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To investigate associations between gender and myocardial involvement in systemic amyloidosis, we reviewed all patients presenting between 1994 and September 2006 in our institutional network (100 AL and 98 familial transthyretin-related amyloidosis (ATTR) patients, plus 12 elderly men with senile systemic amyloidosis). We focused on echocardiographic descriptors of myocardial involvement (height-indexed mean left ventricular (LV) wall thickness, LV mass index), and baseline LV function. Among familial ATTR patients, female prevalence was lower within the highest tertile of either echocardiographic indicator of myocardial involvement. Gender was independently associated with height-indexed mean LV wall thickness (as were gene mutations). Female prevalence appeared rather similar across the different neurological stages. Within the subgroup of familial ATTR patients with amyloidotic cardiomyopathy, women tended to display a considerably less severe morphological and functional echocardiographic profile. We explored the possible role of female sex hormones by considering menopausal status: women in the highest tertile of mean LV wall thickness index were more often postmenopausal than those in the other two tertiles and had a much higher ( approximately 15 years) mean age; analogous age-related associations were not observable for men. In conclusion, these findings raise the hypothesis that some biological characteristic associated with female gender protects against myocardial involvement in familial ATTR.

Background: More evidence is needed to assess the pros and cons of maintaining age-limit policies in heart transplantation (HT)., Methods: We analyzed clinical data from a heart failure management unit to investigate the impact of age on prognosis of two distinct cohorts: (i) 309 patients (median age, 57 yr; 62% male) with severe chronic heart failure (CHF) consecutively screened for HT; (ii) 336 HT recipients (median age 56 yr, 82% male)., Results: In CHF patients (screened for HT), prognosis was conditioned by the underlying severity of cardiac disease (i.e., New York Heart Association class III-IV, decreasing blood pressure, presence of atrial fibrillation and severe mitral regurgitation), whereas increasing age showed no sign of predicting all-cause or cardiovascular mortality (both p > or = 0.4). In HT recipients, age did not retain significance at multivariate analysis as an independent predictor (p > or = 0.14 for both all-cause and cardiovascular death), whereas ischemic etiology of pre-existing CHF did (p < or = 0.02)., Conclusions: Age did not appear to be a primary determinant of all-cause or cardiovascular mortality among potential HT candidates or eventual recipients (ischemic etiology of CHF turned out to be the major determinant of post-transplant outcome). These results support the concept that HT may be considered a treatment option in patients with more advanced age strata, particularly when affected by non-ischemic cardiomyopathy.

Heart transplantation (HT) is the sole therapeutic option for selected patients with hypertrophic cardiomyopathy (HC) and refractory heart failure. However, the results of HT have not been systematically investigated in HC. We assessed the pathophysiologic profile of HT candidates and the outcome after transplantation in 307 patients with HC consecutively evaluated at our tertiary referral center from 1987 to 2005; follow-up was 9.9+8.2 years. Outcome of recipients with HC was compared with that of 141 patients who underwent transplantation for idiopathic dilated cardiomyopathy at our center over the same period. Of 21 patients with HC who entered the transplantation list, 20 had end-stage evolution with systolic dysfunction and 1 had an extremely small left ventricular cavity with impaired filling and recurrent cardiogenic shock during paroxysmal atrial fibrillation. Of 33 study patients with HC who showed end-stage evolution during follow-up, the 23 who were included on the waiting list or died from refractory heart failure (2 patients) were significantly younger than the 10 patients who remained clinically stable (37+/-14 vs 57+/-17 years, p=0.004). Of the 21 HT candidates, 18 underwent transplantation during follow-up. In heart transplant recipients, 7-year survival rate was 94% and not different from that of the 141 patients who received transplants for idiopathic dilated cardiomyopathy (p=0.66). In conclusion, long-term outcome after HT in patients with HC is favorable and similar to that of patients with idiopathic dilated cardiomyopathy. In patients with end-stage HC, young age is associated with more rapid progression to refractory heart failure.

Background: Although left ventricular (LV) pacing has been proposed as an alternative to biventricular (BIV) pacing for heart failure (HF) patients, few comparative data are available on the electromechanical effects of these pacing modalities at mid-term follow-up., Aim: To investigate the clinical and echocardiographic effects of LV versus BIV pacing in a mid-term randomized study., Methods: After implantation of a device with LV/BIV pacing capabilities, 22 patients with chronic HF and left bundle branch block were randomized to LV or BIV pacing. Patients were assessed both preimplantation and after 3 months by clinical examination, ECG and echocardiography with pulsed tissue Doppler imaging., Results: At 3 months LV pacing improved clinical parameters, LV ejection fraction (+5%, range 5-8%, P = 0.007) and intraventricular dyssynchrony (-40 ms, range -50 to -15 ms, in septal to lateral delay, P = 0.008) to a similar extent to BIV pacing. A decrease in interventricular mechanical delay (-25 ms, range -40 to -5 ms, P = 0.008) and QRS duration (-28 ms, range -40 to -5 ms, P = 0.008) was observed in BIV, but not in LV patients., Conclusion: In this pilot evaluation, LV pacing appeared to be associated with clinical benefits similar to BIV pacing at mid-term follow-up, and this was combined with an improvement in intraventricular dyssynchrony, regardless of variations in interventricular dyssynchrony and QRS duration. Echocardiographic evaluation of intraventricular dyssynchrony seems to be an appropriate method for assessing the chronic response to LV pacing.

