Evidence of parasympathetic impairment in some patients with cardiac syndrome X.

OBJECTIVES: Cardiac syndrome X (SX) is a clinical condition characterised by angina, positive exercise stress test and negative coronary angiography; it has often been attributed to sympathetic hyperactivity. Here we tested the hypothesis that a parasympathetic, rather than a sympathetic, dysfunction could be the cause of the autonomic imbalance observed in SX. METHODS: In 20 subjects with diagnosed SX and in 12 age-matched controls, we studied autonomic function by performing spectral analysis of RR interval and finger arterial pressure (SAP), in supine position and during head-up tilting. We also carried out a set of tests of parasympathetic function. RESULTS: The group of SX patients did not differ significantly from control subjects in any of the variables tested. In a subgroup of 13 SX, however, tilting increased the low-frequency power of SAP, but did not induce the expected increase in low-frequency and decrease in high-frequency power of RR. These patients, in supine position, had significantly lower sinus arrhythmia and a higher ratio of low to high frequency of RR, in comparison with control subjects. We interpreted these differences as signs of reduced parasympathetic, but essentially normal sympathetic, activity. The parasympathetic tests confirmed vagal impairment in the same SX subjects. On the other hand, all the tests indicated normal parasympathetic functions in the control subjects and in those SX patients who displayed the expected spectral changes in tilting. CONCLUSIONS: In about two thirds of the patients with SX, the pathophysiological mechanism causing the symptoms could be related to the reduced parasympathetic tone, rather than to an augmented sympathetic activity.

Coronary artery vasomotion and post-stenotic coronary artery blood flow after intracoronary lacidipine in patients with ischaemic heart disease: a pilot study.

BACKGROUND: The calcium antagonist lacidipine has been shown to be highly vasoselective and to improve myocardial perfusion in hypertensive patients. However, its effects on coronary artery vasomotility and on post-stenotic coronary flow reserve in patients with atherosclerotic heart disease are unknown. OBJECTIVES: This study was designed to investigate the acute direct effects of repeated infusions of lacidipine on epicardial coronary artery vasomotion and on post-stenotic coronary artery blood flow in patients with stable angina pectoris and angiographic evidence of coronary heart disease. METHODS: In 8 patients with stable angina and moderate to severe stenosis of the left coronary artery, measurements of epicardial dimensions (quantitative angiography) and of coronary blood flow (Doppler guidewire) distal to a stenosis were performed at baseline and after 3 repeated intracoronary boluses of 12 microg of lacidipine. Results were compared with those obtained after 10 mg of intracoronary papaverine. RESULTS: The intracoronary administration of lacidipine was well tolerated, without any adverse effects. Lacidipine significantly increased the minimal luminal diameter of the lesion (peak relative increase of 43.7%), without significant changes in heart rate and systolic aortic pressure. Intracoronary lacidipine caused a dose-dependent increase in coronary flow reserve. Maximal vasodilatory effects were equivalent to those obtained with intracoronary papaverine. CONCLUSIONS: These results suggest that lacidipine acts directly as a potent vasodilator in stenotic epicardial vessels and improves myocardial perfusion distal to a moderately severe stenosis in patients with stable angina.

Update on mechanical revascularization in acute myocardial infarction: which role and when?

Mechanical revascularization in the acute myocardial infarction by primary angioplasty has several advantages over thrombolytic therapy. The short-term patency rates of the infarct-related artery range from 95 to 99% and a normal flow is achieved in more than 90% of the cases. This prompt and effective reperfusion is probably responsible for the improved prognosis with primary angioplasty. The better outcome after primary angioplasty is observed both in low- and in high-risk patients, in all ages and in patients presenting late (>6 h) after the chest pain. Pooled analysis of randomized studies, show that primary angioplasty as compared to thrombolysis, has a lower incidence of death, stroke and reinfarction. Additional advantages of primary PTCA include the possibility of reperfusion in patients in whom lysis is contraindicated or less effective (e.g. patients in cardiogenic shock, or with prior coronary artery bypass surgery) and the ability to provide prognostic information helpful in the patient triage. Thus, primary PTCA results in better outcome than thrombolysis when performed in centers with success rates comparable to those achieved in the randomized trials. Further studies are still needed to assess its long-term efficacy. Several randomized trials are underway to assess the role of stents and the use of more potent antiplatelet drugs, as the GPIIb/IIIa receptor blockers, in adjunct to balloon angioplasty in the treatment of acute myocardial infarction.

