Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice.

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety-one recipients comprised the early cohort, receiving IVUS at weeks 3-6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01-0.77]; p = 0.02) but it did not appear to influence late CAV progression. High-dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time-dependent sequence during CAV development.

ARNIs: balancing "the good and the bad" of neuroendocrine response to HF.

BACKGROUND: A new class of drugs-angiotensin receptor, neprylisin inhibitors, ARNI-has shown to be prognostic superior in HFrEF to the sole inhibition of the renin-angiotensin axes with enalapril. The ultimate mechanism of action of ARNIs is unknown. AIM: We have considered that ARNI exerts a positive modulation of the neuroendocrine balance, with enhancement of the physiological diuresis and dilatation due to neprylisin inhibition by sacubitril. This represents a shift in HF medical therapy always directed to counteract (with inhibitors of the renin-angiotensin system, beta blockers or inhibitors of aldosterone) the so-called "bad" neuroendocrine response. Development of ARNI, on the contrary, has led to consider the neuroendocrine response to HFrEF from a different angle, which is to say that the activation is not always deleterious, but it could also be beneficial. This concept is highlighted by the enhancement of the activity of atrial natriuretic peptide, induced by sacubitril/valsartan in the PARADIGM trial, and found as proof from early studies on untreated patients with constrictive pericarditis. The possibility that sacubitril inhibition of neprylisin acts by enhancing substance P and gene-related calcitonin peptide is also considered, as well as the negative effect of neprylisin inhibition. CONCLUSIONS: The beneficial effects of ARNI are related, in part at least, to a positive modulation of the neuroendocrine response to the disease, resulting in an increase of physiological diuresis and dilatation.

The residual risk of cerebral embolism after carotid stenting: the complex interplay between stent coverage and aortic arch atherosclerosis.

AIM: This study investigated the fate of the stent inner surface in carotid artery stenting (CAS). In addition, the occurrence of late cerebral micro-embolism after CAS has been studied in order to identify predictors and correlate it with a possible neo-intimal layer. METHODS: A series of patients were evaluated before CAS through aortic arch trans-oesophageal echocardiography. Six months after CAS, the stent coverage by neo-intima and the possible presence of uncovered plaques were determined by high-resolution duplex scanning (5-17-Hz probe and 3D reconstruction). Possible micro-embolic signals (MESs) were evaluated through transcranial duplex scanning (30-min analysis of ipsilateral middle cerebral artery with a 1-4-Hz probe) and correlated with patients' characteristics, intimal media thickness (IMT) (>0.9mm vs. <0.9mm) and uncovered proximal plaques, type of stent (closed vs. open cells) and aortic arch complicated plaques (>4mm). Fisher's and Wilcoxon tests were used to evaluate differences across groups for categorical and continuous variables, respectively. RESULTS: In the 68 CASs examined (40 closed cells and 28 open cells), the stent was completely covered by neo-intima in 52 cases (76.4%). Complete coverage was significantly correlated with IMT<0.9mm and the absence of a proximal plaque uncovered by the stent (100% vs. 0%, p<0.001). Hypertension was an independent predictor of complete intimal coverage (p=0.002), while the stent type did not influence this process. The MESs were significantly more frequent in patients with complicated aortic arch plaques (62.5% vs. 23.8%, p<0.012), independently from all other factors. CONCLUSIONS: The extent of the stent neo-intimal formation is independent of stent type, but it is correlated with proximal plaque coverage. Six months after CAS, MESs are still possible and are not prevented by complete neo-intimal stent coverage. Complicated aortic arch atherosclerosis is an independent predictor of late MES, thus underlying its importance in cerebral ischaemia onset.

Cardiac resynchronization therapy: a comparison among left ventricular bipolar, quadripolar and active fixation leads.

