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.

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.

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.

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.

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.

Wide spectrum of presentation and variable outcomes of isolated left ventricular non-compaction.

OBJECTIVES: To investigate diagnostic routes, echocardiographic substrates, outcomes and prognostic factors in patients with isolated ventricular non-compaction (IVNC) identified by echocardiographic laboratories with referral from specialists and primary care physicians. PATIENTS AND DESIGN: Since 1991, all patients with suspected IVNC were flagged and followed up on dedicated databases. Patients were divided into symptom-based and non-symptom-based diagnostic subgroups. RESULTS: 65 eligible patients were followed up for 6-193 months (mean 46 (SD 44). In 53 (82%) patients, IVNC was associated with variable degrees of left ventricular (LV) dilatation and hypokinesia, and in the remaining 12 (18%) LV volumes were normal. Diagnosis was symptom based in 48 (74%) and non-symptom based in 17 (26%) (familial referral in 10). The non-symptom-based subgroup was characterised by younger age, lower prevalence of ECG abnormalities, better systolic function and lower left atrial size, whereas the extent of non-compaction was not different. No major cardiovascular events occurred in the non-symptom-based group, whereas 15 of 48 (31%) symptomatically diagnosed patients experienced cardiovascular death or heart transplantation (p = 0.01, Kaplan-Meier analysis). Independent predictors of cardiovascular death or heart transplantation were New York Heart Association class III-IV, sustained ventricular arrhythmias and left atrial size. CONCLUSIONS: IVNC is associated with a broad spectrum of clinical and pathophysiological findings, and the overall natural history and prognosis may be better than previously thought. Adult patients with incidental or familial discovery of IVNC have an encouraging outlook, whereas those who have symptoms of heart failure, a history of sustained ventricular tachycardia or an enlarged left atrium have an unstable course and more severe prognosis.

Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance.

OBJECTIVE: To investigate the prevalence and distribution of gadolinium (Gd) enhancement at cardiac magnetic resonance (CMR) imaging in patients with cardiac amyloidosis (CA) and to look for associations with clinical, morphological, and functional features. PATIENTS AND DESIGN: 21 patients with definitely diagnosed CA (nine with immunoglobulin light chain amyloidosis and 12 transthyretin related) underwent Gd-CMR. RESULTS: Gd enhancement was detected in 16 of 21 (76%) patients. Sixty six of 357 (18%) segments were enhanced, more often at the mid ventricular level. Transmural extension of enhancement within each patient significantly correlated with left ventricular (LV) end systolic volume (r = 0.58). The number of enhanced segments correlated with LV end diastolic volume (r = 0.76), end systolic volume (r = 0.6), and left atrial size (r = 0.56). Segments with > 50% extensive transmural enhancement more often were severely hypokinetic or akinetic (p = 0.001). Patients with > 2 enhanced segments had significantly lower 12 lead QRS voltage and Sokolow-Lyon index. No relation was apparent with any other clinical, morphological, functional, or histological characteristics. CONCLUSION: Gd enhancement is common but not universally present in CA, probably due to expansion of infiltrated interstitium. The segmental and transmural distribution of the enhancement is highly variable, and mid-ventricular regions are more often involved. Enhancement appears to be associated with impaired segmental and global contractility and a larger atrium.

Long term outcome in patients with silent versus symptomatic ischaemia during dobutamine stress echocardiography.

OBJECTIVES: To compare the long term prognosis of patients having silent versus symptomatic ischaemia during dobutamine stress echocardiography (DSE). DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 931 patients who experienced stress induced myocardial ischaemia during DSE. RESULTS: Silent ischaemia was present in 643 of 931 patients (69%). The number of dysfunctional segments at rest (mean (SD) 9.6 (5.1) v 8.8 (5.0), p = 0.1) and of ischaemic segments (3.5 (2.2) v 3.8 (2.1), p = 0.2) was comparable in both groups. During a mean (SD) follow up of 5.5 (3.3) years, there were 169 (18%) cardiac deaths and 86 (9%) non-fatal infarctions. Multivariable Cox regression analysis showed age (hazard ratio (HR) 1.1, 95% confidence interval (CI) 1.02 to 1.05), previous myocardial infarction (HR 1.4, 95% CI 1.1 to 2.0), and number of ischaemic segments during the test (HR 2.0, 95% CI 1.0 to 3.7) as independent predictors of cardiac death and myocardial infarction. For every additional ischaemic segment there was a twofold increment in risk of late cardiac events. The annual cardiac death or myocardial infarction rate was 3.0% in patients with symptomatic ischaemia and 4.6% in patients with silent ischaemia (p < 0.01). Silent induced ischaemia was an independent predictor of cardiac death and myocardial infarction (HR 1.7, 95% CI 1.1 to 2.0). During follow up symptomatic patients were treated more often with cardioprotective therapy (p < 0.01) and coronary revascularisation (145 of 288 (50%) v 174 of 643 (27%), p < 0.001). CONCLUSIONS: Patients with silent ischaemia had a similar extent of myocardial ischaemia during DSE compared to patients with symptomatic ischaemia but received less cardioprotective treatment and coronary revascularisation and experienced a higher cardiac event rate.

Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation.

AIM: The spectrum of histological alterations, namely atrial amyloidosis, in the right and left atria of patients with chronic persistent atrial fibrillation (AF) and rheumatic heart disease is not completely known. METHODS AND RESULTS: One hundred and twenty-eight atrial appendages (66 left and 62 right), obtained from 72 patients with rheumatic valve disease and chronic AF undergoing cardiac surgery for valve replacement or repair and AF treatment were histologically evaluated for the presence of amyloid deposits. One hundred and four specimens of left and right auricles from 52 patients in sinus rhythm with severe chronic heart failure undergoing heart transplant were also analyzed (controls). Amyloid was found in 33 (46%) valvular patients with chronic persistent AF and in 6 (12%) controls. Amyloid was related to the presence and duration of AF, was more frequently found in left atrial samples and was independent of age. On stepwise logistic regression analysis, AF duration and female gender were independently related to amyloid deposition. CONCLUSIONS: Patients with long-standing AF and rheumatic heart disease have a very high prevalence of atrial amyloidosis. Amyloid deposition is more frequent in left than in right atrial appendage and correlates with AF duration and female gender. Amyloid deposition could constitute an additional histological feature in the structural remodeling of atria during long-standing AF, at least in rheumatic valve disease. Persistence of AF might play a pivotal role in promoting amyloid deposition.

[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.

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.

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.

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.

[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.