The ventricular ectopic QRS interval (VEQSI): Diagnosis of arrhythmogenic right ventricular cardiomyopathy in patients with incomplete disease expression.

BACKGROUND: The ventricular ectopic QRS interval (VEQSI) has been shown to identify structural heart disease and predict mortality. In arrhythmogenic right ventricular cardiomyopathy (ARVC), early diagnosis is difficult using current methods, and life-threatening arrhythmias are common and difficult to predict. OBJECTIVE: The purpose of this study was to assess the utility of ventricular ectopic indices including VEQSI in ARVC diagnosis. METHODS: We studied 70 patients with ARVC [30 with definite disease (age 47 ± 12 years; 60% male), 40 with incomplete disease expression (age 44 ± 18 years; 44% male)], 116 healthy controls (age 40 ± 15 years; 56% male), and 26 patients with normal heart right ventricular outflow tract (RVOT) ectopy (age 46 ± 17 years; 27% male). The duration of the broadest ventricular ectopic beat during 12-lead Holter monitoring was recorded as VEQSI max. RESULTS: VEQSI max was associated with age and gender, but not with conducted QRS duration. Adjusted VEQSI max was greater in ARVC patients than in control groups. In healthy males (44.5 years), estimated VEQSI max was 163 ms (95% confidence interval [CI] 159-167 ms); in definite ARVC 212 ms (95% CI 206-217 ms); in incompletely expressed ARVC 204 ms (95% CI 199-210 ms); and in normal heart RVOT ectopy 171 ms (95% CI 165-178 ms). VEQSI max >180 ms had 98% sensitivity and specificity for diagnosis of ARVC (area under the curve 0.99, 95% CI 0.980-0.998). In our incompletely expressed ARVC patients, VEQSI max >180 ms identified 88% as affected. CONCLUSION: VEQSI max distinguishes ARVC patients, including those with incomplete disease expression, from healthy controls and patients with normal heart RVOT ectopy.

Efficacy of weekly docetaxel in locally advanced cardiac angiosarcoma.

BACKGROUND: Primary cardiac angiosarcoma is extremely aggressive; however, it is often misdiagnosed because of its rarity. For locally advanced tumors, doxorubicin-based chemotherapy regimens are the standard of treatment, even if the gain in term of progression-free survival is limited and is no longer than 5 months. CASE PRESENTATION: We report the case of a Caucasian 23-year-old man with locally advanced cardiac angiosarcoma who underwent radical surgical resection after a prolonged response to weekly docetaxel and complementary radiotherapy. CONCLUSION: Combined treatment with weekly docetaxel and radiotherapy may be a valid alternative for the treatment of locally advanced cardiac angiosarcoma; the combination can lead to radical surgical resections, avoiding the cumulative cardiotoxicity of antracycline-based regimens.

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: long-term follow-up of the SHIRAKISS randomized, prospective study.

BACKGROUND: Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. METHODS: Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. RESULTS: Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. CONCLUSIONS: Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Safety and efficacy of early aggressive versus cholesterol-driven lipid-lowering strategies in heart transplantation: a pilot, randomized, intravascular ultrasound study.

BACKGROUND: Statins are recommended in heart transplantation regardless of lipid levels. However, it remains unknown whether dosing should be maximized or adjusted toward a pre-defined cholesterol threshold. METHODS: This pilot, randomized, open-label study compares an early maximal dose of fluvastatin (80 mg/day) with a strategy based on 20 mg/day subsequently titrated to target low-density lipoproteins (LDL) <100 mg/dl. Efficacy outcomes consisted of achieving an LDL level of <100 mg/dl at 12 months after transplant, and change in intracoronary ultrasound parameters. RESULTS: Fifty-two patients were randomized. Overall safety, and efficacy in achieving LDL targets (13 [50%] vs 14 [54%]; p = 0.8) were comparable between study arms, but 17 (65%) patients needed a dose increase in the titrated-dosing arm. Early LDL levels and average LDL burden were lower in the maximal-dosing arm (p < 0.05). Few patients developed an increase in maximal intimal thickness of >0.5 mm, with numerical prevalence in the titrated-dosing arm (3 [12.5%] vs 1 [5%]; p = 0.3). Intimal volume increased in the titrated-dosing (p < 0.01) but not in the maximal-dosing arm (p = 0.1), which accordingly showed a higher prevalence of negative remodeling (p = 0.02). CONCLUSIONS: Despite being as effective as the titrated-dosing approach in achieving LDL <100 mg/dl at 12 months after transplant, the maximal-dose approach was associated with a more rapid effect and with potential advantages in preventing pathologic changes in graft coronary arteries.