Maximal myocardial perfusion by videodensitometry in the assessment of the early and late results of coronary angioplasty: relationship with coronary artery measurements and left ventricular function at rest.

In the assessment of the acute results of percutaneous transluminal coronary angioplasty (PTCA), myocardial perfusion at maximal vasodilatation theoretically has fewer limitations than the coronary flow reserve measurements and quantitative coronary angiography. The purpose of this study was to compare the myocardial perfusion to the measurements of the severity of the lesion (minimal luminal diameter and percent area stenosis) and to relate it to the changes of left ventricular function after PTCA. Regional myocardial perfusion was assessed during intracoronary papaverine, using the inverse mean transit time of contrast medium (1/Tmn), before, 15 min after, 18-24 hr after, and 6 months after successful single-vessel PTCA in 14 patients with stable angina. Left ventricular angiography (before angioplasty, 18-24 hr after, and 6 months later) was analysed by area-length and centerline methods. Immediately after PTCA, 1/Tmn increased from 0.14 +/- 0.07 sec-1 to 0.21 +/- 0.09 sec-1 (P = .001). Maximal myocardial perfusion remained higher than the pre-PTCA value the day after angioplasty (1/Tmn of 0.23 +/- 0.09 sec-1), while it reduced to near pre-PTCA values at follow-up (1/Tmn of 0.16 +/- 0.05 sec-1). Before PTCA, three out of ten patients had ejection fraction of < 65%, and seven had mild-to-moderate hypokinesis. The day after PTCA the ejection fraction and the regional dysfunction improved significantly. The change in ejection fraction 18-24 hr after PTCA did not correlate with minimal luminal diameter and percent area stenosis and correlated slightly with the improvement of perfusion (r = 0.54, P = .10). At follow-up left ventricular function deteriorated in the whole group, despite the persistence of angiographic success of PTCA, possibly because of changes in the loading condition. Coronary artery stenosis measurements and 1/Tmn failed to correlate with the left ventricular function. Given the difficulties in routine application of the analysis of time-density curves, the measurement of minimal luminal diameter remains a more practical assessment of the results of the intervention. However, the improvement of myocardial perfusion may give more information than coronary artery dimensions of the early recovery of left ventricular function.

[Coronary recanalization: rationale for stents]. / Ricanalizzazione coronarica: il razionale degli stent.

Coronary stenting is a technique complementary to coronary angioplasty, because it is successful in the management of the two major limitations of conventional balloon dilation, i.e. the acute or threatened closure and the restenosis. The currently available intracoronary stents are far from being ideal, mainly for their thrombogenicity. During abrupt closure, the bailout stenting has, in most of the cases, offered a valuable alternative to emergency coronary artery bypass surgery. The major complications after stent insertion are the result of an inadequate stent placement, of persistence of intra and/or poststent obstruction and of the ineffective anticoagulant therapy. The mechanical support (scaffolding) provided by the stent after dilation significantly reduces the amount of elastic recoil, and, improving laminar flow, eliminates arterial wall shear stress that may contribute to an increase in intimal thickening. Moreover, the reduction of arterial cyclical stretching may reduce the rate of neointimal proliferation. By sealing the exposed subintimal spaces, stents may minimise the formation of local thrombi, and thus also limit their later organization and fibrous conversion into part of the restenotic lesion: two recently completed randomized trials (STRESS and BENESTENT) confirm the lower rate of restenosis in patients treated with single stent placement in de-novo lesions as compared with standard balloon angioplasty. The mechanism of stent benefit in reducing restenosis rate seems to be the wider initial lumen, which can accommodate a greater degree of intimal hyperplasia. In the near future, the improvements of the blood and tissue compatibility of the stents, may allow easier management.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary vasoconstriction in response to acetylcholine after balloon angioplasty: possible role of endothelial dysfunction.

