Discordant electrical and mechanical atrial delays affect intracavitary electrogram-based cardiac resynchronization therapy optimization.

AIMS: It has been shown that atrioventricular (AV) delay optimization improves cardiac resynchronization therapy (CRT) response. Recently, an automatic algorithm (QuickOpt™, St Jude Medical), able to quickly identify the individual optimal AV interval, has been developed. The algorithm suggests an AV delay based on atrial intracavitary electrogram (IEGM) duration. We hypothesized that the difference between electrical and mechanical atrial delays could affect the effectiveness of QuickOpt method. The aim of this study was to test this hypothesis in 23 CRT patients who were recipients of St. Jude Medical devices. METHODS AND RESULTS: Using echocardiography, aortic flow velocity time integral (VTI) was evaluated at baseline, at QuickOpt suggested AV delay and after reducing it by 25 and 50%. Mechanical inter-atrial delay (MIAD) derived from echo/Doppler and electrical inter-atrial delay (EIAD) derived from IEGM were also analysed. Optimal AV delay was identified by the maximal VTI. In 11 patients (Group 1) the maximal VTI was achieved at the AV delay suggested by the algorithm, in 6 patients (Group 2) after a 25% reduction, and in 6 patients (Group 3) after a 50% reduction. While EIAD was similar among the three groups, MIAD was significantly different (P< 0.001). MIAD was longer than EIAD in Group 1 (P= 0.028) and shorter than EIAD in Groups 2 (P= 0.028) and 3. (P< 0.001). Mechanical inter-atrial delay was the only independent predictor of the AV interval associated with the best VTI (R(2) = 0.77; P< 0.001). CONCLUSION: Our results show that MIAD plays the main role in determining the optimal AV delay, thus caution should be taken when optimizing AV by IEGM-based methods.

Application of the Seattle Heart Failure Model in patients on cardiac resynchronization therapy.

BACKGROUND: The Seattle Heart Failure Model (SHFM) is a multimarker risk assessment tool able to predict outcome in heart failure (HF) patients. AIM: To assess whether the SHFM can be used to risk-stratify HF patients who underwent cardiac resynchronization therapy with (CRT-D) or without (CRT) an implantable defibrillator. METHODS AND RESULTS: The SHFM was applied to 342 New York Heart Association class III-IV patients who received a CRT (23%) or CRT-D (77%) device. Discrimination and calibration of SHFM were evaluated through c-statistics and Hosmer-Lemeshow (H-L) goodness-of-fit test. Primary endpoint was a composite of death from any cause/cardiac transplantation. During a median follow-up of 24 months (25th-75th percentile [pct]: 12-37 months), 78 of 342 (22.8%) patients died; seven patients underwent urgent transplantation. Median SHFM score for patients with endpoint was 5.8 years (25th-75th pct: 4.25-8.7 years) versus 8.9 years (25th-75th pct: 6.6-11.8 years) for those without (P < 0.001). Discrimination of SHFM was adequate for the endpoint (c-statistic always ranged around 0.7). The SHFM was a good fit of death from any cause/cardiac transplantation, without significant differences between observed and SHFM-predicted survival. CONCLUSION: The SHFM successfully stratifies HF patients on CRT/CRT-D and can be reliably applied to help clinicians in predicting survival in this clinical setting.

Multicenter experience with implantable defibrillators subject to recall.

BACKGROUND: The management of implantable cardioverter defibrillators (ICDs) affected by advisories, which often include generator replacement, is complex and the risk of device failure needs to be carefully assessed for each patient. METHODS: We analyzed the response to the advisory communication in the Italian centers involved in the recall for the Prizm 1861 and Renewal (Boston Scientific-formerly Guidant-St. Paul, MN, USA) communication. RESULTS: One hundred and thirty-nine of 843 Prizm (16.5%) and 458 of 2,342 Renewal devices (19.6%) were explanted. The total incidence over a 4-year time frame of the failure event was equal to zero of 710 (0%) for Prizm ICDs and eight of 2,342 (0.34%) for Renewal ICDs. A limited percentage of devices affected by recall were definitely explanted following the indications stated by the advisory. The failure rates that resulted from analysis of our data (0% for Prizm and 0.34% for Renewal) were inferior to those already found or projected along the device lifetime globally, as reported in the most recent Company Product Performance Report (0.72% for Prizm and 1.83% for Renewal). CONCLUSIONS: In absence of underestimation of the events, a lower incidence than expected could resize the dimension of the problem, justifying the concept of a more frequent follow-up of patient with respect to the choice of an immediate device explant.

