Determination of volatile organic compounds in exhaled breath of heart failure patients by needle trap micro-extraction coupled with gas chromatography-tandem mass spectrometry.

The analytical performances of needle trap micro-extraction (NTME) coupled with gas chromatography-tandem mass spectrometry were evaluated by analyzing a mixture of twenty-two representative breath volatile organic compounds (VOCs) belonging to different chemical classes (i.e. hydrocarbons, ketones, aldehydes, aromatics and sulfurs). NTME is an emerging technique that guarantees detection limits in the pptv range by pre-concentrating low volumes of sample, and it is particularly suitable for breath analysis. For most VOCs, detection limits between 20 and 500 pptv were obtained by pre-concentrating 25 ml of a humidified standard gas mixture at a flow rate of 15 ml min-1. For all compounds, inter- and intra-day precisions were always below 15%, confirming the reliability of the method. The procedure was successfully applied to the analysis of exhaled breath samples collected from forty heart failure (HF) patients during their stay in the University Hospital of Pisa. The majority of patients (about 80%) showed a significant decrease of breath acetone levels (a factor of 3 or higher) at discharge compared to admission (acute phase) in correspondence to the improved clinical conditions during hospitalization, thus making this compound eligible as a biomarker of HF exacerbation.

Role of cardiac imaging in heart failure.

Heart failure is the leading cause of mortality and rehospitalization in Western countries. With the development of new technologies applied to medical diagnostic pathways, cardiovascular imaging has rapidly gained ground. Therefore, the clinical cardiologist has to keep updated on the management of such innovative diagnostic tools which were once the exclusive domain of radiologists. The need to understand a new language is fundamental for the selection of diagnostic and therapeutic strategies in patients with heart failure, which is often the final destination for many cardiovascular diseases. Alongside standard diagnostic techniques such as chest radiography two-dimensional ultrasound and cardiac color Doppler, all of which are indispensable in daily practice, innovative tools have been defining their incremental role in cardiovascular imaging. Cardiac magnetic resonance (CMR), cardiac computed tomography (CT), speckle tracking, 3D echocardiography, new applications in nuclear medicine (SPECT MIBG), and "cardiac hybrid imaging" are emerging for research and are also playing a pivotal role in the clinical scenario. These techniques are useful the for non-invasive acquisition of diagnostic and prognostic information in heart failure. Whether the radiological and economic impact of these new technologies is sustainable is a question the clinical cardiologist will need to answer when considering the cost/benefit of the diagnostic tool selected among these methods.

Techniques for transvenous leads extraction.

The number of implanted cardiac pacing and defibrillating devices is currently increasing, leading to an increasing number of device-related complications, due to either malfunction or infection. Removal of the whole system, including the leads, was proven to be the most effective therapy. At present the importance of transvenous lead extraction is consequently increased. In order to remove pacing and implantable cardioverter defibrillators (ICD) leads, they have to be made free from any binding site from the entry in the vein to the tip. Different techniques, including mechanical dilation, powered dilation and intravascular approaches have been developed over the last years and are currently available. Results reported in the literature show a significant success rate (ranging between 90% and 98% of the leads) and a reduced incidence of serious complications (1% to 3% in different series) in selected centres. The extraction procedures are complex and life-threatening complications may always occur, suggesting the need of trained and experienced operators as well as the availability of a surgical standby. At present indications to removal are restricted to infection or to damage of the leads inducing serious risk for the patients; the availability of a more effective and safe technique will probably spread indications to most of abandoned leads.

Non-invasive prediction of angiographic progression of coronary artery disease by dipyridamole-stress echocardiography.