BACKGROUND: Abnormal endothelium-dependent vasomotion has frequently been observed early after coronary angioplasty. The aim of this study was to investigate endothelium-mediated coronary vasomotion caused by increasing intracoronary infusions of acetylcholine into epicardial coronary arteries 3-6 months after coronary angioplasty in patients without restenosis (50% luminal diameter reduction). METHODS: Intracoronary acetylcholine was infused during follow-up coronary angiography followed by an intracoronary bolus of 250 g nitroglycerin in 18 patients who had undergone successful angioplasty of 21 isolated coronary artery lesions. Using an automated edge-detection program, coronary artery measurements were performed in the proximal reference segment, in the proximal part of the angioplasty site, at the site of previous maximal stenosis, in the distal part of the angioplasty site, and in the distal reference segment. RESULTS: In the segments of the coronary artery not manipulated by balloon catheter, acetylcholine did not produce significant luminal diameter changes (+2 +/- 23% in the proximal segment and -3 +/- 27% in the distal segment at 10(-4) mol/l). All the angioplasty vessel segments, excluding the proximal reference segments, showed an abnormal dose-related reactivity to the acetylcholine. Maximal vasoconstriction was observed at 10(-4) mol/l and was 4.9 +/- 11.1% in the proximal reference segment, 9.3 +/- 19.1% in the proximal angioplasty site (P = 0.0314), 20.3 +/- 24.1% at the site of previous maximal stenosis (P = 0.0005), 10.7 +/- 16.8% at the distal angioplasty site (P = 0.0098), and 9.3 +/- 14.1% in the distal reference segment (P = 0.0032). The maximal response of the angioplasty site to acetylcholine and to nitroglycerin did not correlate either with the time to follow-up or with the follow-up stenosis. Nitroglycerin-induced vasodilation was significant in all segments, but was lower in the lesion-related segments. Acetylcholine evoked the same effect on both the vessels that were manipulated and those that were not. CONCLUSIONS: Three to 6 months after coronary angioplasty, endothelium-dependent vasodilation was impaired not only at the site of previous maximal stenosis, but also in segments directly injured by balloon inflation. In contrast, endothelium-independent vasodilation by nitroglycerin is maintained in all segments. These observations suggest that the endothelium is still functionally impaired in the area of balloon dilation.

[Endothelial dysfunction in ischemic syndromes]. / La disfunzione endoteliale nelle sindromi ischemiche.

Several studies have shown evidence of the key role of the endothelium in modulating the tone of epicardial coronary vessels, in the different manifestations of coronary artery disease. Recently, the role of endothelium-dependent vasodilation has been focused, because clinical observations have suggested that myocardial ischemia might be caused or aggravated by inappropriate vasoconstriction of resistance vessels. An abnormal endothelium-dependent vasodilation, either of epicardial and of coronary microvasculature, has been documented in patients with syndrome X and in patients with history of hypertension and left ventricular hypertrophy. Vasoconstriction of the small coronary vessels is probably the mechanism underlying the impaired increase of coronary blood flow during atrial pacing and the wide variations of the ischemic threshold in some patients with chronic stable angina. In patients with variant angina, the endothelial function seems abnormal only in the conductance vessels. It is likely that the endothelial dysfunction of the small coronary arteries be present in many clinical situations in which a discrepancy between a mild atherosclerosis of epicardial coronary artery and signs of ischemia exists, as it has been observed early after successful angioplasty and after coronary artery reperfusion during acute myocardial infarction.

Lipoprotein(a) concentrations are increased in patients with myocardial infarction and angiographically normal coronary arteries.

It is generally accepted that Lp(a) is an independent risk factor of cardiovascular diseases. Since the apolipoprotein component of Lp(a) shows some homologies to plasminogen, it is, however, unclear as to whether the pathological effect is due to the role played by the lipoprotein in lipid metabolism or in the fibrinolytic system. We compared two groups of patients with myocardial infarction, with and without angiographically documented coronary artery disease. In the latter group, imbalances in the clotting system are very likely, while members of the former group may also display disturbances of lipid metabolism. The results show that the two groups display differences in lipid metabolism, whereas they have similar patterns of thrombogenicity indices and Lp(a) values. This study seems to support the hypothesis that Lp(a) does play a role in the fibrinolytic system, since even those myocardial infarctions without obstructive coronary artery disease have a high frequency of Lp(a) concentrations above 300 mg/l, i.e. similar to the situation found in the myocardial infarctions with angiographically documented coronary artery disease. Whether the high Lp(a) concentrations in the two groups are related to an impaired fibrinolysis will be the subject of further investigation.

