the phenomenon of low-flow perfusion-contraction matching, or repetitive stunning or preconditioning. Clear-cut evidence for the mechanism of hibernation in the clinical setting seems likely to remain elusive, because of the nature of the studies needed to document it. Current experimental evidence supports the view that hibernation, stunning, preconditioning, or their coexistence can be responsible for regional myocardial contractile dysfunction which is reversible upon reperfusion. These are all adaptive and protective phenomena independent of their terminology and strict definitions and do not always apply to the extremely complex situation of myocardial ischemia in man.

Metabolic derangement in ischemic heart disease and its therapeutic control.

The term myocardial ischemia describes a condition that exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations that have been extensively studied in recent years. Experimental research has been directed toward establishing the precise sequence of biochemical events leading to myocyte necrosis, as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time, there is no simple answer to the question of what determines cell death and the failure to recover cell function after reperfusion. Problems arise because: (1) ischemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually linked (both the processes being dependent on the duration of ischemia) and it is impossible to establish a causal relation; and (3) the inevitability of necrosis can only be assessed by reperfusion of the ischemic myocardium. Restoration of flow, however, might result in numerous other negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, we have recently learned that there are several potential manifestations and outcomes associated with myocardial ischemia and reperfusion. Without a doubt, ventricular dysfunction (either systolic or diastolic) of the ischemic zone is the most reliable clinical sign of ischemia, since electrocardiographic changes and symptoms are often absent. The ischemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischemic zone, recovery of contraction may occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the "stunned" myocardium. On the other hand, when ischemia is severe and prolonged, cell death may occur. Reperfusion at this stage is associated with the release of intracellular enzymes, damage of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called "reperfusion damage" by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than a result of changes occurring during the period of ischemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985, Rahimtoola described another possible outcome of myocardial ischemia. He demonstrated that late reperfusion (after months or even years) of an ischemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term "hibernating myocardium," referring to ischemic myocardium wherein the myocytes remain viable but in which contraction is chronically depressed. In this article we review our data on metabolic changes occurring during ischemia followed by reperfusion, obtained either in the isolated and perfused rabbit hearts or in ischemic heart disease patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting.

Different outcomes of the reperfused myocardium: insights into the comments of stunning and hibernation.

There are several potential outcomes of myocardial ischaemia. When ischaemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand either before ischaemia or during reperfusion have been shown to delay the onset of ischaemic damage and to improve recovery during reperfusion. When myocardial ischaemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischaemia leading to a reversible, chronic left ventricular dysfunction has been termed 'hibernating myocardium'. It is important clinically recognize hibernation as reperfusion of hibernating myocardium by angioplasty or heart surgery restores contraction and this correlates with long term survival. A third possible outcome after a short period of myocardial ischaemia is a transient post-ischaemic ventricular dysfunction, a situation termed 'stunned myocardium'.

The neuroendocrine and sympathetic nervous system in congestive heart failure.

A review of recent randomized clinical trials has shown that neurohormonal activation starts early in the natural history of left ventricular dysfunction and levels of the circulating hormones increase in proportion to the severity of heart failure. Most studies suggest that high levels of neurohormones predict a poor prognosis. Among the several neurohormones, the sympathetic system is the one which is activated earlier, it increases in proportion to the severity of the disease and has a negative prognostic implication. These concepts have been also proven in untreated patients. Augmented sympathetic activity in the syndrome of heart failure is initially beneficial, appears to be adaptive and helps support blood pressure and cardiac output. Prolonged and excessive sympathetic activation has deleterious effects with adverse consequences at both cardiac and vascular levels which aggravates the clinical status of the syndrome and negatively affects its prognosis. Evidence is accumulating that, contrary to popular belief, beta-blockers may be beneficial in heart failure by inhibiting sympathetic activation. In addition to neuroendocrine activation, another class of biologically active molecules, termed cytokines, are excessively secreted by cells in heart failure. Important among these cytokines are tumour necrosis factor-alpha and interleukin-6. They appear to exert deleterious effects on the heart and circulation which may be also involved in the progression of heart failure.

Aortic intramural hematoma: an increasingly recognized aortic disease.

Aortic intramural hematoma (IMH) is a rarely diagnosed pathological condition that is not well characterized to date. We diagnosed IMH in 4 of 31 patients with suspected aortic dissection admitted to our coronary care unit from 1992 to 1995. In all 4 cases, IMH was located in the ascending aorta. At the time of hospitalization, all patients showed tachycardia, hypotension and pericardial effusion. Diagnosis of IMH was made by transesophageal echocardiography and computed tomography. We performed aortography in 2 patients, but it was non-diagnostic in both of them. One patient died before surgery. Autopsy confirmed the diagnosis of IMH and showed severe pericardial effusion. In another patient, the diagnosis was confirmed during successful surgery, while the remaining 2 patients recovered after medical therapy. The 3 surviving patients are still under follow-up control 12, 16 and 20 months after the initial acute event. We briefly discuss the epidemiological, clinical, diagnostic, therapeutic and prognostic aspects of IMH.

