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AIMS: The angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) is recommended for the treatment of patients with heart failure in New York Heart Association (NYHA) class II-III and left ventricular ejection fraction (LVEF) 35% or less. We examined the effects of sacubitril/valsartan on cardiac remodeling and their correlation with heart failure duration in patients enrolled in our heart failure clinic from March 2017 to December 2019. METHODS: Echocardiographic and clinical/laboratory data were collected at baseline and at 6-month and 12-month follow-up visits in 69 patients (age 67 ± 12 years, disease duration 8.4 ± 5.8 years, 93% men). RESULTS: At both time points, mean NYHA class, NT-proBNP level, LVEF, LV end-systolic volume, and estimated systolic pulmonary pressure significantly (P

Objectives In patients with abnormal left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI), cardiac rehabilitation with physical training prevents cardiac remodelling. To define the role of rehabilitation in the recovery of ventricular function in less severe cases, we studied its effects on more refined indexes of left ventricular function in uncomplicated, low-risk patients. Methods and results Fifty-five patients underwent percutaneous coronary revascularization after uncomplicated first AMI. Thirty-four started cardiac rehabilitation with counselling and physical training; 21 patients did not train, followed a counselling program and were taken as controls. Echocardiography was performed at baseline, after rehabilitation or counselling program and at six months follow-up. We measured: global strain (GS%) with speckle tracking analysis, E/e’ by tissue Doppler imaging (TDI), left ventricular elastance (K LV ) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, K LV , LVEF, DT, E/e’, systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO 2 by 18% (P < 0.05) and improved GS%, K LV , LVEF, E/e’ and WMSI (P < 0.02) that were unchanged in controls. The improvement persisted at six months. Conclusions After a first uncomplicated AMI, abnormalities of left systolic and diastolic ventricular function may be present persisting over time despite a normal LVEF, which are fully reverted by cardiac rehabilitation.

Graphical abstract Pathophysiology of “atriogenic” functional tricuspid regurgitation in patients with persistent atrial fibrillation., Highlights • 3D echo is key to understand the pathophysiology of FTR. • AF may be the primary cause of FTR through right atrial (RA) and TA remodeling. • In some patients, restoring the sinus rhythm is associated with improvement of FTR. • Our findings reinforce the concept of the atriogenic FTR. • Aggressive rhythm control in patients with AF seems to prevent RA and TA remodelling.

Background: In patients with heart failure, many indexes are available for noninvasive identification of pulmonary congestion: E/E′ at echocardiography; plasma levels of brain natriuretic peptide (BNP) (pg/ml); number of B-lines at lung ultrasound; and transthoracic conductance [thoracic fluid content (TFC)TT = 1/Ω] at impedance cardiography (ICG). Methods: We obtained 75 measures from 50 patients (72 ± 10 years, NYHA 2.4 ± 0.7, ejection fraction 31 ± 7%), 25 of them studied before and after intravenous diuretics, in whom we assessed the following: E/e′ from Doppler echocardiogram; BNP plasma levels; presence and number of B-lines at lung ultrasound; and TFCTT from ICG. We determined the relationship among these indexes and their change with treatment, and compared B-lines and TFC for the diagnosis of pulmonary congestion. Finally, we considered the timing and the personnel required for performing and interpreting each test. Results: A mutual relationship was observed between all the variables. After clinical improvement, changes in each variable were of similar direction and magnitude. Congestion (estimated by chest radiograph) was present in 59% of the patients: TFC value and B-line number had the best sensitivity and specificity for its detection. BNP determination and ICG assessment were performed by a nurse (15 min), and echocardiography and lung ultrasound were performed by a cardiologist (15 min). Conclusion: The correlation between all indexes and their consensual change after improvement of the clinical status suggests that they all detect pulmonary congestion, and that using at least two indexes improves sensitivity and specificity. The choice among the methods may be determined by the patient characteristics or by the clinical setting.

Background and purpose: Both obstructive sleep apnea (OSA) and cardiac organ damage have a crucial role in acute ischemic stroke. Our aim is to explore the relationship between OSA and cardiac organ damage in acute stroke patients. Methods: A total of 130 consecutive patients with acute ischemic stroke were enrolled. Patients underwent full multichannel 24-h polysomnography for evaluation of OSA and echocardiography to evaluate left ventricle (LV) mass index (LV mass/BSA, LV mass/height 2.7), thickness of interventricular septum (IVS) and posterior wall (LVPW), LV ejection fraction and left atrium enlargement. Information on occurrence of arterial hypertension and its treatment before stroke was obtained from patients' history. Results: 61.9% (70) of patients, mostly men (67.1%), with acute stroke had OSA (AHI > 10). Patients with acute stroke and OSA showed a significant increase (P < 0.05) of LV mass index, IVS and LVPW thickness and a significant left atrial enlargement as compared with patients without OSA. LV ejection fraction was not significantly different in stroke patients with and without OSA and was within normal limits. No relationship was found among cardiac alterations, occurrence of OSA and history of hypertension. Conclusion: Acute stroke patients with OSA had higher LV mass and showed greater left atrial enlargement than patients without OSA. This study confirms the high prevalence of OSA in stroke patients, suggesting also an association between OSA and cardiac target organ damage. Our finding of structural LV abnormalities in acute stroke patients with OSA suggests a potential role of OSA as contributing factor in determining both cerebrovascular and cardiac damage, even in absence of clear link with a history of blood pressure elevation.