Rotational mechanics of the left ventricle in AL amyloidosis.

AIMS: The aim of this study was to investigate whether alterations in left ventricular (LV) twisting and untwisting motion could be induced by cardiac involvement in patients with immunoglobulin light-chain (AL) systemic amyloidosis. METHODS AND RESULTS: Forty-five patients with AL amyloidosis and 26 control subjects were evaluated. After standard echocardiographic measurement and two-dimensional (2D) speckle tracking echocardiography, LV rotation at both basal and apical planes, twisting, twisting rate, and longitudinal strain were measured. Tissue Doppler imaging (TDI) derived early diastolic peak velocity at septal mitral annulus (E') was also evaluated. Twenty-six of 45 patients with systemic amyloidosis were classified as having cardiac amyloidosis (CA) if the mean value of the LV wall thickness was ≥ 12 mm or not (NCA) if this value was not reached. In NCA patients, both LV twist and untwisting rate were increased while they were decreased in CA patients making them similar to the control group. Longitudinal strain was reduced only in CA patients. Impaired relaxation as indicated by E' values was progressively reduced in the course of the disease. CONCLUSIONS: Both twisting and untwisting motions are increased in patients with AL systemic amyloidosis with no evidence of cardiac involvement while they are reduced in patients with evident amyloidosis cardiac involvement. This finding suggests that impaired LV relaxation induces a compensatory mechanism in the early phase of the disease, which fails in more advanced stage when both twisting and untwisting rates are reduced. The increase in LV rotational mechanics could be a marker of subclinical cardiac involvement.

Has mechanical dyssynchrony still a role in predicting cardiac resynchronization therapy response?

UNLABELLED: Current guidelines for cardiac resynchronization therapy (CRT) include electrical but not mechanical dyssynchrony assessment. Our study aims to investigate the effects of isolated or combined mechanical and electrical dyssynchrony, according, respectively, to a standard deviation of tissue Doppler imaging (TDI) derived time to systolic peak ≥32.6 ms and to a QRS duration ≥120 ms, in predicting CRT reverse remodeling. METHOD: One hundred ninety-two CRT patients were studied. All patients underwent a complete standard and TDI echocardiography examination before and 6 months after CRT. According to baseline evaluation patients were divided into Group 1, patients with isolated electrical dyssynchrony (QRS ≥ 120 ms, TS-SD < 32.6), Group 2, patients with isolated mechanical dyssynchrony (QRS < 120 ms, TS-SD ≥ 32.6) and Group 3, patients with combined electrical and mechanical dyssynchrony (QRS ≥ 120 ms, TS-SD ≥ 32.6). Patients were considered CRT responders according to ≥15 left ventricular end-systolic volume (LVESV) reduction at follow-up (FU). RESULT: At FU, 86 (45%) patients were responders. The highest CRT response rate was observed in Group 3 (62/119, 52%, P < 0.001 vs. Group 1). No significant differences in response rate were observed between Group 1 (13/47, 27%) and Group 2 (11/26, 42%). In Group1, CRT did not induce any significant change in LV end-diastolic volume (LVEDV), LVESV, LV ejection fraction (LVEF), myocardial performance index (MPI), while in Group 2, LVEF (P < 0.001) and MPI (P < 0.05) were improved. In Group 3, LVEDV, LVESV, LVEF, MPI were significantly improved (P < 0.0001 for all). CONCLUSION: Our data demonstrate that the highest CRT response rate can be achieved by combining traditional QRS criterion and a currently used echocardiographic dyssynchrony parameter.

Is ectopia lentis in some cases a mild phenotypic expression of Marfan syndrome? Need for a long-term follow-up.