[Angina due to anatomical anomalies and to functional changes in the epicardial coronary vessels]. / Angina da anomalie anatomiche e da alterazioni funzionali dei vasi coronarici di conduttanza.

Myocardial ischemia with normal coronary arteries can be due to anatomic or functional reasons. The more severe congenital coronary anomalies in the adulthood are the origin of the left main of the left coronary artery from the right aortic sinus, with a course between the aorta and the pulmonary trunk, and the origin of the left main from the pulmonary trunk. Both these anomalies can cause sudden death, usually associated with physical exertion. The coronary vasomotion of epicardial vessels depends on the interaction of several neurohumoral substances. We report the hemodynamic, angiographic and stress test data of 30 patients affected by chest pain, with myocardial ischemia and normal coronary arteries. In 8 patients the response of epicardial coronary arteries to intracoronary infusion of acetylcholine was evaluated.

[Myocardial infarct and angiographically normal coronary arteries]. / L'infarto miocardico a coronarie angiograficamente normali.

Myocardial infarction and normal coronary arteries is not a rare event in the ischemic heart disease. Even if the patients with acute myocardial infarction and angiographically normal coronary arteries represent a small percentage (reported incidence varies from 1% to 12%) of all patients with acute ischemic attacks, they might be useful to highlight the pathogenetic mechanisms of this syndrome. To improve the understanding of this clinical entity, we reviewed our experience of 18 patients with myocardial infarction and normal coronary arteries. They were compared with a control group of patients with similar clinical characteristics (gender, age, infarct location) and residual coronary artery stenosis. The myocardial damage was less extensive in patients without residual stenosis (peak CK-MB: 56.1 +/- 71.9 vs 126.5 +/- 87.9 IU/I, p < 0.05), with a better left ventricular function either global (ejection fraction: 64 +/- 11 vs 55 +/- 13%, p < 0.05) and regional (SD/chord: -1.36 +/- 1.20 vs -2.42 +/- 1.04, p < 0.02). These findings probably reflect a more prompt and complete reperfusion of the infarct related artery. Myocardial necrosis may occur without obstructive coronary artery disease by the interaction of multiple factors such as abnormal platelet aggregation, thrombus formation and localized or diffuse changes of coronary vascular tone.

[Value of serial exercise tests after coronary angioplasty in relation to extension of heart disease and the degree of revascularization]. / Valore di prove da sforzo seriate dopo angioplastica coronarica in rapporto all'estensione della coronaropatia e al grado di rivascolarizzazione.

With the aim of investigating the functional result of the coronary angioplasty (PTCA) and verifying the predictive value of the exercise test for detecting restenosis, 165 patients who underwent successful PTCA were evaluated through exercise stress tests performed 10, 75 and 165 days after PTCA and through coronary angiography performed 5 to 6 months after PTCA. The percentage of negative tests and the rate-pressure product (RPP) increased significantly with respect to the tests performed before PTCA, both in patients with single-vessel and those with multivessel disease. Maximal ST segment depression and ST/HR were significantly reduced only in patients with complete revascularization. The percentage of positive tests 10 days after PTCA was lower in patients with single-vessel than in those with multivessel disease (2.5% versus 10.8%) and, of the latter, in patients with complete rather than incomplete revascularization (0% versus 13.5%). In patients with complete revascularization, the mean exercise time rose significantly (703 s versus 538 s). The percentage of positive tests increased progressively with time, in accordance with probable increasing restenosis. In comparison with the results of angiography, sensitivity of the exercise stress test proved to be poor (59%), especially in patients with single-vessel disease (45%), while the specificity was very high (98%). The predictive value of a negative test was 77% in patients with multi-vessel and 87% in patients with single-vessel disease. The predictive value of a positive test was over 90% in both groups of patients.

Open-ended guidewire: new technique for balloon angioplasty of chronically occluded coronary arteries.