Heart failure with preserved ejection fraction (HFpEF) is a widely heterogeneous clinical condition. Left ventricular diastolic dysfunction is the leading etiology of HFpEF, but there might be patients presenting with a predominant disease of the left atrium (LA). We report a case of HFpEF secondary to a stiff LA, in which we corroborated invasive hemodynamic assessment with LA strain analysis. Pathognomonic, tall V-waves were observed in the wedge position in the absence of mitral regurgitation and with a near-normal QRS-gated, pre-V-wave pressure, indicating that left ventricular diastolic dysfunction was not a major issue in this case. These hemodynamic findings were mirrored by very low LA strain values, compatible with a stiff and noncompliant chamber.

BACKGROUND: Subcutaneous almost substituted subpectoral approach of implantable cardioverter-defibrillator (ICD) implantation as a less invasive surgical technique. However, the impact of this change in placement site on procedure-related shoulder impairment is poorly understood. METHODS: Candidates for ICD implantation were prospectively evaluated at baseline, 2-weeks and 3-months after the procedure. Assessment of shoulder function included: Constant Score, Numeric Rating Scale (NRS) for pain and the Disability of the Arm, Shoulder and Hand (DASH) scoring method. The Short Form-36 (SF-36) questionnaire was adopted for quality of life. RESULTS: Fifty consecutive patients were enrolled (21 single-chamber, 5 dual-chamber and 24 biventricular ICD). Significant changes in the short term were observed: physical component summary (regarding SF-36) decreased from 44.5±9.1 to 41.8±11.4 (p=0.016), patients with NRS >1 increased from 14% to 44% (p

AimsThis study compared the clinical, functional, and haemodynamic characteristics and current era survival of subgroups of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD): Eisenmenger syndrome (ES); PAH-CHD associated with systemic-to-pulmonary shunts (SPs); PAH with small defects (SDs); and PAH after defect correction (CDs).Methods and resultsData from consecutive PAH-CHD patients referred to our centre from 1 January 1998 to 31 May 2011 were collected. A contemporary group of idiopathic PAH patients was utilized for comparison. Treatment was per PAH guidelines, including combination therapy, with approved PAH-specific drugs. Survival was assessed with Kaplan-Meier analysis from the first invasive haemodynamic confirmation of PAH and compared across subgroups by log-rank test. Of 192 patients (mean age 41 ± 17 years; 61% female), 90 had ES (aged 41 ± 16 years); 48 SP (aged 47 ± 18 years); 10 SD (aged 25 ± 21 years); and 44 CD (aged 36 ± 17 years). Patients with ES had the highest baseline pulmonary vascular resistance and the lowest exercise capacity. Seventy-eight per cent were treated with approved PAH-specific drugs, and 44% were treated with combination therapy. Kaplan-Meier survival estimates (95% confidence interval) at 20 years for ES, SP, and CD were 87% (77-93%), 86% (60-96%), and 36% (12-72%, P = 0.0001 vs. ES; P = 0.004 vs. SP), respectively, and at 15 years for SD was 66% (16-91%, P = 0.015 vs. ES; P = 0.016 vs. SP). The survival of the 278 patients with idiopathic PAH appeared to be worse when compared with the PAH-CHD subgroups.ConclusionRelevant clinical, functional, haemodynamic, and survival differences were observed among subgroups. In particular, patients with CD and SD had the worst survival. These findings should be considered when planning medical or interventional treatment strategies in PAH-CHD patients.

Objectives: To assess safety and effectiveness of balloon aortic valvuloplasty (BAV) in patients with symptomatic severe aortic stenosis (AS) and significant aortic regurgitation. Background: BAV is a palliative procedure that has possibly been underused in patients with symptomatic AS not suitable for surgical aortic valve replacement or transcatheter aortic valve implantation. Significant aortic regurgitation is commonly perceived as a contraindication to BAV. Methods: Among 416 consecutive patients undergoing BAV at our Institution, 73 patients showed moderate or severe AR before the procedure. Demographics and baseline characteristics, as well as in-hospital clinical outcome, have been prospectively collected in a dedicated database. Transthoracic echocardiography was regularly performed in all patients undergoing BAV before the procedure and at hospital discharge. Results: Patients had a high-risk profile, confirmed by advanced age (77.2 ± 11.8 years) and important comorbidity (logistic Euroscore 26.5 ± 16.3%). Advanced heart failure was present in 73.9%. Indication to BAV was cardiogenic shock in 9.6%, palliation in 31.5%, bridge in 58.9% of the patients. BAV was performed with standard retrograde approach. Aortic valve area increased from 0.62 ± 0.15 cm2 at baseline to 0.83 ± 0.17 cm2 before discharge (P < 0.001). The degree of AR was improved or unchanged in 65 patients (89%). In-hospital mortality was 6.9%, mainly limited to terminal patients. Symptomatic status at discharge was improved in all surviving patients. Acute AR occurred in seven patients; in five of them it was successfully resolved in the catheterization laboratory. Conclusions: When clinically indicated, BAV can be safely performed in patients with combined aortic stenosis and significant aortic regurgitation. © 2011 Wiley Periodicals, Inc.