In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies. In clinical medicine, similar principles are used to standardise the nomenclature of disease. For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases). In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme. The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.

Background: Relatively few data are available on long-term echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay programming in cardiac resynchronization therapy (CRT). We assessed variations in optimized AV and VV delays during long-term follow-up., Methods: Thirty-seven consecutive heart failure patients received Doppler echocardiographic optimization of AV and VV delay within 48 hours from CRT device implantation, at 6 months and at 12 months (the last for the first enrolled 14 patients)., Results: After implantation, median optimized AV delay was 100 ms (range, 45 ms); VV optimization led to simultaneous biventricular activation in 4 patients, left ventricular preactivation in 17 patients and right ventricular preactivation in 16 patients. At 12 months median AV delay decreased to 85 ms (23 ms) (P < 0.05 vs. baseline). With respect to previous assessment, VV delay variations > or =40 ms were observed in 41% of the patients at 6 months and in 57% of the tested patients at 12 months. A nonconcordance (by Kappa test) of optimized VV delays was found between each new assessment and the previous one. VV delay optimization was associated with significant (P < 0.001) increases in aortic velocity time integral both at baseline and during follow-up., Conclusions: Echocardiographic optimization of AV and VV delay is associated with broad intraindividual variability during follow-up. A new assessment of optimized VV delays during long-term follow-up reveals a nonconcordance with previous values and provides increases in forward stroke volume.

We investigated frequency/characteristics of acute coronary syndrome-like (ACS-like) electrocardiographic (ECG) profiles among patients with a final diagnosis of acute aortic syndrome (AAS), and explored pathophysiologic determinants and prognostic relevance within each Stanford subtype. We blindly reviewed presentation electrocardiograms of 233 consecutive patients with final diagnosis of AAS (164 Stanford type A) at a regional treatment center. Prevalence of ACS-like ECG findings was 27% (type A, 26%, type B, 29%); most were non-ST-elevation myocardial infarction-like. Patients with ACS-like ECG findings more often had coronary ostia involvement (p=0.002), pleural effusion (p=0.02), significant aortic regurgitation (p=0.01), and troponin positivity (p=0.001). ACS-like ECG profile in type A disease was independently associated with coronary ostia involvement (odds ratio [OR] 5.27, 95% confidence interval [CI] 1.75 to 15.88). ACS-like ECG profile predicted in-hospital mortality (OR 2.90, 95% CI 1.24 to 6.12), as did age (each incremental 10-year: OR 1.59, 95% CI 1.14 to 2.22), and syncope at presentation (OR 2.90, 95% CI 1.16 to 7.24). In conclusion, about 25% of our AAS patients (in either Stanford subtype) presented ACS-like ECG patterns-often with non-ST-elevation myocardial infarction characteristics-which could cause misdiagnosis. ACS-like ECG profile was associated with more complicated disease, and in type A disease was a strong independent predictor of in-hospital mortality.

The aim of the present study was to investigate outcomes of implantable cardioverter-defibrillator (ICD) treatment in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We reviewed baseline/follow-up data of 15 consecutive ARVC patients (mean age 55 +/- 15 years) and 30 randomly drawn patients with coronary artery disease (CAD) (mean age 60 +/- 10 years) with matching durations of follow-up (all implanted with ICDs for primary/secondary prevention of sudden death). At implant, appropriate placement of the RV lead was more difficult in ARVC patients. During follow-up (median 41 months), appropriate interventions for any ventricular tachyarrhythmias occurred in 8 (53%) ARVC patients and 17 (57%) CAD patients, but the occurrence of high rate (>240 beats/min) ventricular tachyarrhythmias was higher in ARVC patients. Inappropriate ICD interventions occurred in 5 (33%) ARVC patients and 10 (33%) CAD patients. Lead-related adverse events requiring surgical revision occurred in 7 (47%) ARVC patients as compared with 4 (13%) CAD patients (P = 0.0004). While ICD implantation is highly effective for prevention of sudden death in ARVC, it does carry elevated burdens of long-term lead-related adverse events. These findings underline the need of careful follow-up in ARVC aimed at early recognition of complications that can impair ICD function.