PURPOSE: Ectopia lentis (EL) and Marfan syndrome (MFS) are considered two distinct clinical entities. We performed genetic and clinical studies to investigate whether EL is actually distinct from MFS or if it is a mild phenotypic expression of it. METHODS: Seven patients with EL were followed for 5-10 years. Mutation screening analysis of the 65 exons of FBN1 was performed by polymerase chain reaction (PCR) amplification of genomic DNA, denaturing high pressure liquid chromatography analysis, and direct sequencing of heteroduplexes. RESULTS: Yearly examinations during the 10 years of follow-up allowed the detection of a late onset of dural ectasia in six out of seven patients (age range: 32-64 years versus 8-55 years in MFS previously reported). We also detected the onset of mild thoracic aortic dilatation in a sporadic case (age 45). Six out of seven index cases of EL turned out to be mild forms of Marfan syndrome with possible late cardiovascular involvement as detected in one case. Four novel missense mutations and one known splicing mutation were detected in five out of seven (71%) patients. Their localization confirmed the presence of a first hot spot within exons 1-15 and suggested the presence of a second one between exons 31-39. CONCLUSIONS: The presence of a second major criterion in six EL patients shifted the clinical diagnosis from EL to MFS. These data demonstrate that some cases, which are initially diagnosed as EL, turn out to be mild Marfan patients. A clinical cardiovascular follow-up is therefore highly recommended for all EL patients since they may develop thoracic aortic aneurysm (TAA) or dissection later in life. Also magnetic resonance imaging (MRI) for dural ectasia (DE) should be performed in a complete follow up for a MFS diagnosis.

Relation of inflammatory status to major adverse cardiac events and reverse remodeling in patients undergoing cardiac resynchronization therapy.

BACKGROUND: Inflammatory markers are involved in heart failure (HF) pathophysiology. However, the link between these markers and reverse remodeling as well as major adverse cardiac events (HF death, sudden death, and unplanned cardiac rehospitalizations) in patients who undergo cardiac resynchronization therapy (CRT) has not been evaluated. METHODS AND RESULTS: We recorded major adverse cardiac events of 140 patients (on optimized medical therapy, left ventricular ejection fraction 29.9 +/- 9.6%, New York Heart Association Class III-IV, with intraventricular dyssynchrony) who underwent CRT (enrolled since April 2004). Moreover, we evaluated before and after 6 months of CRT: interleukin-6, high-sensitivity C-reactive protein, New York Heart Association class, quality of life (score on Minnesota Living with Heart Failure questionnaire), 6-minute walking test, left ventricular end-diastolic and end-systolic volumes (nonindexed and indexed by body surface area), and left ventricular ejection fraction. Adverse cardiac events were observed in 40 patients (28.6%): 22 deaths and 18 cardiac unplanned rehospitalizations. Only patients without adverse events during follow-up showed a significant reduction of inflammatory markers and left ventricular volumes (reverse remodeling), despite a significant improvement of clinical status observed in both groups of patients. CONCLUSIONS: The reduction of inflammatory status seems to be linked to reverse remodeling as well as to a better clinical prognosis in patients with HF who underwent CRT.

Temporal variation in optimal atrioventricular and interventricular delay during cardiac resynchronization therapy.

BACKGROUND: Tailored atrioventricular delay (AVd) and interventricular delay (VVd) combination improves hemodynamics in patients treated with cardiac resynchronization therapy (CRT). Whether tailored AVd-VVd combination changes over time is not known. METHODS AND RESULTS: Twenty-two patients (18 M, aged 69.9 +/- 12.5 years, New York Heart Association class III, QRS > or = 130 ms, ejection fraction 29.6 +/- 8.8%) were implanted with a biventricular device with programmable VVd. Myocardial performance index (MPI) was evaluated during pacing at different VVds and AVds at baseline and after 6 and 12 months. The optimal AVd-VVd combination was identified by the minimum MPI. After optimization, the appropriate AVd-VVd combination was programmed in each patient. MPI at 6-month follow-up after optimization was significantly higher compared with baseline (.79 +/- .21 vs. .59 +/- .15, P < .05). Re-optimization of AVd-VVd combination was required after 6 months in 21 of 22 (95%) patients. Re-optimization significantly reduced MPI compared with the value prior to re-optimization (.56 +/- .15 vs. .79 +/- .21, P < .05). The MPI remained unchanged at 12-month compared with 6-month follow-up (.59 +/- .19 vs. .56 +/-.15, P = NS). Clinical symptoms and reverse left ventricular remodeling were sustained at 6-month and 12-month follow-up. CONCLUSION: Optimal AVd and VVd combination changes over time in patients with heart failure. Sustained improvement in clinical symptoms and reverse left ventricular remodeling after CRT are not temporally associated with improvement in MPI.

Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy.

In 21 patients implanted with a biventricular pacing device with programmable interventricular delay (VVd), the myocardial performance index (MPI) was evaluated during spontaneous sinus rhythm, simultaneous biventricular pacing, and sequential biventricular pacing at different VVds and atrioventricular delays (AVds). The AVd-VVd combination associated with the minimum MPI defined patient-tailored biventricular pacing. Simultaneous biventricular pacing significantly improved MPI compared with spontaneous sinus rhythm. An additional improvement was obtained by tailored biventricular pacing. The optimal AVds were significantly shorter during right ventricular preactivation than during left ventricular preactivation.

Myocardial perfusion imaging using gated SPECT in heart failure patients undergoing cardiac resynchronization therapy.

UNLABELLED: Cardiac resynchronization therapy (CRT) by biventricular pacing is indicated in patients with severe heart failure and left bundle branch block who remain symptomatic despite optimal medical therapy. The relationship between baseline resting perfusion pattern and hemodynamic response to CRT has not been fully investigated. We tested the usefulness of perfusion gated SPECT for baseline evaluation and follow-up of these patients. METHODS: In 20 patients, we performed gated SPECT before CRT and at the 3-mo follow up. Left ventricular (LV) ejection fraction (EF), end-diastolic (ED) and end-systolic (ES) volume indexes (VI), and wall motion score index (WMSI) were measured and compared with clinical outcome. RESULTS: One patient died before follow-up. The 19 remaining patients were classified into 1 of 2 groups according to the presence (group A) or absence (group B) of a significant severe perfusion defect at baseline before CRT. At the 3-mo follow-up, 6 of 10 group A and 8 of 9 group B patients had an improvement in New York Heart Association class. In both groups, quality of life, 6-min walking distance, and WMSI significantly improved. In group A, no significant change was registered in LVEF, LVEDVI, or LVESVI. In group B, LVEF increased from 23.1% +/- 8% to 27.1% +/- 11% (P < 0.03) and LVEDVI and LVESVI decreased from 159 +/- 70 mL to 135 +/- 68 mL (P < 0.02) and from 127 +/- 67 mL to 104 +/- 65 mL (P < 0.01), respectively. CONCLUSION: Perfusion gated SPECT appears useful to characterize and follow up candidates for CRT. Despite clinical improvement, patients with severe resting perfusion defects do not show significant improvement in LVEF or reduction in LV volumes.

[Prevalence of cardiovascular manifestations in Marfan syndrome]. / Prevalenza delle manifestazioni cardiovascolari nella sindrome di Marfan.