Antisense modulation of both exonic and intronic splicing motifs induces skipping of a DMD pseudo-exon responsible for x-linked dilated cardiomyopathy.

Antisense-mediated exon skipping has proven to be efficacious for subsets of Duchenne muscular dystrophy mutations. This approach is based on targeting specific splicing motifs that interfere with the spliceosome assembly by steric hindrance. Proper exon recognition by the splicing machinery is thought to depend on exonic splicing enhancer sequences, often characterized by purine-rich stretches, representing potential targets for antisense-mediated exon skipping. We identified and functionally characterized two purine-rich regions located within dystrophin intron 11 and involved in splicing regulation of a pseudo-exon. A functional role for these sequences was suggested by a pure intronic DMD deletion causing X-linked dilated cardiomyopathy through the prevalent cardiac incorporation of the aberrant pseudo-exon, marked as Alu-exon, into the dystrophin transcript. The first splicing sequence is contained within the pseudo-exon, whereas the second is localized within its 3' intron. We demonstrated that the two sequences actually behave as splicing enhancers in cell-free splicing assays because their deletion strongly interferes with the pseudo-exon inclusion. Cell-free results were then confirmed in myogenic cells derived from the patient with X-linked dilated cardiomyopathy, by targeting the identified motifs with antisense molecules and obtaining a reduction in dystrophin pseudo-exon recognition. The splicing motifs identified could represent target sequences for a personalized molecular therapy in this particular DMD mutation. Our results demonstrated for the first time the role of intronic splicing sequences in antisense modulation with implications in exon skipping-mediated therapeutic approaches.

[Consensus document on endomyocardial biopsy of the Associazione per la Patologia Cardiovascolare Italiana]. / Documento di consenso sulla biopsia endomiocardica promosso dall'Associazione per la Patologia Cardiovascolare Italiana.

The Italian Scientific Associations of Cardiologists and Cardiovascular Pathologists have produced this consensus document on the diagnostic role of endomyocardial biopsy (EMB) in terms of techniques, analysis and reporting. The document is intended for clinical cardiologists, hemodynamic experts, electrophysiologists, surgical pathologists, and cardiac surgeons. It has three main aims: a) to collocate EMB in the context of currently available tools for diagnosis of heart diseases; b) to provide recommendations for rational implementation; c) to outline key characteristics (standards) for Italian cardiology and surgical pathology centers that perform and analyze EMB. A general lack of prospective, controlled studies addressing EMB prohibited the use of traditional evidence-based recommendations that rely on classes of available evidence. Thus, it was agreed that three key points should be taken into account: a) the specific pathology to be diagnosed (or excluded); b) the existence of any alternative, non-invasive diagnostic techniques; c) the overall consequences of reaching a definite diagnosis on patients' clinical management. Accordingly, we propose recommendations for EMB based on the following levels of diagnostic value: level 1: no alternative method exists to reach a definite diagnosis that can have obvious consequences for clinical management; level 2a: no alternative method exists to reach a definite diagnosis; however, the implications for clinical management are uncertain; level 2b: no alternative method exists to reach a definite diagnosis; however, the diagnosis would not influence clinical management; level 3: an alternative method exists to reach a definite diagnosis. The second part of the document proposes current protocols for the preparation, analysis and reporting of EMB in the context of each main pathologic entity. Particular attention is given to tissue characterization and implementation of molecular tests.

Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.