Sudden cardiac death (SCD) is the most common cause of death and often occurs in low-risk patients. Present prevention strategies, mainly confined to high-risk subjects (proposed implantable cardioverter defibrillators recipients), have a limited effect on SCD burden in the general population. A relatively unexplored strategy for extending SCD prevention could imply targeting the early (upstream) processes of the complex cascade leading to SCD by non-antiarrhythmic drugs (i.e., beta-blockers, aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor-blocker agents, statins and omega-3 fatty acids). In this innovative pharmacological perspective, agents with upstream effects may also be used in high-risk patients in association with a strictly downstream intervention, such as the implantable cardioverter defibrillator, in an attempt to obtain an additive/synergetic effect.

Background: Isolated left ventricular non-compaction is the result of incomplete myocardial morphogenesis, leading to persistence of the embryonic myocardium. The condition is recognized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricle. Whether these intertrabecular recesses are a favorable substrate for ventricular arrhythmias is unclear. Some reports have found that the fatal ventricular arrhythmias may occur in approximately half of the patients. In this report we investigated about this association., Methods and Results: In total we evaluated a continuous series of 238 patients affected by non-compaction. Periodic Holter monitoring was performed every 6 months for 4 years. Only 11 patients had documented ventricular tachycardia, which was sustained in two cases and non-sustained in nine. In no cases we observed ventricular fibrillation., Conclusions: Non-compaction alone does not seem to be a risk factor for malignant ventricular arrhythmias.

This viewpoint article discusses the potential for incorporation of atrial defibrillation capabilities in modern multi-chamber devices. In the late 1990s, the possibility of using shock-only therapy to treat selected patients with recurrent atrial fibrillation (AF) was explored in the context of the stand-alone atrial defibrillator. The failure of this strategy can be attributed to the technical limitations of the stand-alone device, low tolerance of atrial shocks, difficulties in patient selection, a lack of predictive knowledge about the evolution of AF, and, last but not least, commercial considerations. An open question is how atrial defibrillation capability may now assume a specific new role in devices implanted for sudden death prevention or cardiac resynchronization. For patients who already have indications for implantable devices, device-based atrial defibrillation appears attractive as a "backup" option for managing AF when preventive pharmacological/electrical measures fail. This and several other personalized hybrid therapeutic approaches await exploration, though assessment of their efficacy is methodologically challenging. Achievement of acceptance by patients is an essential premise for any updated atrial defibrillation strategy. Strategies that are being investigated to improve patient tolerance include waveform shaping, pharmacologic modulation of pain, and patient-activated defibrillation (patients might also perceive the problem of discomfort somewhat differently in the context of a backup therapy). The economic impact of implementing atrial defibrillation features in available devices is progressively decreasing, and financial feasibility need not be a major issue. Future studies should examine clinically relevant outcomes and not be limited (as occurred with stand-alone defibrillators) to technical or other soft endpoints.

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.

Purpose: Non-invasive evaluation of coronary artery disease (CAD) in patients with left bundle branch block (LBBB) has limitations inherent to different tests, and the relative merits of these tests are unclear. This meta-analysis assessed the accuracy of the frequently used non-invasive techniques, including exercise electrocardiography (ECG), myocardial perfusion imaging (MPI) and stress echocardiography (SE), for detection of CAD and prediction of cardiac events in patients with LBBB., Methods: A review was conducted of all reports on detection of CAD and prediction of cardiac events in patients with LBBB (published between January 1970 and December 2004), and revealed 55 diagnostic and nine prognostic reports with sufficient details to calculate test accuracy. Weighted (by sample size) sensitivity and specificity were calculated. Summary relative risk ratios (95% confidence intervals) were calculated., Results: Overall sensitivity was higher for exercise ECG and (quantitatively analysed) MPI than for SE (83.4% and 88.5% versus 74.6% respectively, p<0.0001). SE had a higher specificity (88.7%) than MPI (41.2%) and exercise ECG (60.1%) (p<0.0001). Based on analysis of eight reports, the relative risk of cardiac death or myocardial infarction in patients with an abnormal SE and MPI was elevated more than sevenfold, but it did not differ by imaging modality (p=0.9)., Conclusion: Meta-analysis of non-invasive CAD assessment in LBBB patients revealed that exercise ECG and MPI had the highest sensitivity, while SE had the highest specificity. The prognostic accuracy of MPI and SE appeared similar.

Considering the relatively short history of cardiac resynchronization therapy (CRT), the amount of available evidence of efficacy is impressive, and effectiveness studies are now required. Transfer of our experimentally gained knowledge into the real world raises issues that call for synchronization among the many specialists involved in chronic heart failure (CHF) management and CRT decision making. From an economic perspective, the demonstrated ability of CRT to reduce hospitalizations could help ease the burden on health systems derived from the growing incidence of CHF. Recent American College of Cardiology/American Heart Association guideline revisions should encourage a synchronized approach to rational deployment of CRT in selected patients. Nevertheless, current QRS criteria for CRT candidacy do not directly address the key issue of identification of patients with a pacing-correctable mechanical dyssynchrony (and in clinical trials, 25-30% of implanted patients did not respond to CRT). Echocardiography could become an important adjunct (or even an alternative) to QRS duration for patient selection; routine implementation would require use of straightforward, reproducible measurements, possibly obtainable on standard equipment. Echocardiography could also help optimize site location, although this would not eliminate lead placement problems. A series of issues remain open for investigation, including the potential of CRT in patients with atrial fibrillation, impact of devices with defibrillation ability, effects of electrical/pharmacological tailoring, need for confirmation that efficacy of CRT extends into the long term and possible use of CRT in mild CHF. Interdisciplinary synchronization in the various phases of CRT (screening, proposing, implementing, optimizing and monitoring) should eventually help develop a coordinated system for patient referral.