BACKGROUND: Marfan syndrome is an inherited connective tissue disorder with an autosomic dominant transmission. The prevalence is 1:5000-10 000 and the clinical major criteria involve the skeletal and ocular apparatus and the cardiovascular and central nervous system. The main cause of morbidity is represented by the thoracic aortic dissection/aneurysm that is responsible for 80% of the deaths. METHODS: We performed a clinical study on 227 patients enrolled at our Clinical and Research Marfan and Related Disorders Center. The aim of this study was to describe the prevalence of cardiovascular manifestation in this cohort of patients. RESULTS: Aortic dilation was present in 172 patients (75.8%), mitral valve prolapse in 179 (78.9%). Aortic insufficiency was present in 83 patients (36.6%), mitral insufficiency in 165 (72.7%). When analyzed separately, in < 10-year and > 40-year patients aortic dilation was more prevalent than mitral valve prolapse. Three patients presented with interatrial septal defect, 4 aortic bicuspid valve; 23 had a history of ventricular and supraventricular arrhythmias, and in 2 patients an implantable cardioverter device had been implanted. Fifty-seven patients were treated with beta-blockers and 28 had been operated for aortic aneurysmal dilation. CONCLUSIONS: In Marfan syndrome mitral valve prolapse and aortic dilation are the main cardiovascular manifestations, interatrial septal defect and aortic bicuspid valve had the same prevalence than in subjects without Marfan syndrome. These data refer to our first patient evaluation; further studies are needed to evaluate the progression and the natural history of cardiovascular manifestations in Marfan syndrome.

Cardiac amyloidosis: the heart of the matter.

Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissue including the heart. Cardiac amyloidosis could be primary a part of systemic acquired amyloidosis, or a result of heredofamilial amyloidosis. Although the infiltration of the heart from different types of amyloid results in restrictive cardiomyopathy that manifests with refractory congestive heart failure and conduction abnormalities, unequivocal identification of the deposited amyloidogenic protein is mandatory in order to avoid misdiagnosis and inappropriate treatment. Recent developments in imaging techniques and extracardiac tissue biopsy have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis of a patient with amyloidosis is still poor and depends upon the underlying disease, and the type and degree of dysfunction of the involved organs. Thus, early diagnosis is mandatory because patients with advanced disease are usually too ill for intensive therapy. This review outlines current approaches to diagnosis, assessment of disease severity, and treatment of cardiac amyloidosis.

Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in the gene encoding fibrillin-1 (FBN1), a matrix component of microfibrils. Dural ectasia, i.e. enlargement of the neural canal mainly located in the lower lumbar and sacral region, frequently occurs in Marfan patients. The aim of our study was to investigate the role of dural ectasia in raising the diagnosis of Marfan syndrome and its association with FBN1 mutations. We studied 40 unrelated patients suspected for MFS, who underwent magnetic resonance imaging searching for dural ectasia. In all of them FBN1 gene analysis was also performed. Thirty-seven patients resulted affected by Marfan syndrome according to the '96 Ghent criteria; in 30 of them the diagnosis was confirmed when revaluated by the recently revised criteria (2010). Thirty-six patients resulted positive for dural ectasia. The degree of dural ectasia was grade 1 in 19 patients, grade 2 in 11 patients, and grade 3 in 6 patients. In 7 (24%) patients, the presence of dural ectasia allowed to reach a positive score for systemic feature criterion. Twenty-four patients carried an FBN1 mutation, that were represented by 13 missense (54%), and 11 (46%) mutations generating a premature termination codon (PTC, frameshifts and stop codons). No mutation was detected in the remaining 16 (6 patients with MFS and 10 with related disorders according to revised Ghent criteria). The prevalence of severe (grade 2 and grade 3) involvement of dura mater was higher in patients harbouring premature termination codon (PTC) mutations than those carrying missense-mutations (8/11 vs 2/13, P = 0.0111). Our data emphasizes the importance of dural ectasia screening to reach the diagnosis of Marfan syndrome especially when it is uncertain and indicates an association between PTC mutations and severe dural ectasia in Marfan patients.

Right ventricular function in AL amyloidosis: characteristics and prognostic implication.