BACKGROUND: Coronary angiography is the currently accepted standard means for assessing progression of coronary artery disease. A dipyridamole-echocardiography test (DET) might provide an alternative non-invasive functional imaging method for this purpose. OBJECTIVE: To assess whether variations in results of serial DET match variations in angiographic assessments of coronary artery disease. METHODS: From the Pisa Institute of Clinical Physiology stress-echocardiography data bank (1983-1998), we selected 60 patients satisfying the inclusion criteria of coronary angiography and DET having each been performed and interpreted twice independently and within 1 week. The second angiographic and stress-echocardiographic assessment was performed 45+/-31 months after the initial one. Angiographic progressors were defined a priori as patients with any progression of stenosis to occlusion and those with any stenosis > 30% with > 20% progression of stenosis measured by visual and quantitative coronary angiography. Stress-echocardiography progressors were defined as those patients who had previously had a negative test of a test having a positive result and those patients who had positive results of tests both in initial testing and in a second session of testing with the latter having a peak wall-motion-score index > 0.12 (on a scale of 1, normal to 4, dyskinetic in a 16-segment model) larger than the former. RESULTS: Of the 60 patients, 44 were angiographic 'progressors' and 16 were 'non progressors'. Stress-echocardiographic responses were concordant with angiographic identification for 39 of 44 progressors and 15 of 16 non-progressors, with an overall concordance of 90%. CONCLUSIONS: Measurement of dipyridamole-stress-echocardiographic response allows one to separate angiographic progressors and non-progressors efficiently, simply by taking into account the presence, extent and severity of stress-induced abnormalities of wall motion.

Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease : reversal by angioplasty.

BACKGROUND: The pathophysiology of microvascular response to a severe coronary stenosis has not been conclusively identified. The aim of this study was to characterize the human vasomotor response to pacing-induced ischemia of both the stenotic arterial segment and the distal microcirculation. METHODS AND RESULTS: Sixteen patients with stable angina and single-vessel disease were studied. Blood flow velocity and transstenotic pressure gradient were monitored at baseline, after intracoronary adenosine (2 mg), and during ischemia induced by atrial pacing with and without adenosine. At the end of this protocol, the study was repeated after intracoronary phentolamine in 7 patients and after angioplasty in 9. Stenosis resistance was calculated as the ratio between mean pressure gradient and mean flow, and microvascular resistance as the ratio between mean distal pressure and mean flow; values were expressed as percent of baseline. Adenosine decreased (P<0.05) baseline microvascular resistance to 52+/-17%, but not stenosis resistance. Pacing increased both stenosis and microvascular resistances (244+/-96% and 164+/-60% of baseline, respectively, P<0.05). Addition of adenosine to pacing decreased both stenosis (143+/-96% of baseline, P<0.05 versus ischemia) and microvascular (51+/-17% of baseline, P<0.05 versus baseline and ischemia) resistances. Phentolamine did not affect coronary resistance at any step of the protocol. Angioplasty and stenting restored a progressive decline in microvascular resistance during pacing (51+/-19% of baseline, P<0.05 versus baseline). CONCLUSIONS: In patients with coronary artery disease, tachycardia-induced ischemia was associated with elevated resistance of both the stenotic segment and the microvasculature. Revascularization prevents this paradoxical behavior.

Management of ischaemic heart disease in diabetic patients--is there a role for cardiac metabolic agents?

Diabetes mellitus (DM) increases the risk of cardiovascular events in patients with cardiovascular disease as well as in patients without any previous history of ischaemic heart disease (IHD). The management of IHD in diabetic patients remains a difficult challenge. However, some of these treatments are not as effective or well-tolerated in diabetic patients as in non-diabetic patients. An important effect of diabetes, that in turn influences cardiac function, is the switch from carbohydrate oxidation to free fatty acid and ketone oxidation. The correction of the alterations to cardiac metabolism associated with DM may represent a new approach to the management of IHD in these patients. Results obtained in anginal patients with the metabolic agent trimetazidine and in infarcted patients with glucose-insulin-potassium (GIK) are consistent with this hypothesis.

Clinical evidence for myocardial derecruitment downstream from severe stenosis: pressure-flow control interaction.

To verify the interaction between coronary pressure (CP) and blood flow (CBF) control, we studied nine candidates for angioplasty of an isolated lesion of the left anterior descending coronary artery [i.e. , percutaneous transluminal coronary angioplasty (PTCA)]. CBF (i.e., flow velocity x coronary cross-sectional area at the Doppler tip) and CP were monitored during washout of 2-5 mCi of (133)Xe after bolus injection into the left main artery before and after PTCA. Xe mean transit time (MTT) was calculated as the area under the time-activity curve, acquired by a gamma camera, divided by the dose obtained from a model fit of the Xe curve in the anterior wall. CBF response to intracoronary adenosine (2 mg) was also assessed. PTCA increased baseline CBF (from 14.5 +/- 9.4 to 20 +/- 8 ml/min, P < 0.01), coronary flow reserve (from 1.52 +/- 0.24 to 2.33 +/- 0.8, P < 0.01), and CP (from 64 +/- 9 to 100 +/- 10 mmHg, P < 0.05). MTT decreased from 89 +/- 32 to 70 +/- 19 s (P < 0.05) after PTCA; however, MTT and CBF changes were not correlated (r = -0.09, not significant). Inasmuch as MTT is the ratio of distribution volume to CBF, MTT x CBF was used as an index of perfused myocardial volume. Volume increased after PTCA from 23 +/- 18 to 56 +/- 30 ml. A direct correlation was observed between the percent increase in distal CP and percent increase in perfused volume (r = 0.91, P < 0.01). Thus low CP was not associated with exhaustion of flow reserve but, rather, with reduction of perfused myocardial volume. These data suggest that, in the presence of a severe coronary stenosis, derecruitment of vascular units occurs that is proportional to the decrease in driving pressure. Residual perfused units maintain a vasomotor tone, thus explaining the paradoxical persistence of coronary reserve.