Although mainly described in the context of dilated and hypokinetic left ventricles, it is unclear whether isolated ventricular noncompaction (IVNC) is a distinct cardiomyopathy, a subtype of dilated cardiomyopathy, or a morphogenetic disorder. To investigate the spectrum of cardiomyopathies associated with IVNC, children and adults with stringent echocardiographic diagnoses of IVNC were reviewed. Seventy-three patients (12 children aged <15 years) seen since 1994 satisfied stringent echocardiographic criteria for IVNC. Sixty-five patients (89%; 11 children) had dilated cardiomyopathy, 2 adults had clear-cut hypertrophic cardiomyopathy, 1 adult had restrictive cardiomyopathy (to the investigators' knowledge, the first reported example of this particular association), and 5 patients (1 child) had normal left ventricular morphology and function. In conclusion, knowledge that IVNC can co-exist with restrictive and hypertrophic cardiomyopathy (in addition to the dilated form) supports the concept that IVNC is a morphologic trait rather than a distinct cardiomyopathy. This knowledge should be taken into account during echocardiographic examination and encourage the use of contrast echocardiography (and magnetic resonance) and could also orient molecular biology studies.

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8-120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart-liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.

Despite interest in neurohormonal activation as a determinant of prognosis in chronic heart failure (CHF) and as a target for pharmacological treatments, data are lacking on the time-related effects of electrical cardiac resynchronization therapy (CRT) on a broad spectrum of neurohormones and cytokines. The aim of this study was to assess time-courses and extents of changes within the neurohormonal profile of CHF patients treated with CRT. We performed a prospective follow-up study in 32 patients with NYHA class III-IV CHF to investigate the effects of CRT on a broad panel of neurohormones proposed for characterization of CHF patients. Levels of atrial and brain natriuretic peptides (ANP, BNP), epinephrine, norepinephrine, aldosterone, plasma renin activity, IL-6, TNF, soluble receptors sTNFR1 and 2, and chromogranin A were assessed before implantation and after 3 months of CRT; when feasible, measurements were also performed at 1 week, 1 month and 12 months (clinical evaluation, echocardiography and ECG were also performed at each time-point). The results showed that at 3 months improvement in NYHA class and echographically assessed left ventricular (LV) reverse structural remodeling were accompanied by significant reductions versus baseline in ANP and BNP, but not in other neurohormones. Moreover a baseline ANP concentration < or = 150 pg/ml was a good predictor of response to CRT in terms of NYHA class reduction and reverse LV remodeling. In conclusion 3 months of CRT significantly reduce natriuretic peptides concentrations, while values of other neurohormones and inflammatory cytokines are relatively unvaried. A baseline ANP concentration < or = 150 pg/ml might be a clinically useful predictor of medium-term response to CRT.

Background: In patients with severe heart failure, sinus rhythm and wide QRS complex biventricular (BiV) pacing leads to clinical and haemodynamic improvement, but the immediate reversibility of these changes is not known., Methods: We assessed the acute and medium-term (3-month) haemodynamic effects of BiV pacing and of switching to other pacing modalities in 21 patients with severe heart failure, sinus rhythm and QRS>or=130 ms. Haemodynamic studies were performed: 1) at the time of implantation of a BiV pacing device, during AAI pacing, atrial synchronous right ventricular (RV) pacing, atrial synchronous left ventricular (LV) pacing and atrial synchronous BiV pacing (all at 100 bpm); 2) after 3 months of continuous BiV pacing--with evaluations being made by switching to RV and the other pacing modalities., Results: At both the acute and medium-term evaluations, BiV pacing provided the greatest improvement in cardiac index. Switching from BiV to RV pacing led to a more marked decrease in the cardiac index at 3 months. No strict correlation was evident between acute and medium-term effects of BiV pacing on cardiac index., Conclusion: Cardiac resynchronization by BiV pacing provides acute/medium-term improvements in cardiac index. Sudden, medium-term failure of LV stimulation can lead to an even more pronounced haemodynamic derangement than that inducible by RV pacing at baseline. Acute haemodynamic evaluations do not seem to provide a powerful way for identifying medium-term responders.