Oxidative stress during myocardial ischaemia and heart failure.

Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. The heart needs oxygen but it is also susceptible to oxidative stress, which occurs during post-ischaemic reperfusion, for example. Ischaemia causes alterations in the defence mechanisms against oxygen free radicals. At the same time, production of oxygen free radicals increases. In man, there is evidence of oxidative stress during surgical reperfusion of the whole heart, or after thrombolysis, and it is related to transient left ventricular dysfunction or stunning. At present, there are few data on oxidative stress in the failing heart. It is not clear whether the defence mechanisms of the myocyte are altered or whether the production of oxygen free radicals is increased, or both. Recent data have shown a close link between oxidative stress and apoptosis. Importantly, tumour necrosis factor causes a rapid rise in intracellular reactive oxygen intermediates and apoptosis. This series of events is not confined to the myocytes, but also occurs at the level of endothelium, where tumour necrosis factor causes expression of inducible nitric oxide synthase, production of the reactive radical nitric oxide, oxidative stress and apoptosis. The immunological response to heart failure may result in endothelial and myocyte dysfunction through oxidative stress-mediated apoptosis. A better understanding of these mechanisms may lead to novel therapeutic strategies.

Cardiomyoplasty and implantable cardioverter defibrillator: efficacy and safety of concomitant device implantation: sudden death and cardiomyoplasty.

Sudden death represents a common event in the natural history of patients affected by chronic heart failure. Such an outcome also has been shown to characterize the follow-up of the cardiomyoplasty procedure. We report two cases of patients who had cardiomyoplasty and experienced witnessed episodes of ventricular arrhythmia at variable times after surgery (2 years and 2 months, respectively). In the first case, an implantable cardioverter defibrillator (ICD) was implanted subsequent to the arrhythmic episode, whereas the second patient had a combined cardiomyoplasty and ICD implantation procedure. In particular, this patient underwent a modified wrapping technique, herein described, because of a large left ventricular dilatation. In both cases, ventricular defibrillation did not affect the correct functioning of the implanted cardiomyostimulator. Our article confirms that ventricular arrhythmia is common in cardiomyoplasty patients. The combined use of a skeletal muscle stimulator and implantable defibrillator may therefore be effective in preventing arrhythmia-related sudden death without any concurrent effect on the correct functioning of the wrapped muscle/heart circuit, with likely benefit on long-term cardiomyoplasty patient survival.

Long-term changes in left ventricular mass, chamber size and function after valve replacement in patients with severe aortic stenosis and depressed ejection fraction.

We studied 21 patients undergoing valve replacement for severe aortic stenosis and marked left ventricular dysfunction (mean ejection fraction 27 +/- 7.9%) without significant coronary disease or other valve diseases. At 5-60 months (average 26 +/- 18) after surgery, the patients underwent a clinical history, physical examination and a complete M-mode, two-dimensional and Doppler transthoracic echocardiographic study. Thirteen patients were examined with cardiopulmonary exercise testing. Two patients with a low preoperative transvalvular pressure gradient (<50 mm Hg) died postoperatively. Nineteen patients were tested at follow-up. All patients showed an improvement in functional class, an increase in ejection fraction (EF), a normalization in left ventricular diameters, volumes and stress indices and a reduction in left ventricular mass which correlated with EF increase. Cardiopulmonary exercise testing showed a good exercise capacity. In conclusion, in patients affected by severe aortic stenosis and marked preoperative left ventricular dysfunction valve replacement induces a favorable remodeling of the left ventricle, as shown by a late postoperative examination. The regression of hypertrophy is a positive event which correlates with the improvement in EF.

[Mild hypercholesterolemia. Diagnosis and prognosis]. / Ipercolesterolemia lieve. Diagnosi e prognosi.