Aims Many inoperable patients with severe aortic stenosis (AS) are not immediately eligible for transcatheter aortic valve implantation (TAVI). We evaluated the role of percutaneous balloon aortic valvuloplasty (BAV) in this setting. Methods and results Among 210 consecutive patients referred to our institution for BAV, we identified three groups: immediately eligible for TAVI (n=65, 31%), excluded from TAVI (n=67, 32%), BAV as a bridge to TAVI (n=78, 37%). This last group comprised patients with low left ventricular ejection fraction, frailty or enfeebled status, symptoms of uncertain origin, critical conditions, moderate-to-severe mitral valve regurgitation, need of major non-cardiac surgery. Outpatient clinic visit and echocardiography were performed around one month after BAV to decide the final therapeutic strategy. Mean age was 81±8 years and the vast majority of patients had comorbidities and high-risk features. The incidence of periprocedural adverse events was 6.4%: 5.1% death (four patients: one procedural complication, three, natural disease progression), 1.3% minor stroke. After BAV, 46% of these patients were deemed eligible for TAVI, and 28% for cardiac surgery. Patients who underwent TAVI after bridge BAV showed 94% 30-day survival. Conclusions BAV is a safe and effective tool to bridge selected patients to TAVI when indications are not obvious.

Background— Left atrium (LA) enlargement is common in organic mitral regurgitation (MR) and is an emerging prognostic indicator. However, outcome implications of LA enlargement have not been analyzed in the context of routine clinical practice and in a multicenter study. Methods and Results— The Mitral Regurgitation International DAtabase (MIDA) registry enrolls patients with organic MR due to flail leaflets, diagnosed in routine clinical practice, in 5 US and European centers. We investigated the relation between LA diameter and mortality under medical treatment and after mitral surgery in 788 patients in sinus rhythm (64±12 years; median LA, 48 [43 to 52] mm). LA diameter was independently associated with survival after diagnosis (hazard ratio, 1.08 [1.04 to 1.12] per 1 mm increment). Compared with patients with LA P P for interaction, 0.77). In patients who underwent mitral surgery, LA ≥55 mm had no impact on postoperative outcome ( P >0.20). Mitral surgery was associated with greater survival benefit in patients with LA ≥55 mm compared with LA P for interaction, 0.008). Conclusions— In MR caused by flail leaflets, LA diameter ≥55 mm is associated with increased mortality under medical treatment, independent of the presence of symptoms or left ventricular dysfunction.

Aims: Treatment delay is a powerful predictor of survival in STEMI patients undergoing primary PCI. We investigated the effectiveness of pre-hospital triage with direct referral to PCI, alongside more conventional referral strategies. Methods and results: From January 2003 to December 2007, 1,619 STEMI patients were referred for primary PCI at our cathlab through two main triage groups: i.e., 1) following pre-hospital triage (n=524), 2) via more conventional triages (n=1,095) represented by the S. Orsola-Malpighi hospital emergency department triage (hub hospital) and local hospital triage. Pre-hospital diagnosis was associated with a 76 minute reduction in pain-to-balloon time (143 [107-216] vs. 219 [149-343], p=0.001) allowing mechanical revascularisation within 90 minutes from the first medical contact in the vast majority of the patients (>80%). Clinically, pre-hospital triage showed no significant reductions in terms of adjusted long-term mortality (HR 0.81, 95% CI 0.61-1.08; p=0.16) in the overall population. However, significant adjusted survival benefits were observed in high-risk groups (i.e., cardiogenic shock, TIMI risk score >30, diabetes mellitus). Conclusions: This study shows that pre-hospital diagnosis allows for significant reductions in primary PCI treatment delays and suggests the hypothesis that this referral strategy might provide long-term survival benefits especially in high-risk patients.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. At the same time, ITP patients present an increased risk of thrombosis and atherosclerosis related to the high presence of haemostatic factors and chronic steroid therapy. Although relatively rare, the association of ITP and coronary artery disease represents a complex therapeutic challenge. In particular, no recommendations exist regarding the best management approach. We reviewed the literature making a comparison between coronary artery bypass grafting and percutaneous coronary intervention. © 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

Inoperable or high-risk patients with severe aortic stenosis who undergo transcatheter aortic valve implantation (TAVI) have better outcomes compared with those treated with standard medical therapy. As for any other invasive procedure, peri-procedural complications may occur, reducing the procedural success rate and potentially affecting short- and mid-term outcomes. The transfemoral approach prevails over other possible access-site options in most registries. The use of large introducer sheaths and the need for double arterial vascular access can lead to higher rates of vascular complications in this elderly population, with a high prevalence of baseline peripheral artery disease. In this article, we review the results of recent clinical trials and major registries using the two different bioprosthesis currently available for TAVI, focusing on access site-related complications with transfemoral TAVI, their management and relationship with in-hospital and 30-day survival. Awareness of the mechanisms behind these complications might help in their prevention, recognition and management and may ultimately improve the clinical outcome of TAVI procedures.

Background: Heart failure is increasing in the elderly and represents a socioeconomic burden requiring the correct management for which risk stratification is mandatory. Among younger patients, echocardiogram and cardiopulmonary exercise test are useful in prognostic stratification. Few studies have analyzed the utility of these tests in elderly patients. Methods: We report on 90 patients over 70 years old, on whom cardiopulmonary tests and echocardiograms were performed between 1998 and 2006 (67 M, 23 F; 75 ± 3 years; ejection fraction (EF) 30 ± 6%; NYHA 2.1 ± 0.8; 60% ischemic; therapy according to international guidelines). Echocardiographic variables were (1) left ventricular ejection fraction (EF); (2) severity of diastolic dysfunction on multiparametric examination of Doppler and TDI parameters; (3) severity of functional mitral regurgitation. Cardiopulmonary variables were (1) peak VO2; (2) peak O2 pulse; (3) peak respiratory quotient (RQ); (4) VE/VCO2 slope. Endpoint considered was mortality of any cause at three-years follow-up. Results: Mortality was 21%. At univariate analysis, survivors ( n = 71) and deceased ( n = 19) were similar for age, NYHA class, peakVO2 and RQ; they differed for EF, severity of mitral regurgitation, severity of diastolic dysfunction, O2 pulse and VE/VCO2 slope. At multivariate analysis, only VE/VCO2 slope and severe diastolic dysfunction (restrictive filling pattern) discriminated between the two groups. In particular, the association of restrictive filling pattern and VE/VCO2 slope ≥ 45 predicted 3-year mortality with sensitivity of 84% and specificity of 88%. Conclusions: Echocardiographic and cardiopulmonary data can identify high-risk elderly patients with systolic heart failure, who may need aggressive clinical management.