We evaluated the performance of 3 different left ventricular leads (LV) for resynchronization therapy: bipolar (BL), quadripolar (QL) and active fixation leads (AFL). We enrolled 290 consecutive CRTD candidates implanted with BL (n = 136) or QL (n = 97) or AFL (n = 57). Over a minimum 10 months follow-up, we assessed: (a) composite technical endpoint (TE) (phrenic nerve stimulation at 8 V@0.4 ms, safety margin between myocardial and phrenic threshold <2V, LV dislodgement and failure to achieve the target pacing site), (b) composite clinical endpoint (CE) (death, hospitalization for heart failure, heart transplantation, lead extraction for infection), (c) reverse remodeling (RR) (reduction of end systolic volume >15%). Baseline characteristics of the 3 groups were similar. At follow-up the incidence of TE was 36.3%, 14.3% and 19.9% in BL, AFL and QL, respectively (p < 0.01). Moreover, the incidence of RR was 56%, 64% and 68% in BL, AFL and QL respectively (p = 0.02). There were no significant differences in CE (p = 0.380). On a multivariable analysis, "non-BL leads" was the single predictor of an improved clinical outcome. QL and AFL are superior to conventional BL by enhancing pacing of the target site: AFL through prevention of lead dislodgement while QL through improved management of phrenic nerve stimulation.

Infective endocarditis in hypertrophic cardiomyopathy: prevalence, incidence, and indications for antibiotic prophylaxis.

BACKGROUND: The literature on infective endocarditis in hypertrophic cardiomyopathy (HCM) is virtually confined to case reports. Consequently, the risk of endocarditis in HCM remains undefined. METHODS AND RESULTS: We assessed the occurrence of endocarditis in 810 HCM patients evaluated between 1970 and 1997. Endocarditis was diagnosed in 10 patients, 2 of whom were excluded from analysis of prevalence and incidence because they were referred for acute endocarditis. At first evaluation, echocardiographic features consistent with prior endocarditis were identified in 3 of 808 patients, a prevalence of 3.7 per 1000 patients (95% CI, 0.8 to 11). Of 681 patients who were followed, 5 developed endocarditis, an incidence of 1.4 per 1000 person-years (95% CI, 0.5 to 3.2); outflow obstruction was present in each of these 5 patients and was associated with the risk of endocarditis (P=0.006). In the 224 obstructive patients, incidence of endocarditis was 3.8 per 1000 person-years (95% CI, 1.6 to 8.9) and probability of endocarditis 4. 3% at 10 years. Left atrial size was also associated with the risk of endocarditis (P=0.007). In patients with both obstruction and atrial dilatation (>/=50 mm), incidence of endocarditis increased to 9.2 per 1000 person-years (95% CI, 2.5 to 23.5). Analysis of all 10 patients with endocarditis identified outflow obstruction in each and atrial dilatation in 7. CONCLUSIONS: Endocarditis in HCM is virtually confined to patients with outflow obstruction and is more common in those with both obstruction and atrial dilatation. These results indicate that antibiotic prophylaxis is required only in patients with obstructive HCM.

Usefulness of transesophageal echocardiographic monitoring to improve the outcome of stent-graft treatment of thoracic aortic aneurysms.

The stent-graft procedure is becoming an alternative to surgery for treatment of many diseases of the descending thoracic aorta. This study evaluated the role of transesophageal echocardiography (TEE), used in combination with fluoroscopy and angiography, in monitoring the outcome of stent-graft placement. Twenty-two consecutive patients were submitted to stent-graft positioning in the descending aorta for various pathologies (7 patients had type B aortic dissections, 6 had thoracic aneurysms, 2 had thoraco-abdominal aneurysms, and 7 had post-traumatic aortic aneurysms). Before stent-graft deployment, TEE changed the proximal site of stent positioning initially identified by angiography in 33% of patients (5 of 15) with aortic aneurysms because of calcifications or atheromas that could interfere with stent adhesion to the aortic wall and that were not seen on angiography. In 28% of patients (2 of 7) with aortic dissection, TEE showed the guidewire in the false lumen, allowing an immediate repositioning. After stent-graft deployment, color Doppler TEE showed a perigraft leak in 7 patients, whereas angiography detected a perigraft leak in only 2 patients (p = 0.02). In 4 of these patients, further balloon expansions resulted in resolution of the leak. In the remaining 3 patients, additional stent-graft positioning was necessary. Considering the total patient cohort, TEE yielded relevant information, resulting in procedure changes in 59% (13 of 22). In conclusion, TEE provided additional information with respect to angiography in all phases of stent-graft treatment, improving immediate outcome and reducing complications.

Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF Registry).

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Primary endoleakage in endovascular treatment of the thoracic aorta: importance of intraoperative transesophageal echocardiography.