BACKGROUND: Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. METHODS AND RESULTS: We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1+/-0.5 versus 0.9+/-0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. CONCLUSIONS: AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection may influence the development of cardiac allograft vasculopathy (CAV). Prophylactic or preemptive administration of anti-CMV agents effectively prevents acute CMV manifestations. However, studies comparing allograft-related outcomes between these anti-CMV approaches are lacking. Herein we report a longitudinal observational study comparing CAV development between prophylactic and preemptive approaches. METHODS: The 1-year change in maximal intimal thickening (MIT) assessed by intravascular ultrasound at 1 and 12 months after heart transplantation (the major surrogate for late survival) was compared in groups of patients routinely assigned to a preemptive strategy (from November 2004 to October 2005; n = 21) or receiving valganciclovir prophylaxis (from November 2005 to October 2006; n = 19). CMV infection was monitored with pp65 antigenemia. RESULTS: The 1-year increase in MIT was significantly lower in patients receiving prophylaxis compared with those managed preemptively (0.15 +/- 0.17 vs 0.31 +/- 0.20 mm; p = 0.01). Prophylaxed recipients presented less frequently with MIT change > or =0.3 mm (p = 0.03) and > or =0.5 mm (p = 0.10) than those managed preemptively. Prophylaxis was also associated with later onset of CMV infection (p = 0.01), lower peak CMV detection (p < 0.01) and reduced incidence of CMV disease/syndrome (p = 0.04). After adjusting for metabolic risk factors and other possible confounders, prophylaxis remained independently associated with lower risk for MIT change > or =0.3 mm (odds ratio = 0.09, 95% confidence interval 0.01 to 0.93; p = 0.04). CONCLUSIONS: Universal prophylaxis was associated with delayed onset of CMV infection, lower viral burden, reduced CMV disease/syndrome and less intimal thickening, as compared with a preemptive anti-CMV approach. Randomized studies are required to confirm the potential benefits of prophylaxis vs a preemptive approach in heart transplant recipients.

Syncope and risk of sudden death in hypertrophic cardiomyopathy.

BACKGROUND: The prognostic significance of syncope has not been investigated systematically in hypertrophic cardiomyopathy, and treatment strategies have been based largely on intuition and experience. METHODS AND RESULTS: We assessed the relationship between syncope and sudden death in 1511 consecutive patients with hypertrophic cardiomyopathy. Unexplained (n=153) or neurally mediated (n=52) syncope occurred in 205 patients (14%). Over a 5.6+/-5.2-year follow-up, 74 patients died suddenly. Relative risk of sudden death was 1.78 (95% confidence interval 0.88 to 3.51, P=0.08) in patients with unexplained syncope and 0.91 (95% confidence interval 0.00 to 3.83, P=1.0) in those with neurally mediated syncope compared with patients without syncope. In multivariable analysis, the temporal proximity of unexplained syncope to initial patient evaluation was independently associated with risk of sudden death (P=0.006). Patients with unexplained syncope within 6 months before the initial evaluation showed a 5-fold increase in risk compared with patients without syncope (adjusted hazard ratio 4.89, 95% confidence interval 2.19 to 10.94), a relationship that was maintained throughout all age groups (<18, 18 to 39, and > or =40 years). Older patients (> or =40 years of age) with remote episodes of syncope (>5 years before initial evaluation) did not show an increased risk of sudden death (adjusted hazard ratio 0.38, 95% confidence interval 0.05 to 2.74). CONCLUSIONS: In the present large cohort of patients with hypertrophic cardiomyopathy, unexplained syncope was a risk factor for sudden death. Patients with syncopal events that occurred in close temporal proximity to the initial evaluation showed a substantially higher risk of sudden death than patients without syncope. Older patients with remote syncopal events did not show an increased risk.

Safety and efficacy of ezetimibe with low doses of simvastatin in heart transplant recipients.