Objective We sought to assess what proportion of patients with severe symptomatic aortic stenosis who are excluded from cardiac surgery are eligible for transcatheter aortic valve implantation (TAVI). Methods Between July 2007 and December 2008, 98 patients with severe symptomatic aortic stenosis judged inoperable were referred to our institution for percutaneous aortic balloon valvuloplasty (PABV). They entered a screening for TAVI with the CoreValve Revalving System or the Edwards-Sapien valve, comprising general clinical evaluation, echocardiogram, coronary angiography, angiography and angio-CT scan of thoracic aorta and ilio-femoral axes. Results Mean patients' age was 82 +/- 7 years; the vast majority presented relevant comorbidities. Mortality risk predicted by the logistic European System for Cardiac Operative Risk Evaluation was on average 25.3 +/- 14.5%. Overall, 45 (45.9%) patients met the criteria for TAVI: 29.6% for percutaneous transfemoral access, 6.1% for trans-subclavian and 10.2% for transapical approaches. Reason for exclusion was severe noncardiac comorbidity in around half of the cases. PABV allowed re-classification of several patients with very poor left ejection fraction and severe mitral regurgitation. Among the 39 patients undergoing TAVI after the screening, in-hospital mortality was 3.7% for transfemoral and 0 for trans-subclavian and transapical approaches. Conclusions TAVI represents a viable therapeutic option for elderly patients with severe symptomatic aortic stenosis who are not candidates for surgical aortic valve replacement. However, presently less than half of them actually fulfil the criteria for these procedures.

Background: Diastolic dysfunction in long-term heart failure is accompanied by abnormal neurohormonal control and ventricular stiffness. The diastolic phase is determined by a balance between pressure gradients and intrinsic ventricular wall properties: according to a mathematical model, the latter (ie, left ventricular [LV] elastance, KLV) may be calculated by the formula: KLV = (70/[DT-20])2 mm Hg/mL, where DT is the transmitral Doppler deceleration time. Methods and Results: In 54 patients with chronic systolic heart failure (39 men, 15 women; age 65 ± 10 years; New York Heart Association [NYHA], 2.3 ± 0.9; ejection fraction [EF], 32% ± 5%), we analyzed the relationship between KLV and an index of neurohormonal derangement (levels of brain natriuretic peptide [BNP]), and investigated whether 3 months of physical training could modulate diastolic operating stiffness. Patients were randomized to physical training (n = 27) or to a control group (n = 27). Before and after training, patients underwent Doppler echocardiogram and cardiopulmonary stress test. At baseline, ventricular stiffness was related to BNP levels (P < .01). Training improved NYHA class, exercise performance, and estimated pulmonary pressure. BNP was reduced. Ventricular volumes, mean blood pressure, and EF remained unchanged. A 27% reduction of elastance was observed (KLV, 0.111 ± 0.044 from 0.195 ± 0.089 mm Hg/mL; P < .01), whose magnitude was related to changes in BNP (P < .05) and to KLV at baseline (P < .01). No changes in KLV were observed in controls after 3 months (0.192 ± 0.115 from 0.195 ± 0.121 mm Hg/mL). Conclusions: In heart failure, left ventricular diastolic stiffness is related to neurohormonal derangement and is modified by physical training. This improvement in LV compliance could result from a combination of hemodynamic improvement and regression of the fibrotic process. © 2009 Elsevier Inc. All rights reserved.

We assessed incidence, magnitude, and time course of cardiac troponin I (cTnI) increase after pacemaker implantation in patients without acute coronary syndromes (ACSs). Seventy patients (mean age 71 years, interquartile range 44 to 92, 38 men) undergoing elective implantation of a single-/dual-chamber pacemaker with active/passive fixation leads were enrolled, excluding subjects with clinical suspicion of ACS, abnormal basal cTnI level, or presenting conditions predisposing to abnormal cTnI. Cardiac TnI concentrations were determined in basal conditions, at the end of the procedure, and after 8, 12, and 24 hours. Single-/dual-chamber devices were implanted in 31 of 39 patients. Cardiac TnI peak concentration occurred within the 12-hour assay in 69 of 70 patients; 26 of 70 had a cTnI above the normal cut-off range. All patients presented normal cTnI at 24-hour assay. In conclusion, pacemaker implantation is associated with increases of cTnI levels in up to 37% of patients. This can affect the specificity of cTnI assessment for ruling out ACS, especially within 12 hours after the procedure. These data deserve consideration in a contemporary setting, in which troponin has gathered a pivotal role in the diagnosis and therapy of ACS, and in particular clinical presentations in which electrocardiogram loses its diagnostic capabilities (due to paced rhythms) and symptoms may be lacking or confusing.