Adenosine and angiotensin system interact in the regulation of renal microcirculation in humans.

We sought to evaluate the possible interaction between the adenosine and angiotensin systems in the regulation of renal microcirculation in humans. Twenty normotensive patients entered the study. Ten patients (group 1) were pretreated with 50 mg of captopril, an inhibitor of angiotensin-converting enzyme, whereas 10 patients (group 2) were pretreated with placebo. Incremental doses of adenosine (from 10(-5) to 1 mg) were injected into a renal artery to all patients at 5-min intervals. Adenosine injection reduced mean renal blood flow velocity in both groups (from 17.3+/-2.8 and 16.7+/-2 cm/s to 5.1+/-1.1 and 3.8+/-0.8 cm/s, in groups 1 and 2, respectively). The decrease in flow velocity was immediate after adenosine, and its duration was proportional to dosage (y = 3.05 x -2.7; R2 = 0.46; p < 0.01). However, group 1 had a slope of regression lower than group 2 (2.37 vs. 3.82 s; p < 0.03). The index of renal resistance (mean arterial pressure/mean blood flow velocity) increased linearly in both groups with adenosine, but group I showed a lower slope of increment (2.77 vs. 5.57 mm Hg/cm/s; p < 0.01). Adenosine administration induced a marked and transient increase in human renal resistance. This vasoconstrictive effect of adenosine was blunted by captopril pretreatment.

Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction.

BACKGROUND: The benefits of vessel recanalization in acute myocardial infarction (AMI) are limited by reperfusion damage. In animal models, adenosine limits reperfusion injury, reducing infarct size and improving ventricular function. The aim of this study was to evaluate the safety and feasibility of adenosine adjunct to primary PTCA in AMI. METHODS AND RESULTS: Fifty-four AMI patients undergoing primary PTCA were randomized to intracoronary adenosine or saline. The 2 groups were similar for age, sex, and infarct location. Adenosine administration was feasible and well tolerated. PTCA was successful in all patients and resulted in TIMI 3 flow in all patients given adenosine and in 19 given saline (P<0.05). The no-reflow phenomenon occurred in 1 adenosine patient and in 7 saline patients (P=0.02). Creatine kinase was lower in the adenosine group, and a Q-wave MI developed in 16 adenosine patients and in 23 saline patients (P=0.04). Sixty-four percent of dyssynergic segments improved in the adenosine group and 36% in the saline group (P=0. 001). Function worsened in 2% of dysynergic segments in the adenosine group and in 20% in the saline group (P=0.0001). Adverse cardiac events occurred in 5 patients in the adenosine group and in 13 patients in the saline group (P=0.03). CONCLUSIONS: Intracoronary adenosine administration is feasible and well tolerated in AMI. Adenosine adjunct to primary PTCA ameliorates flow, prevents the no-reflow phenomenon, improves ventricular function, and is associated with a more favorable clinical course.

Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina.

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.

Interaction between coronary artery stenosis and coronary microcirculation in ischemic heart disease.