Although statins have proven efficacy in lowering lipids and improving survival in heart transplantation (HT) recipients, potential drug interactions may limit efficacy and reduce tolerability. This observational study explored the efficacy and tolerability of ezetimibe (10 mg/day) combined with simvastatin (10 or 20 mg/day) prescribed to HT recipients with intolerance to statins (n = 11) or inadequate lipid control despite high-dose statins (n = 14). Substantial reductions in lipid levels were apparent after 2 months (total cholesterol, -22%; low-density lipoproteins, -28%; triglycerides, -31%) and were maintained at 6 months. Reductions were significant in both subgroups of recipients; the vast majority (12 of 14, 85%) of recipients with a history of statins intolerance were able to tolerate ezetimibe plus low-dose simvastatin. This study provides suggestive evidence that treatment with ezetimibe plus low-dose simvastatin is well tolerated by HT recipients and may be effective for treatment of dyslipidemia in HT recipients with statins intolerance or resistance.

Long-term effect of folic acid therapy in heart transplant recipients: follow-up analysis of a randomized study.

BACKGROUND: Folic acid therapy reduces homocysteine plasma levels, which seem to influence occurrence of cardiac allograft vasculopathy, but its effect on medium- or long-term prognosis after heart transplantation is unknown. METHODS: We analyzed 7-year outcome of 51 recipients randomized to receive 15 mg/day of methyltertrahydrofolate for 1 year after heart transplantation or standard therapy alone (originally, for intravascular ultrasound study of short-term cardiac allograft vasculopathy progression); recipients were observed for a further 5 to 6 years. RESULTS: Overall, 13 deaths occurred (six oncologic, five cardiovascular, two infective). Estimated 7-year survival was better in recipients randomized to folate (88%+/-6% vs. 61%+/-9%, P=0.04). After adjusting for age, pretransplant coronary artery disease, and hyperhomocysteinemia, posttransplant folic acid therapy was associated with lower mortality (relative risk [RR] 0.53, 95% confidence interval [CI] 0.25-0.97; P=0.036), apparently driven by reductions in both cancer-related and cardiovascular causes. Reduced mortality was marked in a high-risk subgroup comprising older recipients and patients transplanted because of coronary artery disease (RR 0.43, 95% CI 0.17-0.85) but not in the lower-risk subgroup (RR 1.11, 95% CI 0.22-5.61). CONCLUSIONS: Although further studies are needed, it seems reasonable to suggest folate therapy to heart transplant recipients. It is possible that properties other than homocysteine reduction may provide antitumoral benefits.

Age and heart transplantation: results from a heart failure management unit.

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 in hypertrophic 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.

[Coronary allograft vasculopathy: pathophysiological interaction between the immune system, infections and metabolic syndrome]. / La malattia coronarica del cuore trapiantato: interazione fisiopatologica tra sistema immunitario, infezioni e sindrome metabolica.

Cardiac allograft vasculopathy is still the main cause of long-term graft loss after heart transplantation. Indeed, recent advances in immunosuppression management led to a significant improvement in short-term survival, while long-term death rate did not change significantly in the last 20 years. In this paper, we will review the latest advances in the understanding of this peculiar form of atherosclerosis, focusing on the mechanisms that can be potentially targeted by specific therapeutic interventions.

Relevance of cardioverter defibrillators for the prevention of sudden cardiac death on the timing of heart transplantation.

UNLABELLED: Information on the incidence of decompensation of chronic heart failure (CHF) in heart transplantation (HT) candidates eligible for prophylactic implantable cardioverter defibrillators (ICD) could provide insights into the influence of ICD on the timing for HT. METHODS: We investigated the prevalence of candidates satisfying SCD-HeFT and MADIT-II criteria for prophylactic ICD among patients (n = 317) with CHF referred to our tertiary center for HT. In addition to standard clinical and laboratory assessments, baseline evaluation included two-dimensional standard transthoracic echocardiogram and 12-lead electrocardiogram. RESULTS: At baseline, 19% of patients (n = 60) satisfied MADIT II criteria, and 58% (n = 185) fulfilled SCD-HeFT criteria. A total of 60% patients (n = 190) were eligible for prophylactic ICD implantation according to at least one set of criteria. Five-yr CHF decompensation-free survival was 68 +/- 4% in patients eligible for prophylactic ICD (p = 0.003), (RR 2.5, 95% CI 1.35-4.63). CONCLUSIONS: SCD-HeFT could imply a threefold rise in ICD eligibility in tertiary settings. As ICD-eligible patients would likely remain at high risk of progressive ventricular dysfunction, strict follow-up should be considered extremely important to allow a timely referral for HT.

Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure.

BACKGROUND: It is unknown whether time-related changes of pulmonary hypertension (PH) have prognostic relevance in severe chronic heart failure (CHF). METHODS: All CHF patients referred for follow-up from 1996 through 2003 were screened for this study. Eligibility depended on availability of a concomitant clinical, laboratory, electrocardiographic (ECG), echocardiographic and right-heart catheterization (RHC) assessment at index evaluation, as well as absence of pre-capillary PH. RESULTS: One hundred ninety-six patients (age 54 +/- 9 years; 27% women, 73% men; 50% in New York Heart Association [NYHA] Class III or IV) were included. PH at index evaluation was an independent predictor of acute heart failure or cardiovascular death (AHF/CD), with adjusted risk ratio (RR) = 2.30, 95% confidence interval (CI) 1.42 to 3.73 and p < 0.001. A pre-study (> or =6 months) RHC was available for 174 of the 196 patients. Worsening of mean pulmonary artery pressure (mPAP) of > or =30% (a pre-specified cut-off corresponding to the 75th percentile of DeltamPAP%) provided prognostic information independent of all index-evaluation parameters (adjusted RR = 2.60, 95% CI 1.45 to 4.67, p = 0.001), and from time-related changes in the other hemodynamic parameters (p < or = 0.033). CONCLUSIONS: PH retains independent prognostic significance even after adjusting for a large set of clinical/laboratory/instrumental parameters. Furthermore, serial measurements of mPAP seem to provide additional prognostic information as compared with a single assessment. These findings indicate that serial evaluations of PAP may help identify a sub-set of high-risk CHF patients deserving a particularly close follow-up to facilitate timely indications for non-pharmacologic strategies, including (when appropriate) heart transplantation.

Prognostic stratification of women with chronic heart failure referred for heart transplantation: relevance of gender as compared with gender-related characteristics.

BACKGROUND: Few studies are available regarding prognostic stratification of women with severe chronic heart failure (CHF). Although women seem to have a better outcome than men, this may be due to favorable baseline characteristics. METHODS: We analyzed a cohort of CHF patients referred for heart transplantation (HT) who underwent clinical/laboratory/instrumental evaluation. Women and men were frequency matched for baseline age (53 +/- 14 vs 53 +/- 9 years, p = 0.92), left ventricular ejection fraction (33 +/- 10 vs 31 +/- 8%, p = 0.90) and ischemic etiology (17 vs 22%, p = 0.50). RESULTS: A total of 198 patients were analyzed (109 women matched to 89 men). In addition to matching parameters, prevalence of severe symptoms, diabetes and hypertension were also comparable (p > or = 0.25). After 3 years, cardiovascular death or need for HT (CD/HT) event-free survival was 78 +/- 4% in women and 50 +/- 6% in men (p = 0.005). On multivariate analysis, female gender was associated with a lower risk of CD/HT (relative risk [RR] 0.52; 95% confidence interval [CI] 0.30 to 0.89; p = 0.017), independently of symptoms, blood pressure (BP), left ventricular end-diastolic diameter (LVEDD) and mitral regurgitation (MR). Nevertheless, CD/HT event-free survival at 3 years was 49 +/- 9% for women with New York Heart Association (NYHA) Class III or IV status, who presented with either severe MR, mean BP < or =60 mm Hg or LVEDD > or =35 mm/m2. CONCLUSIONS: In advanced CHF, women patients seem to have a better prognosis irrespective of baseline characteristics, supporting the hypothesis that female gender is protective against myocardial injury. However, women with severe symptoms accompanied by either hypotension, severe left ventricular enlargement or MR are at high risk and deserve cautious follow-up and consideration for HT.