Background— Regular slow breathing is known to improve autonomic cardiac regulation and reduce chemoreflex sensitivity in heart failure. We explored the acceptability and usefulness of a device for paced slow breathing at the home setting. Methods and Results— In this open pilot study, 24 patients with chronic heart failure (61% males, mean age, 64�9 years; New York Heart Association class, 2.81�0.01) were randomized to a control group receiving conventional treatment (n=12) or to a group receiving conventional treatment and device-guided paced breathing (n=12). Groups were comparable for age, therapies, and clinical characteristics. They were evaluated at baseline and again after 10 weeks by Doppler echocardiography, pulmonary function, cardiopulmonary stress test, and quality of life (Minnesota Quality of Life questionnaire). The treatment group was instructed to use the equipment for 18 minutes twice daily. The device is a computerized box connected to a belt-type respiration sensor and to headphones; it generates musical tones (based on the user’s breathing rate and inspiration ratio), which guide the user to progressively and effortlessly slow his or her breathing rate e /V co 2 , FEV 1 , and a quality of life measure, as well (all P Conclusions— This pilot investigation demonstrates that device-guided paced breathing at home is feasible and results in an improvement in clinically relevant parameters for patients with heart failure and systolic dysfunction.

Aims To evaluate the clinical impact of early administration of glycoprotein IIb/IIIa agents (IIb/IIIa agents) in the context of a dedicated hub and spoke network allowing very prompt pharmacological/mechanical interventions. Methods and results Using a prospective database, we conducted a cohort study of ST-elevation myocardial infarction (STEMI) patients ( n = 1124) undergoing primary percutaneous coronary interventions (PPCIs) and IIb/IIIa agents administration (period, 2003–2006). Comparisons were planned between patients receiving early IIb/IIIa agents administration (in hub/spoke centre emergency departments or during ambulance transfer; early group, n = 380) or delayed administration (in the catheterization laboratory; late group, n = 744). The primary outcome measure was long-term overall mortality/re-infarction. Baseline characteristics of the two groups were largely comparable. Angiographically, early group patients more often achieved pre-PPCI TIMI Grade 2–3 and TIMI Grade 3 flow. Clinically, the early administration group experienced lower 2-year risk of unadjusted mortality/re-infarction (17 vs. 23%; P = 0.01). After adjustment for potential confounders, early administration was associated with favourable outcome in the overall population (HR = 0.71, P = 0.03) and in high-risk subgroups (TIMI risk index >25, HR = 0.64, P = 0.02; Killip class >1, HR = 0.54, P = 0.01). Conclusion In patients treated by PPCI within a STEMI network setting, early administration of IIb/IIIa agents may provide long-term clinical benefits. Notably, these results appeared magnified in high-risk patients.

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.

A mechanical mock of the cardiovascular system was used to simulate different conditions of ventricular-arterial mechanical matching. Four ventricles and four aortas with different elastances were set up, and all possible connection combinations tested by sampling ventricular and aortic pressures and flows. The mechanical energy produced by the simulated ventricles and the amount transferred to the aorta in the different connection conditions were calculated. The results demonstrate a clear dependence between the mechanical work production of the ventricles and the ventricular elastance (slope of the end-systolic pressure–volume relation) (from 20.42 ± 0.02 mJ/beat to 12.10 ± 0.02 mJ/beat), and an efficiency of energy transfer to the aorta strongly dependent on ventricular-aortic mechanical matching (from 56% to 20.7%). These results show that, even in optimal simulated conditions, only 56% of the energy produced is transferred to the load; and highlight the important role of mechanical aspects in conditions of very limited cardiovascular performance (i.e. final stages of heart failure), where energy transfer efficiency may be as low as 20.7%. This evidence emphasizes that the mechanical aspects must also be entertained in the evolution of complex cardiovascular pathologies, evaluating the possibility of combining mechanical and pharmaceutical interventions.

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger's syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis. The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger's syndrome. Clinically, Eisenmenger's syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger's syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger's syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class. The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger's syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis. The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger's syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger's syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger's syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome.

Objective:LCZ696, i.e. the combination of neprilisin inhibitor (sacubitril) and angiotensin receptor (valsartan) (ARNI) is recommended in heart failure (HF) guidelines for patients (pts) in NYHA II-III with reduced left ventricular ejection fraction (LVEF).Design and method:Forty-six pts followed in

Aims To evaluate the predictive value of high sensitivity (hs) C-reactive protein levels on long-term survival in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI. Methods and results We conducted a retrospective analysis of 758 STEMI patients (from January 2003 to December 2005), with STEMI onset < 12 h and hs-C-reactive protein determination on admission. Patients were classified into four groups [I (hs-C-reactive protein < 0.48 mg/dL), II (hs-C-reactive protein ≥ 0.48 to < 1.2 mg/dL), III (hs-C-reactive protein ≥ 1.2 to < 3.1 mg/dL), IV (hs-C-reactive protein ≥ 3.1 mg/dL)] according to quartiles of hs-C-reactive protein serum level. The IV quartile hs-C-reactive protein group had a higher incidence of in-hospital mortality and cumulative adverse events. At a mean follow-up of 724 ± 376 days (range 0–1393), the IV quartile hs-C-reactive protein group showed lower estimated survival, lower estimated myocardial infarction-free survival and lower estimated event-free survival. At multivariable analysis hs-C-reactive protein appeared to be an independent predictor of long-term mortality (HR: 1.04, 95% CI: 1.01–1.07, P = 0.003), long-term mortality and re-infarction (HR: 1.03, 95% CI: 1.01–1.06, P = 0.008) and adverse events (HR: 1.03, 95% CI: 1.01–1.05, P = 0.03). Conclusion Evaluation of hs-C-reactive protein on admission in STEMI patients undergoing primary PCI allows reliable risk stratification of these patients.