OBJECTIVES: Endovascular treatment of the thoracic aorta has developed as an efficacious alternative to open surgical repair. However, despite the high primary success rate, perigraft leakage constitutes the major concern in long-term follow-up. Endoleaks are widely reported both in abdominal and thoracic endovascular series and are usually identified by intraoperative angiography. Transesophageal echocardiography is a sensitive imaging technique in the evaluation of aortic diseases, widely used to monitor cardiac surgery. The aim of this study was to evaluate the efficacy of transesophageal echocardiography in leakage detection during endovascular stent procedures of the thoracic aorta. METHODS: Intraoperative transesophageal echocardiography was used in conjunction with angiography in 25 patients subjected to endovascular stent treatment of the descending thoracic aorta. Spiral computed tomographic scanning was performed before discharge and 3, 6, and 12 months after treatment. RESULTS: Information from transesophageal echocardiography was relevant in the selection of the landing zone in 62% of cases. In 8 patients, transesophageal echocardiography with color Doppler sonography showed a perigraft leak, 6 of which were not visible on angiography, suggesting the need for further balloon expansion or graft extension. Postoperative computed tomographic scanning in the 25 patients showed 1 endoleak, which sealed spontaneously. At 3 months, computed tomographic examination confirmed the absence of perigraft leakage in all patients. CONCLUSIONS: During implantation of a stent-graft in the descending thoracic aorta, transesophageal echocardiography provides information in addition to that provided by angiography, improving immediate and late procedural results.

Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity.

OBJECTIVE: To investigate the relationships between changes in splanchnic and systemic haemodynamics in liver cirrhosis. DESIGN AND METHODS: Abdominal and peripheral duplex-Doppler sonography and Doppler echocardiography were performed in 42 cirrhotic patients with (group A, ascitic) or without ascites (group NA, non-ascitic) and in a control group of 36 healthy volunteers. RESULTS: There were significant differences (P < 0.05 at ANOVA) between the three groups in portal vein flow velocity (controls, groups NA and A, respectively, 29.2, 21.4 and 20.0 cm/s), portal diameter (9.3, 12.2 and 12.0 mm), superior mesenteric artery (SMA) resistance index (RI) (0.889, 0.854 and 0.816), femoral artery RI (0.988, 0.974 and 0.945), mean arterial pressure (MAP) (101.4, 102.0 and 87.3 mmHg), peripheral vascular resistance (1579, 1404 and 1094 dyn/cm5/s) and cardiac index (CI) (2.91, 3.46 and 3.77 l/min/m2). Multiple regression analysis identified renal interlobular- and SMA RI (respectively, r = -0.58 and r = 0.51) in group A as the two regional vascular beds correlated to MAP. CONCLUSION: The deterioration of the cirrhotic hyperdynamic circulation in the presence of ascites and the correlation between MAP and mesenteric and renal resistances are consistent with the peripheral arterial vasodilation hypothesis. The positive correlation between MAP and SMA RI in ascitic patients shows a link between this region and the general circulation. This seems to suggest that splanchnic hyperafflux plays a part in the formation of ascites.

Left ventricular volumes in liver cirrhosis.

BACKGROUND: Patients with alcoholic cirrhosis have left ventricular dimensions similar to controls. Few data have been reported in patients with cirrhosis of viral origin. AIM: To assess left ventricular dimensions in patients with pure viral cirrhosis. PATIENTS AND METHODS: Thirty patients with virus-related cirrhosis, 23 patients with alcoholic cirrhosis and 12 healthy controls were submitted to measurement of left ventricular volumes, cardiac output, mean arterial pressure and total peripheral resistance. RESULTS: Patients with cirrhosis showed a similar increase in cardiac index and heart rate and reduction of mean arterial pressure and peripheral vascular resistance in comparison to controls, irrespective of the aetiology. Left ventricular end systolic volume index was lower (p<0.01) and ejection fraction higher (p<0.01) in virus-related cirrhotic patients [mean +/- SD, respectively 12.4+/-4.1 ml/sqm and 77.9%) in comparison both to controls (21.5+/-6.3 ml/sqm and 66.8%) and alcoholics (20.6+/-7.0 ml/sqm and 68.8%). End diastolic volume index was not significantly different between the three groups. CONCLUSIONS: Our findings indicate smaller left ventricular volumes and higher ejection fraction in pure virus-related cirrhosis than in alcoholic cirrhosis and controls. Since peripheral haemodynamics proved similar in virus- and alcohol-related cirrhosis, a subclinical alcohol cardiomyopathy may be hypothesised to account for the absence of such left ventricular pattern in alcoholic patients.