The pathophysiologic mechanisms of left ventricular (LV) dysfunction in isolated ventricular noncompaction (IVNC) remain unclear. Evaluating global and segmental systolic LV function in 65 patients with IVNC, this study found that normal wall motion was more common in noncompacted than in compacted segments. The number of noncompacted segments per patient correlated positively with the LV ejection fraction and negatively with LV end-diastolic volume index. These paradoxical findings support the concept that noncompaction represents a marker of a more generalized (cardio)myopathy rather than the direct pathophysiologic substrate of this still little-understood disease.

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.

Background: National registries are advocated as instrumental to the solution of rarity-related problems for patients with hypertrophic cardiomyopathy (HCM), including limited access to advanced treatment options. Thus, an Italian Registry for HCM was created to assess the clinical profile and the level of care nationwide of patients with HCM., Methods: Cardiology centers over the national territory were recruited to provide clinical data of all patients with HCM ever seen at each institution. The enrollment period was from May 2000 to May 2002., Results: The registry enrolled 1677 patients from 40 institutions. Most (69%) were followed at referral centers, whereas 31% were from community centers with intermediate-low patient flow. Patients diagnosed after routine medical examinations or familial screenings were 39%. Most patients were male (62%), in their fourth to sixth decade of life, and in New York Heart Association class I to II (89%); 24% had resting left ventricular obstruction and 18% had atrial fibrillation. During a 9.7-year average follow-up, cardiovascular mortality was 1%/y, mostly because of heart failure, with no significant change over the last 3 decades; sudden death was less common (0.4%/y). Only 4% of patients received a defibrillator; 14% of the 401 patients with LV outflow obstruction underwent invasive relief of obstruction; and <1% were offered genetic analyses or counseling., Conclusions: The Italian Registry represents the first comprehensive attempt to evaluate the clinical impact and management of HCM at a national level. Findings underscore the role of screening strategies for an early diagnosis and suggest limited use of the advanced therapeutic options for HCM.

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Efficacy, safety, and tolerability of perindopril are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUROPA, PROGRESS, and PREAMI have shown that treatment with perindopril reduces morbidity and mortality and prevents cardiovascular disease in a large range of patients with vascular diseases, whether or not they are hypertensive. Thus, the outcomes of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the clinical evidence on efficacy and tolerability that has been gathered, perindopril should be considered a first-line therapeutic agent in hypertension, heart failure and acute myocardial infarction and a tool of secondary prevention of coronary artery disease.

Objectives: This study sought to investigate the incidence, risk factors, and prognosis of dilated-hypokinetic evolution in a large cohort of patients with hypertrophic cardiomyopathy (HCM) followed up at a cardiology center serving both the pediatric and the adult population., Background: The available data on this evolution of HCM mainly regards prevalence (rather than incidence) in adults, with very little being known about the pediatric population., Methods: A total of 222 consecutive HCM patients (65% men, 19% < or =18 years old) were prospectively evaluated for a mean follow-up of 11 +/- 9 years., Results: A diagnosis of dilated-hypokinetic HCM was made in 12 patients at first evaluation (11 without previous septal myectomy surgery; prevalence, 4.9%). Twelve of the 210 patients with classic HCM at first evaluation underwent dilated-hypokinetic evolution (incidence, 5.3/1,000 patient-years). Patients with prevalent/incident dilated-hypokinetic evolution were younger at first evaluation (32 +/- 14 years vs. 41 +/- 21 years, p = 0.04) and more often had a family history of HCM (61% vs. 26%, p = 0.002) or sudden death (43% vs. 19%, p = 0.01) with respect to patients who maintained classic HCM. Moreover, they showed greater interventricular septum (23 +/- 3 mm vs. 19 +/- 6 mm, p = 0.004) and posterior wall (15 +/- 3 mm vs. 13 +/- 4 mm, p = 0.006) thickness. Cardiovascular death-free survival was lower among patients with dilated-hypokinetic HCM (p < 0.04). Cox proportional hazards regression analysis identified left ventricular wall thickness (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 1.01 to 1.14; p = 0.03) and end-diastolic diameter (HR = 1.08; 95% CI 1.04 to 1.11; p = 0.0001) as independent predictors of cardiovascular death., Conclusions: Dilated-hypokinetic evolution is rare but not exceptional in HCM. Young age at diagnosis, family history of HCM, and greater wall thickness are incremental risk factors for dilated-hypokinetic HCM, which carries an ominous prognosis.