A series of landmark randomized trials has validated the role of implantable cardioverter defibrillators (ICDs) not only in the setting of secondary prevention of sudden cardiac death (SCD) but also in the challenging subset of primary prevention of SCD, i.e. for highrisk patients without previous malignant ventricular tachyarrhythmias. Despite definite indications provided by consensus guidelines, the use of ICDs in clinical practice still encounters a series of barriers mainly related to the characteristics of such treatment (a ‘rescue’ treatment) and its up-front cost, resulting in substantial under-referral and rationing. Cost is likely to remain a major determinant of full acceptance, and implementation of ICD therapy and the problem of how broadened evidence-based indications for implantation can be translated into routine clinical practice require an analysis of available economic resources and identification of priorities for health care. Economic analysis (cost-effectiveness, cost–utility and cost–benefit estimates) provides the most appropriate tool for weighing ICD costs against likely eventual outcome benefits. A series of data indicate that the use of ICDs in appropriately selected high-risk SCD patients is associated with cost-effectiveness ratios similar to, or better than, other accepted treatments, such as renal dialysis. Improvement in risk stratification for SCD and assessment of the cost-effectiveness profile of ICD treatment in specific subgroups of patients appears to be a crucial step in any attempt to maximize health outcomes in a context of limited economic resources.

Matrix metalloproteinases (MMPs) are thought to participate in the pathogenesis of coronary artery disease (CAD), particularly in the occurrence of acute coronary syndrome (ACS). Little is known about human in vivo MMP regulation in CAD. The expression and regulation of MMPs and their tissue inhibitors (TIMPs) were evaluated in premature CAD. The distribution of MMP-3 5A/6A and MMP-9 C/T promoter polymorphisms and MMP-9 A/G exon-6 polymorphism were investigated in 200 consecutive male premature CAD patients (aged ≤55 years) and 201 age-matched male blood donors. Plasma concentrations/activities of MMP-2 and MMP-9 were also measured, as were plasma concentrations of MMP-3, TIMP-1, and TIMP-2 in 80 patients (49 with ACSs and 31 with stable CAD) and 40 controls. Inflammation markers were also obtained. MMP genetic polymorphism distributions did not vary between patients and controls and did not seem to influence their respective MMP plasma levels. Patients showed increased MMP-9 and TIMP-1 concentrations and decreased TIMP-2 concentration and MMP-2 total activity (all P ≤ 0.002). Overall, TIMP-1 correlated with C-reactive protein (CPR) (r = 0.594, P < 0.001) and haptoglobin (r = 0.276, P = 0.005), whereas MMP-2 activity correlated inversely with haptoglobin (r = -0.195, P = 0.032). Blood glucose correlated positively with TIMP-1 concentration (r = 0.711, P < 0.001) and negatively with MMP-2 activity (r = -0.250, P = 0.006). In conclusion, MMP and TIMP plasma levels in premature CAD are linked to clinical presentation and markers of inflammation and metabolic disorders rather than to genetic polymorphisms. © 2007 Mosby, Inc. All rights reserved.

Aims Previous studies investigating the effect of hypoxia on left ventricle focused on its global function, an approach that may not detect a selective dysfunction of subendocardial layers that are most sensitive to an inadequate oxygen supply. In the HIGHCARE study, aimed at exploring the effects of high altitude hypoxia on multiple biological variables and their modulation by an angiotensin receptor blocker, we addressed the effects of hypobaric hypoxia on both systolic and diastolic left ventricular geometry and function, focusing on echocardiographic assessment of left ventricle twist to indirectly examine subendocardial left ventricular systolic function. Methods and results In 39 healthy subjects, physiological and echocardiographic variables, including left ventricular twist and a simplified torsion-to-shortening ratio (sTSR), were recorded at sea level, at 3400 m, and at 5400 m altitude (Mount Everest base camp). Both left ventricular twist and sTSR were greater at 5400 m than at sea level (12.6° vs. 9.6° and 0.285 vs. 0.202, P < 0.05 for both), were linearly related to the reduction in arterial oxygen partial pressure ( P < 0.01 for both), and were associated with significant changes in LV dimensions and contractility. No effects of angiotensin receptor blockade were observed on these variables throughout the study. Conclusion Our study, for the first time, demonstrates an increase in left ventricular twist at high altitude in healthy subjects exposed to high altitude hypoxia, suggesting the occurrence of subendocardial systolic dysfunction in such condition.

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.

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.

Although great interest exists in the relative efficacy of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) for the treatment of unprotected left main coronary artery stenosis, data comparing the 2 strategies are scant. Furthermore, no comparison has ever been performed between CABG and drug-eluting stents in this setting. From January 2002 to June 2005, 154 patients with unprotected left main coronary artery stenosis underwent CABG and 157 underwent PCI. Ninety-four patients received a drug-eluting stent in the left main artery. After a median follow-up of 430 days, the rate of mortality, acute myocardial infarction, and target lesion revascularization was 12.3%, 4.5%, and 2.6%, respectively, in the CABG group and 13.4%, 8.3%, and 25.5%, respectively, in the PCI group (death and myocardial infarction p = NS, target lesion revascularization p = 0.0001). Although patients treated with drug-eluting stents had a 25% relative risk reduction in the rate of death, myocardial infarction, and target lesion revascularization compared with patients treated with bare stents, event-free survival was still better for patients treated with CABG. In the multivariate analysis, age >/=70 years, New York Heart Association classes III and IV, acute coronary syndromes, and peripheral vascular disease were the only independent predictors of mortality. In conclusion, our results have indicated that at long-term follow-up no difference exists in the rate of mortality and myocardial infarction between PCI and CABG for the treatment of unprotected left main coronary artery stenosis. However, the rate of target lesion revascularization was higher in the PCI group.