Idiopathic restrictive cardiomyopathy in the young: report of two cases.

Two cases of idiopathic restrictive cardiomyopathy in young age are reported. This rare kind of restrictive cardiomyopathy is characterized by the absence of specific histologic features of myocardial abnormalities. In both cases (aged 12 and 9 years at diagnosis), the clinical picture was characterized by severe and slowly progressive congestive heart failure. The electrocardiogram showed biventricular hypertrophy, right bundle branch block and pseudoinfarctional Q waves. Echocardiography revealed moderate pericardial effusion, biatrial enlargement, and normal or nearly normal biventricular dimensions and systolic function. Cardiac catheterization disclosed the typically restrictive filling pattern. Right ventricular endomyocardial biopsy demonstrated moderate interstitial fibrosis and cellular hypertrophy without any evidence of infiltrative or storage myocardial disease or endocardial pathology. One patient underwent cardiac transplantation, whereas in the other, transplantation was contraindicated because of longstanding pulmonary hypertension and liver cirrhosis. The knowledge of this rare entity may correctly orient the diagnostic process in children suspected of having restrictive myocardial disease. Heart, or even heart-lung, transplantation must be considered in cases with congestive heart failure before irreversible damage occurs in many organs.

Radionuclide evaluation of ventricular function at rest and during exercise in double inlet ventricle.

We studied ventricular volumes and ejection fraction by radionuclide angiography (equilibrium technique) in 15 patients (aged 3-48 years) with double inlet ventricle not yet submitted to corrective surgery. The end-diastolic volume (measured in nine cases) ranged from 108 to 219 ml/m2 (156 +/- 32), being lower than the normal theoretical value (right plus left ventricle) in six cases. Ejection fraction ranged from 30 to 77% (56.4 +/- 13). The value was significantly higher in the subgroup of 10 patients with a dominant left ventricle as compared to the five cases with dominant right or indeterminate ventricular morphology (63.2 +/- 8.3 versus 42.8 +/- 9, P less than 0.01). In seven of the 15 patients, measurements were obtained both at rest and during dynamic exercise in the semi-upright position. The end-diastolic and end-systolic volumes, stroke volume, ejection fraction underwent a slight non-significant reduction (from 158 +/- 29 to 147 +/- 24 ml/m2, from 58 +/- 16 to 56 +/- 24 ml/m2, from 100 +/- 27 to 90 +/- 24 ml/m2, from 64% +/- 9 to 61% +/- 13). During exercise, ventricular volumes mostly behaved as follows: slight reduction of end-systolic volume, decrease of end-diastolic volume, no increase (no change or decrease) of ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

[Interventional or conservative approaches in acute coronary syndromes]. / Approccio interventistico o conservativo nelle sindromi coronariche acute.

The past decade has witnessed a dramatic expansion in the scope of both mechanical and pharmacologic methods for treating patients with acute coronary syndromes. New device technologies, such as intracoronary stenting, more potent and more fibrin-specific thrombolytic agents, and new antithrombotic and antiplatelet drugs are now available. What is the best strategy to treat patients with acute coronary syndromes still remains a matter of debate. This article briefly reviews this topic.

[Angiotensin receptor antagonists and ACE inhibitors in heart failure: alternative or combined therapies?]. / Antagonisti recettoriali dell'angiotensina e Ace inibitori nello scompenso cardiaco: terapie alternative o di associazione?

The theoretical advantages of the angiotensin II receptors blockers (ARB) are slowly but progressively becoming a reality for patients with congestive heart failure. ARB are recommended in patients who cannot take ACE inhibitors as a plausible alternative for modulating the renin angiotensin system. After the recently published Val-HeFT trial, the addition of an ARB (valsartan) can be considered in patients who remain severely symptomatic despite optimal therapy in order to reduce hospitalization for heart failure and improve symptoms particularly if the patients cannot tolerates beta-blockers. Among patients with type 2 diabetes and no clinical signs of congestive heart failure ARB (losartan) are able to reduce the probability of developing congestive heart failure.