Background: Dobutamine stress echocardiography (DSE) was shown to provide incremental prognostic information. However, its role in the prediction of mortality in elderly persons is not well defined. We assessed the value of DSE in the prediction of mortality and hard cardiac events during long-term follow-up in patients older than 65 years., Methods: We studied 1434 patients >65 years old (mean age 72 +/- 3 years) who underwent DSE for evaluation of coronary artery disease. Ischemia was defined as new or worsening wall motion abnormalities. Follow-up events were total mortality and hard cardiac events (cardiac mortality and nonfatal myocardial infarction). Multivariable Cox regression analysis was used to identify the independent predictors of follow-up events., Results: Ischemia was detected in 675 patients (47%). Five hundred six patients (35%) had a normal study, and 253 (18%) had fixed wall motion abnormalities. During a mean follow-up of 6.5 years, 532 (37%) deaths occurred, of which 249 (17%) were due to cardiac causes. A nonfatal myocardial infarction occurred in 45 patients (3%). Independent predictors of all-cause mortality in a multivariate analysis model were age (hazard ratio [HR] 1.06; 95% confidence interval [CI], 1.05-1.08), male sex (HR 1.5; 95% CI, 1.2-1.8), hypertension (HR 1.2; 95% CI, 1.1-1.4), smoking (HR 1.3; 95% CI, 1.1-1.6), diabetes (HR 1.4; 95% CI, 1.1-1.8), rest wall motion abnormalities (HR 1.07; 95% CI, 1.06-1.09), and ischemia (HR 1.3; 95% CI, 1.1-1.6). Independent predictors of hard cardiac events were age (HR 1.07; 95% CI, 1.05-1.09), male sex (HR 1.3; 95% CI, 1.1-1.7), smoking (HR 1.3; 95% CI, 1.1-1.6), diabetes (HR 1.6; 95% CI, 1.2-2.2), rest wall motion abnormalities (HR 1.13; 95% CI, 1.12-1.16), and ischemia (HR 2.1; 95% CI, 1.5-2.8)., Conclusion: DSE provides independent prognostic information to predict all-cause mortality and hard cardiac events in elderly patients.

Background: Little is known about the morphological and functional evolution of ventricular abnormalities in Loeffler endocarditis., Methods and Results: We describe 5 patients, including 3 with long-term echocardiographic follow-up, in whom apical obliteration due to fibro-thrombotic thickening of the endocardium showed favorable patterns of evolution. In one patient there was almost complete resolution of the obliterative process with consequently increased effective ventricular volume. In two patients formation of a flow-passage in the fibrocalcific apical 'floor' between the main medioventricular cavity and the apical chamber, leading to a 'double-chambered' left ventricle was observed., Conclusions: Medical therapy and appropriate anticoagulation, can induce favorable long-term ventricular remodeling in Loeffler endocarditis.

Objectives: We investigated the diagnostic accuracy of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy for differentiation of monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-related cardiac amyloidosis., Background: Differential diagnosis between TTR-related and AL amyloidosis is often complex and time-consuming., Methods: Patients under routine observation with TTR-related/AL systemic amyloidosis and echocardiographic evidence of cardiac involvement were studied with 99mTc-DPD scintigraphy., Results: Patients with cardiac involvement of TTR-related (group A; n = 15) and AL (group B; n = 10) etiology were comparable for left ventricular mass and renal function. Heart and heart/whole-body tracer retention were significantly higher (p < 0.05) in group A as compared with group B and with 10 unaffected controls. At visual scoring, cardiac 99mTc-DPD uptake was present in all group A patients and absent in all group B patients; thus, using genotyping/immunohistochemistry as the reference technique, the accuracy of 99mTc-DPD scintigraphy for distinction of TTR-related and AL etiology was 100%. Cardiac 99mTc-DPD uptake was also absent among unaffected controls. Using echocardiography as the reference standard for recognition of cardiac involvement, sensitivity and specificity of scintigraphy were both 100% for group A patients; in group B, sensitivity was 0% and specificity was 100% (accuracy, 50%). Eleven patients with myocardial 99mTc-DPD uptake underwent 99mTc-methylene diphosphonate (99mTc-MDP) scintigraphy; all patients showed a 99mTc-MDP myocardial visual score of 0., Conclusions: Etiology is a third major cause--in addition to type of organ-involved (soft-tissue/heart) and tracer type--of scintigraphic variability in cardiac amyloidosis. This is a highly relevant consideration for future studies. We conclude that 99mTc-DPD scintigraphy is a useful step in the workup of the differential diagnosis of TTR versus AL etiology in patients with documented cardiac amyloidosis.

Objectives: This study was designed to assess the functional and prognostic significance of left anterior hemiblock (LAHB) in patients with no history of myocardial infarction referred for dobutamine stress echocardiography (DSE)., Background: The significance of isolated LAHB in patients with suspected coronary artery disease (CAD) is unclear., Methods: We studied 1,187 patients with suspected CAD and no history of myocardial infarction who underwent DSE and were followed for occurrence of cardiac death., Results: Left anterior hemiblock was detected on baseline electrocardiogram in 159 patients (13%). Ischemia occurred more frequently in patients with LAHB (43% vs. 33%, p = 0.02). During a mean follow-up of 5.0 +/- 2.5 years, 125 patients (11%) died of cardiac causes. The annual cardiac death rate was 4.9% in patients with LAHB and 1.9% for patients without (p < 0.0001). Patients with both LAHB and an abnormal DSE had the highest annual cardiac death rate (6.3%). In a Cox multivariable analysis, independent predictors of cardiac death were age, smoking, history of heart failure, diabetes, and ischemia. Left anterior hemiblock was independently associated with increased risk of cardiac death among patients with normal DSE (hazard ratio 1.8, 95% confidence interval 1.1 to 3.8) and in patients with abnormal DSE (hazard ratio 1.7, 95% confidence interval 1.1 to 2.7)., Conclusions: In patients with suspected CAD referred for stress testing, LAHB is associated with increased risk of cardiac death. This risk is persistent after adjustment for major clinical data and abnormalities on the stress echocardiogram. Therefore, isolated LAHB should not be considered a benign electrocardiographic abnormality in these patients.