Aims Treatment delay is a powerful predictor of survival in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated effectiveness of pre-hospital diagnosis of STEMI with direct referral to PCI, alongside more conventional referral strategies. Methods and results From January 2003 to December 2004, 658 STEMI patients were referred for primary PCI at our intervention laboratory. Three predefined referral routes were compared: (1) for patients within 90 min drive of the PCI centre, pre-hospital diagnosis and direct transportation ( n =166), (2) diagnosis at the interventional hospital emergency department ( n =316), (3) diagnosis at local hospitals before transportation ( n =176). Pre-hospital diagnosis was associated with more than 45 min reduction in treatment delay ( P =0.001). No significant difference in in-hospital mortality was apparent in the overall study population. In the cardiogenic shock subgroup ( n =80), pre-hospital diagnosis was associated with a two-thirds reduction in in-hospital mortality ( P =0.019); mortality was only 6.2% in shock patients who underwent PCI in

Background More information is required on the relationship between electrical and structural reverse remodeling in patients treated with cardiac resynchronization theraphy. Methods QRS and JT intervals were investigated during different pacing modes before and 3 months after implantation of a device for biventricular (BiV) pacing in 20 patients with severe drug-refractory heart failure (with left ventricular ejection fraction 120 ms); structural remodeling was evaluated by echocardiography. Results QRS interval was significantly shortened by BiV pacing both acutely ( p =0.002) and at 3 months ( p =0.007). No significant change was found in the JT interval. The extent of QRS shortening obtained by BiV pacing showed moderate correlations with the reduction of end-systolic and end-diastolic volumes ( r =0.53, p =0.016 and r =0.45, p =0.045, respectively) as well as with increase of left ventricular ejection fraction ( r =0.49, p =0.028) at 3 months. The widening of QRS observed during right ventricular (RV) pacing was greater after 3 months of BiV pacing (with respect to acute assessments), suggesting accentuation of pacing-induced electrical dyssynchrony after a period of pacing-induced resynchronization. Conclusion The extent of QRS shortening induced by BiV pacing appears to correlate with the reverse structural remodeling (in terms of reduction in end-systolic volume). The acute changes and the remodeling process occurring at mid-term in the overall population of CRT-treated patients do not appear to involve the JT interval. A period of pacing-induced resynchronization appears to accentuate the potential for RV pacing-driven electrical dyssynchrony.

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.

Rupture of a vulnerable plaque is the main cause of acute coronary syndromes and myocardial infarction. The features of rupture-prone atherosclerotic plaques have been previously described by pathologists. However, identification of vulnerable plaques in vivo is essential to study their natural history and to evaluate potential treatment modalities. Coronary angiography is the gold standard for the diagnosis of coronary artery disease, but it is unable to distinguish between stable and unstable plaques and to accurately predict future cardiac events. This current perspective describes the recently developed invasive imaging techniques to detect atherosclerotic vulnerable plaques in the coronary tree.

Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung. METHODS: In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study. RESULTS: The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P

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.

We investigated the diagnostic accuracy of (99m)Tc-3,3- diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-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 (99m)Tc-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 (99m)Tc-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 (99m)Tc-DPD scintigraphy for distinction of TTR-related and AL etiology was 100%. Cardiac (99m)Tc-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% (accu racy, 50%). Eleven patients with myocardial (99m)Tc-DPD uptake underwent (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) scintigraphy; all patients showed a (99m)Tc-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 (99m)Tc-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: 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.

The presence of myocardial ischemia during dobutamine stress echocardiography is independently associated with an increased risk of all-cause mortality in women after adjustment for clinical data. This association is observed in patients who have proved coronary artery disease and in patients who have no history of coronary artery disease.

This study tested the hypothesis that venular resistance increases during ischaemia and that a prevalent nitrates-induced venodilationis the cruc a mechanism underlying their ability to relieve ischaemia. Using the model of postreactive hyperaemia we used mercuryin-rubber surain gauges to measure forearm blood flow (FBF) and forearm circumference (FC) before and after 5 mg sublingual isosorbide dinitrate in twelve healthy volunteers. The FC change during reactive hyperaemia was evaluated according to a hydraulic model which assumes that arteriolar resistance (AR) controls the blood inflow and that venular resistance (VR) controls the blood outflow of the vascular capillary reservoir. In this setting FC represents the reservoir volume and any change in this parameter represents the instantaneous difference between input and output flows. In the absence of nitrates and five minutes of arterial closure, the hyperaemic FC curve shows a rapid increase followed by a slow recovery demonstrating a rapid inflow followed by a delayed outflow of the reservoir. This behaviour may be explained by assuming an initial very low arterial resistance and high venular resistance, followed by a slow requilibrium of the two. Repeating the experiment after nitrates intake, the hyperaemic FC curve shows a reduced dimension and a faster recovery to the baseline. Compared with the previous condition, this finding may be explained by assuming a reduced initial venular resistance, which facilitates the blood outflow and hence muscle perfusion. Our findings are coherent with an ischaemia-induced arteriolar dilatation which facilitates filling, and a simultaneous venular constriction which opposes emptying (arteriovenous ischaemic mismatch): the action of the nitrates seems to restore the mismatch by acting on the venous side.