The hallmark of ischemic heart disease is the presence of focal obstructions in the major coronary arteries. Classically, epicardial stenoses are thought to exert their pathogenetic role mainly through a limitation on maximal flow capacity in the distal vascular bed. Ischemia is thus thought to occur whenever oxygen consumption exceeds the flow availability. Although a number of experimental studies confirmed these assumptions, the adherence of this experimental model with the clinical observations is still far from being convincing. Evidence now exists that atherosclerosis causes more profound alterations in the regulation of myocardial perfusion, besides the hydraulic effects of epicardial obstructions. These alterations affect endothelial regulation of coronary vasomotor tone both in the large arteries and in the distal microcirculation. In agreement with this experimental evidence, an abnormal response to endothelium-mediated vasodilators has been reported in patients with coronary artery disease. Moreover, several studies also reported an abnormal response of atherosclerotic coronary microcirculation to atrial pacing tachycardia and dipyridamole, which are thought to be largely endothelium independent. An even more striking observation is the finding of an intense microvascular constrictor response in the myocardium, supplied by a severely stenotic coronary artery, to pacing-induced ischemia. This observation strongly suggests that coronary microcirculation might aggravate the flow reduction imposed by the epicardial stenosis, thus playing some role in the pathogenesis of ischemia. This phenomenon might reflect the presence of a primary abnormality of coronary microcirculation in patients with coronary artery disease or the existence of a pressure-oriented regulation of vascular tone which prevent trans-stenotic pressure drop by means of a heterogeneously distributed microcirculatory vasoconstriction.

Clinical benefits of a metabolic approach in the management of coronary patients.

Patients with Angina Pectoris benefit from therapy with nitrates, beta-blockers, and calcium channel antagonists. All these drugs, through different action mechanisms, tend to reduce cardiac work and restore the balance between myocardial metabolic demand and blood supply. Failure of this conventional haemodynamic treatment in controlling symptoms and preventing ischemia is however frequent, and many such patients are then referred for myocardial revascularization. This scenario has been innovated by Trimetazidine, an anti-ischemic agent that exerts its beneficial effects by increasing cell tolerance to ischemia and improving functional recovery at the time of reperfusion. Compared with classic "hemodynamic" agents, Trimetazidine demonstrated similar efficacy in reducing frequency and severity of ischemic attacks and in increasing exercise tolerance, with a lower incidence of side effects. The adjunct of Trimetazidine to propranolol was found superior to nitrates in reducing ischemic episodes. In angina patients not controlled by CA-antagonists, Trimetazidine lowered the frequency of ischemic attacks and prolonged the time to ischemia during exercise. More recently, Trimetazidine has been shown to improve left ventricular dysfunction in patients with congestive heart failure, and in ischemic patients undergoing PTCA. In chronic coronary artery disease, Trimetazidine improved regional dysfunction at rest and during dobutamine stress echocardiography. Given the metabolic mechanism of action of Trimetazidine, focused on improving energy metabolism and restoring membrane homeostasis, it is expected to especially benefit patients in whom metabolic alteration contribute to the pathogenesis of ischemia, namely diabetic patients. Preliminary data from a multicenter study do support this hypothesis. In conclusion, available data indicate that the cardioprotective effect of Trimetazidine results in improvement of symptoms and preservation of left ventricular function in patients with acute and chronic ischemic syndromes.

Adenosine causes the release of active renin and angiotensin II in the coronary circulation of patients with essential hypertension.

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.

Contrast echocardiography in the diagnosis of myocardial stunning.

The identification of viable myocardium within dysfunctional myocardium has important clinical implications. By using a microvascular tracer, myocardial contrast echocardiography may have the potential for prediction of myocardial viability in the acute and subacute phases of myocardial infarction. In the case presented, the normal myocardial perfusion observed after intravenous injection of the contrast agent, combined with severe wall motion abnormality following prolonged chest pain, suggested myocardial stunning. This was confirmed by normal coronary angiography and by restoration of normal left ventricular function at 1-month follow-up echocardiography.

Primary coronary angioplasty in acute myocardial infarction: clinical correlates of the 'no reflow' phenomenon.

The purpose of this study was to assess clinical correlates of the 'no reflow' phenomenon in 21 consecutive patients with acute myocardial infarction and complete occlusion of the infarct related artery (TIMI 0 flow) that underwent successful direct PTCA. After successful recanalization, 11 patients (group I) maintained TIMI 3 flow and ten patients presented with the 'no reflow' phenomenon (Group II). New Q wave on the surface ECG appeared in six patients in group I and in nine patients in group II (P=NS), clinical and radiologic signs of cardiac failure were detected in two patients in group I and in seven patients in group II (P<0.03). Early recurrence of ischemia was reported in three patients of group II but not in group I (P=NS). We conclude that the 'no reflow' phenomenon occurs in about half the cases of direct PTCA for complete occlusion and predicts adverse clinical events.