The finding of normocholesterolaemia, characterized by plasmatic values of total cholesterol < 2 g/l, which may hide silent lipidic alterations, is not by itself sufficient to rule out the existence of cardiovascular risk. First level screening of patients exposed to atherogenic risk must begin from dosage of three basic lipidic indicators, represented by total cholesterol, triglycerides, and HDL cholesterol. By using the values of the three above-mentioned indicators and by applying Friedewald's formula, it is possible to calculate LDL cholesterol indirectly. Atherogenic risk is present when HDL cholesterol and LDL cholesterol show plasmatic concentration inferior to 0.35 g/l and superior to 1,3 g/l respectively. The European Atherosclerosis Society lists five hyperlipidaemic classes, from A to E, determined on the basis of plasmatic levels of cholesterol and triglycerides. Mild hypercolesterolaemia associated with modest atherogenic risk and which largely occurs in people and is frequently underestimated form a diagnostic point of view, contributes to cardiovascular mortality more considerably than more serious forms of hypercholesterolaemia. On the basis of this observation, there originated the programmatic proposal for the prevention of hyperlipidaemic complications, presented by the Authors.

Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries.

We investigated the effects of human calcitonin gene-related peptide (CGRP) on isolated rabbit hearts to evaluate the mechanisms responsible for the vasodilatory action of the peptide on the coronary district, monitoring contemporaneously the effects on left ventricular pressure (LVP) and heart rate (HR). We also evaluated the reactivity of the human internal mammary artery (IMA) to excitatory drugs acting with different mechanisms and the inhibitory response to CGRP in comparison with the commonly used vasodilatory agents. The peptide induced a slight inhibitory effect on the basal coronary perfusion pressure (CPP), whereas it was ineffective on the inotropism and chronotropism. A more detectable coronary vasodilation was evident when CPP was increased by spasmogenic agents [vasopressin, methoxamine, Bay K 8644, and prostaglandin F2 alpha (PGF2 alpha)]. This inhibitory effect was dose dependent (10(-11)-10(-8) M) and apparently not specific, occurring to the same extent on different stimuli. Forskolin (10(-8) M), an adenylate-cyclase activator, and indomethacin (1.4 x 10(-5) M), a cyclooxygenase inhibitor, did not modify the spasmolytic activity of CGRP on precontracted coronary smooth muscle. The experiments performed on the segments of IMA, used for myocardial revascularization of patients affected by coronary diseases, have shown an evident spasmolytic action of CGRP on increased vascular tone induced by KCl (90 mM), noradrenaline (10(-5) M), serotonin (10(-6) M), and angiotensin II (10(-6) M). These inhibitory responses of CGRP on the spasmogenic compounds disappeared when the endothelial function of IMA, validated by the acetylcholine test, was abolished by mechanical ablation. A series of IMA segments was incubated (30 min) with N(G)-monomethil-L-arginine (L-NMMA), which inhibits nitric oxide (NO) synthase. In these experiments, the peptide failed to induce the vasodilation, suggesting that its action may be related to synthesis of NO. All these results show that CGRP is able to induce a potent vasodilatory action on different vessels of humans (internal mammary artery) and animals (rabbit coronary arteries). In particular the data obtained from IMA demonstrated that the vasorelaxant effect was related to synthesis of NO, one of the most studied endothelium-derived relaxing factors (EDRFs).

Heat shock protein changes in hibernation: a similarity with heart failure?

Myocardial hibernation is an adaptive phenomenon occurring during ischaemia. Patients with hibernating myocardium often have a history of an acute ischaemic insult, followed by prolonged hypoperfusion and symptoms of congestive heart failure (CHF), which is a complex syndrome involving several adaptational mechanisms. We tested the hypothesis that these two conditions evoke the myocardial expression of heat shock protein 72 (hsp72) as an adaptive response at the molecular level. Short-term acute hibernation was induced in isolated and perfused rat hearts subjected to 8 min total ischaemia followed by 292 min low-flow ischaemia (coronary flow: 1.0 ml/min), followed by 60 min of reperfusion. Total ischaemia caused quiescience. Subsequent low-flow resulted in a temporal early increase of lactate release, no re-establishment of developed pressure, no increase in diastolic pressure. Reperfusion resulted in 85.7 +/- 7.2% recovery of developed pressure, a small washout of lactate and CPK, no contracture, confirming that viability was maintained despite prolonged hypoperfusion. This sequence of events was linked to an increase in hsp72 content in the right (from 18.1 +/- 3.8% to 34.6 +/- 2.3%. P < 0.01) and left (from 19.7 +/- 2.6% to 37.6 +/- 3.3%, P < 0.01) ventricles. Three-hundred min of low-flow perfusion of the rat heart in absence of the short period of total ischaemia caused irreversible damage and failed to induced hsp72. CHF was induced in rats by intraperitoneal administration of monocrotaline. As a result, right ventricular weight increased from 171.3 +/- 7.2 to 412.3 +/- 18.7 mg. P < 0.001, peripheral and pleural effusion were evident and measurable, plasma arterial natriuretic peptide increased from 15.2 +/- 1.9 to 123.5 +/- 5.4 pg/ml, P < 0.001, confirming the occurrence of the syndrome of CHF. This was concomitant with significant expression of hsp72, more evident in the right (from 5.0 +/- 0.9% to 39.4 +/- 1.6%, P < 0.001) than in the left (from 3.5 +/- 0.6% to 13.0 +/- 1.2%, P < 0.001) ventricle. These data suggest that an adaptational process occurs at myocardial level during either hibernation or CHF. The expression of hsp72 could be viewed as a stereotyped adaptational reaction of the cardiac cell to stress conditions.