In patients with heart failure and wide QRS complex, cardiac resynchronization therapy (CRT) is associated with improvement of symptoms and cardiac function. This study examined the effects of a 3-month period of CRT on left ventricular (LV) and right ventricular (RV) ejection fraction (EF) and on LV volumes, both at rest and during exercise. A CRT system was implanted in 15 patients with severe heart failure and wide QRS. Before implant and 3 months later, all patients underwent assessment of cardiac performance with equilibrium Tc 9 9 radionuclide angiography with imaging in the best septal left anterior oblique view. Exercise was performed on a bicycle ergometer. At 3 months, a significant improvement in New York Heart Association functional class was observed, and radionuclide angiography showed a significant decrease in LV volumes and a significant increase in LVEF at rest, as well as a significant increase in LVEF during exercise. The remodeling processes associated with CRT did not appear to include RV function, since RVEF did not improve, and changes in RVEF did not correlate with changes in LVEF, neither at rest nor during exercise.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. We evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. These effects were paralleled by a progressive increase in cGMP content, followed by an accumulation of cAMP. The treatment with 8-bromo-cGMP or dibutyryl-cAMP mimicked all the effects of sildenafil. On the other hand, treatment of PASMC with inhibitors of cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) reversed the antiproliferative effect of sildenafil. In addition, sildenafil inhibited the phosphorylation of ERK, a converging point for several pathways leading to cell proliferation. This effect was partially reduced by PKG inhibition and completely abolished by PKA inhibition.We conclude that sildenafil exerts an antiproliferative effect on human PASMC that is mediated by an interaction between the cGMP-PKG and the cAMP-PKA activated pathways, leading to inhibition of PDGF-mediated activation of the ERK.

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.

Background— Statins exert anti-inflammatory effects independently of cholesterol-lowering properties. Cytomegalovirus (CMV) infection appears to be implicated in the pathophysiology of atherosclerosis by inducing inflammatory modifications in endothelial cells, especially in immunosuppressed patients. We investigated whether the activity of statins can inhibit replication of CMV in human endothelial cells. Methods and Results— Human umbilical vein endothelial cells (HUVECs) were infected with CMV and coincubated with fluvastatin at 0.1 and 0.2 μmol/L. Fluvastatin inhibited ( P P 3 pfu/mL, P Conclusions— HMG-CoA inhibition by fluvastatin restrains CMV replication in HUVECs by inhibiting viral antigen expression, DNA synthesis, and viral particle production, conceivably by involving a reduction of nuclear factor-κB binding activity.

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.

First-generation drug-eluting stents (DES), which impart the controlled release of sirolimus or paclitaxel from durable polymers to the vessel wall, have been consistently shown to reduce the risk of restenosis and target vessel revascularization compared with bare metal stents (BMS). However, stent thrombosis (ST) emerged as a major safety concern with first-generation DES early after their adoption in clinical practice, requiring prolonged dual antiplatelet therapy. Pathological studies have shown that first-generation DES are associated with delayed arterial healing and polymer hypersensitivity reactions resulting in chronic inflammation, predisposing to late and very late ST. Second-generation DES have been developed to overcome these issues with improved stent designs and construction and the use of biocompatible and bioabsorbable polymers. Meta-analyses have shown that the thin-strut, fluoropolymer-coated cobalt-chromium everolimus-eluting stent (CoCr-EES) may be associated with lower rates of definite ST than other DES and, unexpectedly, even lower than BMS. The thin-strut structure of the stent platform, the thromboresistant properties of the fluoropolymer, and the reduced polymer and drug load may contribute to the low rate of ST with CoCr-EES. The notion of DES being safer than BMS represents a paradigm shift in the evolution of percutaneous coronary intervention. The relative safety and efficacy of fluoropolymer-coated CoCr-EES, DES with bioabsorbable polymers, and fully bioresorbable scaffolds are the subject of numerous ongoing large-scale trials.

Aims Define the impact of age at diagnosis on degenerative mitral regurgitation (MR) prognosis. Methods and results The Mitral regurgitation International DAtabase (MIDA) is a multicentre registry of MR due to flail leaflets including 862 patients (65 ± 12 years) diagnosed by echocardiography. The 498 older patients (≥65 years at diagnosis) were compared with the 364 younger (

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55–80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected.

Background: In patients with chronic heart failure, physical evaluation and clinical judgment may be inadequate for prognostic stratification. Hypothesis: Information obtained with simple bedside tests would be helpful in patient management. Methods: We report on 142 outpatients with systolic heart failure seen at our heart failure unit from 2007 to 2010 (ages 69.4 ± 8.9 years; ejection fraction [EF] 30.6 ± 6.1%; 43% with implanted defibrillators and/or resynchronization devices). At their first visit, we assessed levels of brain natriuretic peptide (BNP) (pg/mL), evaluated transthoracic conductance (TFC) (1/kΩ) by transthoracic bioimpedance, and performed echocardiography. Results: Four-year mortality was 21.2%. At multivariate analysis, surviving and deceased subjects did not differ regarding New York Heart Association, age, gender, heart failure etiology, or EF at index visit. Patients who died had higher BNP and TFC (BNP = 884 ± 119 pg/mL vs 334 ± 110 pg/mL; TFC = 50 ± 8/kΩ vs 37 ± 7/kΩ, both P < 0.001]. Patients with BNP < 450 pg/mL and TFC < 40/kΩ had a 2.1% 4-year mortality, compared to 46.5% mortality of patients having BNP ≥ 450 pg/mL and TFC ≥ 40/kΩ. BNP ≥ 450 pg/mL and TFC ≥ 40/kΩ showed high sensitivity (91%) and specificity (88%)in identifying patients who died at follow-up. Conclusions: The combined use of BNP and impedance cardiography during the first assessment of a patient in a heart failure unit identified those carrying a worse medium-term prognosis. This approach could help the subsequent management of patients, allowing better clinical and therapeutic strategies. The authors have no funding, financial relationships, or conflicts of interest to disclose.