Chronic total coronary occlusion is a growing indication to percutaneous transluminal coronary angioplasty. Since primary success of balloon angioplasty in this condition is usually limited by the difficulty of crossing the occlusion, different techniques have been described for this purpose, such as use of stiff guidewires, coronary infusion catheters, guidewires with an olive-shaped tip, or new developing methods (atherectomy, laser), in association with balloon dilatation. Here, we describe our initial experience with a thick (0.035 in) and relatively stiff open-ended guidewire, which has an inner (0.018 in diameter) lumen provided with a core wire. Several advantages are considered. The core wire yields a perfect means of steerability of the whole system, while pushability of a thicker guidewire is much greater. Moreover, the core wire can be removed, and contrast injections beyond the occlusion through the inner lumen can assure proper intraluminal location. Finally, position across the occlusion can be kept easily, since an exchange wire for conventional balloon catheters can be inserted in the inner lumen of the open-ended guidewire.

Single coronary artery from the left sinus of Valsalva.

A patient with chronic exertional angina and electrocardiographic signs of myocardial ischemia at exercise stress test had recent onset of rest chest pain and underwent coronary arteriography. Besides severe atherosclerotic coronary disease (which was probably responsible for clinical presentation), a single coronary artery arising from the left sinus of Valsalva was discovered. This is an exceptional finding, and its in-life diagnosis may be relevant for surgical treatment.

[Correlation between coronary angiographic and ergometric studies after coronary angioplasty]. / Correlazioni coronarografiche ed ergometriche dopo angioplastica coronarica.

In 35 patients with effort angina exercise tests before and after coronary angioplasty (PTCA) were compared, aimed at evaluating functional improvement and at correlating some ergometric parameters with angiographic results. All tests were performed during therapy with verapamil 360 mg/die. After PTCA mean diameter of the stenosis was reduced from 68 +/- 11% to 19 +/- 12%. Duration of exercise and rate-pressure product (RPP) were significantly greater in the test after PTCA. While all tests before PTCA were positive, after PTCA ST segment depression occurred in 9 patients (26%). In 7 of these patients it was less than 1 mm. In 26 patients (74%) tests were negative after PTCA. In patients with ST segment depression, ischemia threshold significantly rose from 5.2 +/- 1.5 min (RPP 15,875 +/- 3,253 to 7.6 +/- 1.2 min (RPP 20,157 +/- 3143). Maximal ST segment depression and ST/HR slope were significantly reduced. In negative stress tests the time free from ischemia significantly rose from 6.5 +/- 2.6 min (RPP 18,872 +/- 3,861) to 10.5 +/- 2.3 min (RPP 28,476 +/- 4,289). In patients with positive tests stenosis after PTCA was more severe than in patients without ST segment depression (29 +/- 13% vs 17 +/- 13%). In patients with ST segment depression improvement of ischemia threshold and of stenosis were correlated. In these patients improvement of ischemia threshold is the ergometric parameter more useful to evaluate the angiographic result of PTCA.

Coronary arterial aneurysms after percutaneous transluminal coronary angioplasty--a not uncommon finding at elective follow-up angiography.

Five coronary arterial aneurysms were found in 4 of 80 (5%) patients who underwent elective coronary arteriography 6 months after successful percutaneous transluminal coronary angioplasty. None of them was present immediately after dilatation. All patients had been suffering from stable angina before angioplasty, while no case had recurrent angina or definite angiographic restenosis at the 6-month follow-up. Quantitative coronary angiography was performed in all angiograms. The coronary aneurysms only developed in the dilated portions (4 in left anterior descending and 1 in an intermediate branch of the left coronary artery): their diameter ranged from 3.1 to 4.4 mm, and their length from 2.2 to 4.9 mm. The ratio between the aneurysm diameter and the coronary arterial diameter (aneurysm: artery ratio) varied from 1.15 to 1.91 (mean 1.47). No significant clinical or technical differences were found between patients who developed aneurysm after angioplasty, and patients who did not. On the other hand, 4 of the 5 patients who developed aneurysm had angiographic evidence of "non-pathologic" dissection immediately after balloon dilatation. Moreover, the ratio between the measured angiographic diameters of the balloon (at maximal inflating pressure) and of the coronary artery selected for the procedure showed that the balloon was mildly oversized (balloon: artery ratio ranging from 1.10 to 1.37, mean 1.28) in all cases with aneurysm except the only 1 in whom dissection did not occur. In conclusion, aneurysm formation after coronary angioplasty is not infrequent in our experience: balloon size and wall dissection seem to be the major factors related to this event.

Comparison of different pharmacological interventions on enzymatic parameters during acute myocardial infarction.