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.

Objectives: The aim of this study was to investigate the effects of gender on long-term prognosis of patients undergoing dobutamine stress echocardiography (DSE)., Background: Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease undergoing DSE have not been adequately studied., Methods: We studied 2,276 men and 1,105 women with known or suspected coronary artery disease who underwent DSE. Follow-up events were cardiac death and nonfatal myocardial infarction (MI)., Results: Dobutamine stress echocardiography was normal in 687 men (30%) and 483 women (44%) (p <0.0001). Ischemia on DSE was present in 1,194 men (52%) and 416 women (38%) (p <0.001). During a mean follow-up of 7 +/- 3.4 years, there were 894 (26%) deaths (442 attributed to cardiac causes) and 145 (4%) nonfatal MIs. The annual cardiac event rate was 2.5% in men and 1.2% in women with normal DSE. Independent predictors of cardiac events in patients with normal DSE using a Cox proportional hazards regression analysis were male gender (hazard ratio [HR]: 1.7 [range 1.1 to 2.8]), age (HR: 1.02 [range 1.01 to 1.04]), history of heart failure (HR: 3.4 [range 1.5 to 7.9]), previous MI (HR: 1.7 [range 1.1 to 2.8]), and diabetes (HR: 2.4 [range 1.3 to 4.5]). Independent predictors of cardiac events in patients with an abnormal DSE were age (HR: 1.03 [range 1.02 to 1.04]), history of heart failure (HR: 1.7 [range 1.3 to 2.1]), diabetes (HR: 1.4 [range 1.1 to 1.8]), heart rate at rest (HR: 2.8 [range 1.4 to 5.8]), wall motion abnormalities at rest (HR: 1.06 [range 1.04 to 1.09]), and ischemia on DSE (HR: 1.04 [range 1.02 to 1.07]). Myocardial ischemia was an independent predictor of cardiac events in both men and women., Conclusions: Dobutamine stress echocardiography provides independent prognostic information in both men and women. In patients with normal DSE, gender is independently associated with cardiac events. The outcome of patients with abnormal DSE is not related to gender, after adjusting for stress echocardiographic abnormalities.

To investigate ventricular long-axis function in cardiac amyloidosis (CA) and idiopathic restrictive cardiomyopathy (IRC), 16 patients with CA and 14 with IRC were studied. Left ventricular (LV) long-axis function was depressed in all patients with CA compared with only 36% of patients with IRC. Impairment in longitudinal function was clearly evident, even if fractional shortening and LV filling were normal. Ventricular long-axis function may be used as a sensitive marker of early systolic dysfunction. CA and IRC have quite distinct pathophysiologic profiles, raising some concerns about the appropriateness of considering them as 2 subtypes of a single nosographic entity.

Objective: Endovascular stent-graft placement is replacing traditional surgery in type B aortic dissection. Usually stent-graft implantation is performed under fluoroscopic and angiographic guidance, but this relatively new procedure is still burdened with some complications. We investigated the value of a developed algorithm based on transesophageal echocardiography (TEE) for guiding stent-graft implantation in type B aortic dissection., Methods: Forty-two patients with type B aortic dissection (chronic in 28 patients with aneurysmal dilatation of the false lumen, and acute complicated in 14 patients) underwent endovascular stent-graft reconstruction of the descending thoracic aorta. TEE was always performed after angiography. TEE-induced variations of the procedure, based on the algorithm, were compared with initial angiography-based decisions., Results: TEE was decisive for guidewire repositioning (not possible with fluoroscopy) from the false to the true lumen in 3 patients and for correct guidewire entrance in an elephant trunk prosthesis in another patient. After stent-graft implantation color Doppler TEE enabled detection of proximal peri-stent leaks in 13 patients, whereas only 6 (46%) of the 13 leaks were detectable at angiography (P = .008). Most leaks were subsequently eliminated with balloon dilation or further stent grafting. Pulsed Doppler TEE was also useful for differentiating true leaks (13 patients) from Dacron porosity (7 patients). A pulsed-Doppler velocity cutoff value of 50 cm/s enabled differentiation of Dacron porosity (characterized by slow blood flow) from true peri-stent leak (fast flow). After stent-graft implantation TEE demonstrated new intimal tears in the thoracic aorta in 7 patients, whereas only 2 of the 7 new tears were detectable at angiography (P = .024); in 6 of 7 patients the new distal tears were subsequently resolved with placement of additional stents, whereas in a patient with Marfan syndrome new proximal tears determined a type I endoleak, which could not be resolved. Overall, TEE furnished decisive information additional to angiography in determining successful procedural changes in 16 of 42 patients (38%). There were no in-hospital deaths, and pre-discharge spiral computed tomograms showed a good outcome of stent-graft implantation in 37 of 42 patients (88%), with 5 residual type I endoleaks, all previously detected with TEE but impossible to eliminate with either balloon molding or further stent implantation. All but 2 patients (95%) are currently alive at mean follow-up of 30 +/- 18 months., Conclusions: TEE algorithm is an easy and useful tool in the operating room to guide correct stent-graft positioning in type B aortic dissection.