[Critical analysis of beta blockers in heart failure: certainty and incompleteness]. / Analisi critica dei trial sui betabloccanti nello scompenso cardiaco: certezze e incompletezze.

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of beta-blockers in heart failure has been the subject of debate for many years. The results of recent prospective, placebo-controlled studies of the addition of beta-blockers to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect on ventricular function, clinical status, morbidity and mortality. The importance of these trials suggests that beta-adrenergic blocker therapy can save one life out of every 35 patients treated with mild-to-moderate heart failure. These major trials have used one of four beta-blockers (metoprolol, bisoprolol, carvedilol, or bucindolol) in varying study designs with different patient populations. Beta-blockers improve function of the failing left ventricle, prevent or reverse progressive left ventricular dilation, chamber sphericity, and hypertrophy, and consequently have a positive impact on cardiac remodeling. Beta-blockers also reduce heart rate and left ventricular wall stress, leading to reduced myocardial oxygen consumption, a clear benefit to the failing heart. Moreover, beta-blockers can improve the intrinsic contractile function of cardiomyocytes and have been shown to improve myocardial energetics in heart failure, possibly through desirable changes in substrate utilization. Many important clinical questions still remain unanswered. These questions include whether beta-blockers are of benefit in patients with severe NYHA functional class (IIIB-IV), in patients with asymptomatic left ventricular dysfunction, in the extreme elderly, in patients with diabetes mellitus and renal impairment. Furthermore, it is not clear whether beta-blockade by itself is the real mechanism of clinical benefit. Although certain effects of beta-blockers may be considered class effects, it is not yet clear whether there are differences between beta 1-selective antagonists and nonselective agents. Major studies are currently being undertaken to address the above questions.

[Myocardial involvement in rhabdomyolysis caused by acute heroin intoxication]. / Interessamento miocardico in corso di rabdomiolisi da intossicazione acuta da eroina.

It is well known that heroin overdose may cause rhabdomyolysis. Sometimes a myocardial involvement complicates its course. We report a case of heroin intoxication followed by rhabdomyolysis associated with myocardial injury, with symptoms, laboratory findings, ECG and echocardiography features of non-Q wave infarction. However, a 201 Tl myocardial scintigraphy, performed after patient discharging, did not show any abnormality. We think that heroin has a direct myotoxic effect on both myocardium and skeletal muscle. Yet we cannot exclude that hypoxia, acidosis, vasoconstrictive substances released by muscle necrosis, or hypersensitivity reactions associated with heroin or some of its adulterants are involved in myocardial injury.

C-reactive protein and embolization during carotid artery stenting. A serological and morphological study.

INTRODUCTION: High-sensitivity C-Reactive Protein (hsCRP) levels are correlated with vulnerable carotid plaques, although their impact on the outcome of carotid revascularization is unknown. The aim of our study was to investigate the correlation between hsCRP and embolization during carotid artery stenting (CAS). METHODS: Patients with symptomatic carotid stenosis were submitted to CAS with distal protection filters. Serum hsCRP was analysed prior to CAS and patients were divided into two groups: Class I, patients presenting hsCRP < 5 mg/l and, Class II, patients presenting hsCRP≥5 mg/l. Plaques were categorised by ultrasound grey scale measurement as homogenous and dishomogenous. Afterwards CAS filters were analyzed microscopically and ultrastructurally to determine the type and the amount of debris present, based on percentage of surface involvement (SI) and pore occluded (PO) by embolic material. RESULTS: Fourteen patients underwent uneventful CAS, with a mean hsCRP of 11.5±18.4 mg/l. Eight patients were in Class I and six in Class II. All filters had microscopic debris. SI was 25.4% in Class I and 33.3% in Class II (p=ns), PO 22.9% and 33.3% respectively (p=0.049). Patients in Class II who also had a dishomogenous plaque showed greater SI and PO compared with patients in Class I with homogenous plaque (35.0% vs. 21.8% and 40.4% vs. 22.7% respectively, p<0.05). Microscopically embolic material was identified as atherosclerotic plaque fragments and platelet aggregates and was similar in both groups. DISCUSSION: High hsCRP levels are associated with significantly greater embolization during CAS in symptomatic patients, particularly in dishomogenous plaque. Although these results need further investigation due to the limited number of enrolled patients, this study suggests that CAS may not be indicated as a method of carotid revascularization in this setting.