Activation of the neuroendocrine response in heart failure: adaptive or maladaptive process?

Congestive heart failure is a clinical syndrome in which the capacity of the heart to maintain cardiac output is impaired. As a consequence, blood pressure is threatened and endocrine and paracrine mechanisms are activated to preserve circulatory homeostasis and to maintain blood pressure. At terminal stages, a complex multiorgan syndrome develops with severe pump failure, intense systemic vasoconstriction, and avid water and sodium retention. Increasing evidence points to humoral circulating or locally synthesized substances as one of the causes of the terminal consequences of heart failure. Therefore, the hypothesis that the syndrome of heart failure is, at least in part, a humoral disease has developed and is obtaining scientific credibility. Consequently, the neuroendocrine response to heart failure is no longer viewed as a compensatory beneficial mechanism. Instead, we have learned through the years that pharmacological treatment aimed at reducing the effect of the neuroendocrine response is indeed clinically and prognostically advantageous for the patient.

Cardioprotective effect of angiotensin-converting enzyme inhibitors in patients with coronary artery disease.

Clinical and experiments study with angiotensin-converting enzyme (ACE) inhibitors suggest that these agents may improve coronary artery disease by acting at multiple sites in the series of events leading to end-stage heart disease. These agents reduce blood pressure, improve prognosis and symptoms in patients with severe heart failure and in patients after acute myocardial infarction with left ventricular dysfunction. They are useful in the early, acute phase of myocardial infarction. More recently, ACE inhibitors have been shown to reduce in vitro vascular hypertrophy, to attenuate arteriosclerosis, and to maintain endothelium function. Whether these effects occur at clinical levels is still uncertain. The exciting clinical data have led to the proposal that alteration of ACE activity, particularly in tissue, is an important factor in development and progression of CAD. The ACE system is complex, with endocrine, paracrine, and autocrine effects. ACE is present in cardiac and vascular tissue. Therefore, the beneficial effects of ACE inhibitors can be classified as "cardio" and "vasculo" protective. This article summarizes a number of independent and complementary mechanisms pointing to a role of ACE and ACE inhibition in coronary artery disease.

[Activation and role of the tumor necrosis factor-alpha in congestive heart failure]. / Attivazione e ruolo del fattore di necrosi tumorale alfa nello scompenso cardiaco congestizio.

Recently, an activation of the immune system has been demonstrated in congestive heart failure (CHF). Aim of this study was to evaluate the effects of CHF on the activation of alpha tumor necrosis factor (TNF-alpha), a pleiotropic cytokine. Since the soluble forms of the TNF membrane receptors, sTNF-RI and sTNF-RII, have been shown to modulate TNF-alpha biological activity, we determined antigenic TNF-alpha, bioactive TNF-alpha, sTNF-RI and sTNF-RII in 52 patients with varying degrees of CHF (NYHA functional class II, III, IV). The etiology of CHF was coronary artery disease in 51% of the patients, idiopathic dilated cardiomyopathy in 38% and valvular disease in 11%. All patients were treated with ACE-inhibitors, digoxin and inotropic agents. Antigenic TNF-alpha was significantly increased in NYHA functional class IV patients (from 12.1 +/- 7.6 to 38.5 +/- 12.4 pg/ml, p < 0.001) whereas cytotoxic activity was always under the detection limit of the assay (100 pg/ml). Soluble TNF receptors were significantly elevated in NYHA functional class IV patients: sTNF-RI increased from 1.27 +/- 0.48 to 4.54 +/- 2.11 ng/ml (p < 0.001) and sTNF-RII from 2.25 +/- 0.55 to 7.78 +/- 2.13 ng/ml (p < 0.001). The possible modulation of TNF-alpha biological activity by the soluble receptors was investigated by means of spiking experiments after addition of 625 pg/ml human recombinant TNF-alpha to each serum sample. The biological activity of the added TNF-alpha was significantly inhibited by the high levels of soluble receptors present in the sera of NYHA functional class IV patients (from 625 to 249 +/- 176 pg/ml, p < 0.001). The results show that TNF-alpha and its soluble receptors are activated in severe CHF. The high concentration of soluble TNF receptors circulating in CHF patients are likely to play a protective role against TNF-alpha biological activity.