The presence of a right bundle branch block (RBBB) is associated with increased mortality. We studied the role of dobutamine stress echocardiography for the prognostic stratification of patients with RBBB. The presence of an abnormal dobutamine stress echocardiography was the strongest predictor of cardiac events and provided incremental prognostic information to clinical and stress test data.

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.

Internal cardioversion can restore sinus rhythm with energies below 6-10 J, often without anaesthesia/sedation. We investigated its safety and short-/medium-term efficacy in patients with persistent atrial fibrillation (AF) with left ventricular dysfunction (defined as ejection fraction < or = 40%). Among 34 patients with persistent AF who agreed to receive internal cardioversion, 16 had left ventricular dysfunction and 18 did not (the groups were similar as regards age, duration of AF and pretreatment with amiodarone). Internal CV was performed delivering 3.0/3.0-ms biphasic shocks between coil catheters using a step-up protocol. Sinus rhythm was always restored. General anaesthesia (administered only when discomfort was not tolerated) was required only in 2 of the 16 (12.5%) patients with left ventricular dysfunction. The defibrillation threshold was similar in patients with and without left ventricular dysfunction (10.2+/-6.9 vs. 8.4+/-4.9 J; p=0.37). Short-term (within 72 h) AF recurrence rates in the presence and absence of left ventricular dysfunction were 19% (3/16) and 6% (1/18), respectively (p=0.51). After cardioversion, all patients received antiarrhythmic drugs (mostly amiodarone in patients with left ventricular dysfunction and class IC agents in the remainder). With mean follow-up periods of about 220 days, AF recurrence rates among patients with and without left ventricular dysfunction were 50% (8/16) and 28% (5/18), respectively (p=0.328). We conclude that even in patients with left ventricular dysfunction, internal CV is safe and effective, minimizing risks from anaesthesia. Although these patients may have a higher risk of short- or medium-term AF recurrence, 6-month maintenance of sinus rhythm is possible in about 50% of cases.

Various modalities of cardiac pacing have been proposed in the past to improve hemodynamics, either directly or indirectly. Some of these are conventional ways of cardiac stimulation, others such as biventricular or left ventricular pacing, represent dedicated pacing techniques. Left ventricular and biventricular pacing are successfully applied in those patients with congestive heart failure who have conduction disturbances (i.e. left bundle branch block) as they correct the ensuing intra- and interventricular dyssynchrony. This is the reason why these pacing modalities are described as cardiac resynchronization therapy. According to the results of a series of studies, the cardiac resynchronization therapy seems to have a favourable clinical impact in terms of quality of life, morbidity and hospitalization rate. On-going and future studies should assess the impact of resynchronization therapy on overall mortality and its cost-effectiveness profile in specific subgroups of patients. Other open issues regard (i) the convenience of using biventricular pacing as a pacing-alone therapy or in combination with ventricular defibrillation capability, especially for potential candidates to heart transplantation, and (ii) the ways to identify properly the responders to resynchronization therapy.

The possibility of using implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death in selected high-risk patients has prompted a series of prospective controlled studies. Recently, the MADIT II study highlighted the possibility of effective primary prevention of sudden death in patients with coronary artery disease selected by straightforward clinical data and without expensive screening (electrophysiological study). For patients with previous myocardial infarction and low left ventricular ejection fraction (

Since a depressed contractility has long been considered the primary defect in patients with heart failure, the use of inotropic agents has been regarded as a logical approach to treat this syndrome. Despite this conceptual framework, these drugs have not yet established themselves in the treatment of chronic heart failure and their long-term use was associated with an excessive mortality while the short-term intravenous administration in critically ill patients produced only acute hemodynamic results without a stable clinical improvement. At least four mechanisms could explain this discrepancy: their arrhythmogenicity, their direct cardiotoxic effects, the downregulation of the beta-adrenoreceptors, and the energetic cost of inotropic intervention. Moreover, in many patients with ischemic cardiomyopathy the reduction in contractility could be considered as a compensatory mechanism since hibernation is able to decrease the metabolic requirements of the heart. The contractile force of the heart can be augmented not only by an increased availability of intracellular calcium for troponin C but also by an increased sensitivity of the contractile proteins to calcium. A new class of inotropes working with this mechanism is now available and could represent a real improvement in this challenging therapeutic area.