The concept that acute myocardial infarction is a dynamic event and that different interventions can modify the extent of the necrosis, has led to renewed interest in early pharmacological and surgical treatments designed to reduce the ischemic injury. To evaluate the effects of different pharmacological interventions aimed to reduce the extent of necrosis, we studied 166 patients (138 male and 28 female, mean age of 59.4 +/- 11.3 years) admitted within 6 h after chest pain and treated with a single therapy during the first 72 h. Enzymatic infarct size (IS) was calculated by serial creatine kinase isoenzyme MB determinations using a compartmental model. Six groups of patients were evaluated: 33 patients were treated only with antiplatelet drugs, 38 with anticoagulants, 34 with intravenous thrombolytic therapy, 20 with calcium channel blockers, 25 with nitrates, and 16 with beta-blockers. Estimated IS (gEq/m2) and elimination constant (Kd, U/L/h) did not differ in the six groups, but patients treated with streptokinase had higher release constant (Ka, U/L/h) and shorter time to peak CK-MB value. Early treatment (less than or equal to 2 h after chest pain) had a favourable effect on the enzymatic IS only in patients treated with calcium channel blockers (p less than 0.005).

Laser irradiation and balloon dilatation in experimental transluminal angioplasty.

Percutaneous transluminal balloon angioplasty (PTA) is being currently used in patients with coronary artery disease. Laser irradiation (LI) has been effective in vaporizing atherosclerotic plaques. The purpose of this work was twofold: to compare PTA and LI techniques in the recanalization of experimental obstructive arterial lesions, and to evaluate the possibility of reducing the failures and local complications and increasing the success rate of PTA by the combined use of LI. Atherosclerotic iliac stenoses were induced in 27 rabbits; lesions were evaluated angiographically before and after intervention and were studied histologically and by electron microscopy. Argon-ion LI delivered through microlens-tip optic fibers reduced the stenotic area from 64.2 +/- 21.8% to 40.3 +/- 10.7% (n = 10, P less than .01) and PTA from 60.7 +/- 15.9% to 30.4 +/- 7.7% (n = 9, P less than .01). However, percentage reduction was higher in PTA-treated stenoses (48.4 +/- 10.1% vs 34.5 +/- 13.5%, P less than .0125). In eight more rabbits, low power LI (4.55 +/- 1.25 J) was delivered after PTA in dilated segments. Post-PTA LI further decreased stenoses (from 31.2 +/- 7.8% to 29.1 +/- 8.1%, P less than .0125); laser-irradiated segments showed diffuse carbonization of the disrupted intimal layer. The normalized transtenotic pressure gradient decreased significantly in all groups: LI reduced the gradient from .40 +/- .25 to .17 +/- .07 (P = .005); PTA from .37 +/- .14 to .11 +/- .04 (P = .001); LI after PTA from .40 +/- .16 to .12 +/- .06 (P = .001). Thus, LI is effective (less than PTA) in relieving experimental atherosclerotic stenoses and seems useful when combined with PTA.

[Return to work and cardiovascular status after myocardial infarction]. / Ritorno al lavoro e condizioni cardiocircolatorie dopo infarto del miocardio.

110 male subjects, under 60, admitted for myocardial infarction in 1980 and 1981, have been considered. 85 answers to the questionnaire, sent by post have been obtained, 6 pertaining to patients who died in the meanwhile. Among the 79 living patients who replied, 57 (72.1%) had resumed work within the average time of 4.8 months (min. 0.5-max. 12). Return to work has been significantly higher among self-employed people than employees; only 15 subjects had changed job or task. The subjective rating of the actual health status, two years after the infarction, has been satisfactory in 90.5% of cases, in spite of 56.5% complaining of heartburn, 38.1% of dyspnea and 35.7% of palpitation. The work-load has been rated as tiring only by 12.6% of them, while 65.6% have maintained unchanged their work capacity. Electrocardiographic monitoring (by the Holter method), during a normal workday, showed no significant differences between working and retired subjects and, also, in work and normal activity periods. 19 subjects (47.5%) presented ventricular arrhythmias, in 12 cases at high risk, most of them being unaware of it. These arrhythmias were more frequent during wake periods, but not strictly connected to the type and the quality of the work activity. The patients subjected to rehabilitation showed no differences in the cardiovascular patterns during the ergometric test and ECG monitoring when compared to those not subjected to rehabilitation.