AIM: The importance of right ventricle (RV) dysfunction in AL amyloidosis has been underestimated. This study was designed to comprehensively evaluate RV function and its prognostic role in patients with AL amyloidosis with and without echocardiographic evidence of cardiac involvement. METHOD AND RESULTS: Fifty-two biopsy-proven AL amyloidosis patients underwent a thorough echocardiographic evaluation. Twenty-seven patients (CA) met the international echocardiographic criteria for cardiac involvement [left ventricular (LV) wall thickness ≥ 12 mm] and 25 patients had no cardiac amyloidosis features (NCA). Patients were compared with a sex- age-matched control group. Patients and controls underwent traditional, tissue Doppler (TDI), speckle-tracking left and RV echocardiographic evaluation. No difference was observed between groups in RV diastolic diameter, whereas CA patients showed increased RV free wall thickness (P< 0.0001). Compared with controls and NCA patients, traditional echocardiography, TDI, and speckle-tracking evaluation detected significantly (P< 0.0001) depressed RV longitudinal systolic function in CA patients. No difference was observed between groups at Doppler diastolic evaluation, whereas at tricuspidal annulus TDI analysis, CA subject showed significantly lower E' and A' values with increased E/E' ratio (P< 0.0001). Over a 19 months median follow-up period, 18 patients died. Cox multivariate analysis showed that N-terminal pro-Brain natriuretic peptide and RV longitudinal strain were the strongest death predictor. CONCLUSION: Our data show that in patients with AL amyloidosis, RV involvement develops later than LV amyloid deposition but when it occurs, prognosis dramatically worsens. Moreover RV longitudinal strain was the only echocardiographic predictor of prognosis. We suggest that RV function analysis should be performed routinely as a part of echocardiographic evaluation in these patients.

Acute hemodynamic effect of left ventricular endocardial pacing in cardiac resynchronization therapy: assessment by pressure-volume loops.

BACKGROUND: During cardiac resynchronization therapy (CRT) device implantation, the pacing lead is usually positioned in the coronary sinus (CS) to stimulate the left ventricular (LV) epicardium. Transvenous LV endocardial pacing via transseptal puncture has been proposed as an alternative method. In the present study, we evaluated the acute hemodynamic effects of CRT through LV endocardial pacing in heart failure patients by analyzing LV pressure-volume relationships. METHODS AND RESULTS: LV pressure and volume data were determined via conductance catheter during CRT device implantation in 10 patients. In addition to the standard epicardial CS pacing, the following endocardial LV sites were systematically assessed: the site transmural to the CS lead, the LV apex, the septal midwall, the basal lateral free wall, and the midlateral free wall. Four atrioventricular delays were tested. There was a significant improvement of systolic function with CRT in all LV pacing configurations, whereas no differences in systolic or diastolic function were detected between LV epicardial and endocardial transmural sites. The optimal pacing site varied among patients but was rarely related to relatively longer activation delays, as assessed by analyzing endocardial electric activation maps. Nonetheless, positioning the pacing lead at the optimal endocardial LV site in each patient significantly improved LV performance in comparison with conventional CS site stimulation (stroke volume, 83 [79-112] mL versus 73 [62-89] mL; P=0.034). CONCLUSIONS: Pacing at the optimal individual LV endocardial site yields enhanced LV performance in comparison with conventional CS site stimulation. Endocardial LV pacing might constitute an alternative approach to CRT, when CS pacing is not viable.

Cardiac memory in humans: vectocardiographic quantification in cardiac resynchronization therapy.

BACKGROUND: "Cardiac memory" (CM) refers to a change in repolarization induced by an altered pathway of activation. The effects of biventricular pacing on CM induction have not been investigated. OBJECTIVE: To investigate the development of CM during cardiac resynchronization therapy (CRT) through vectorcardiography (VCG). METHODS: Eleven patients undergoing CRT were enrolled. VCG was acquired during spontaneous ventricular activation at baseline and during AAI and DDD pacing immediately after and 7, 14, 21 and 60 days after the implantation. RESULTS: At 1-week follow-up, during AAI pacing T vector angles significantly changed (azimuth 23 ± 19°; p = 0.002; elevation 23 ± 27°; p = 0.019) and magnitude significantly increased (baseline 1.13 ± 0.69 mV; 7 days: 1.77 ± 1.27 mV; p = 0.026). T angle changes remained stable throughout the follow-up period while a further significant increase in magnitude was observed at 60 days (2.21 ± 1.50 mV; p = 0.01 vs. baseline and p = 0.04 vs. 7 days). Paced T vector magnitude at implant (2.24 ± 1.25 mV) decreased significantly at 7 days (1.64 ± 1.26 mV; p = 0.030) with a further significant decrease at 60 days (1.40 ± 1.18 mV; p = 0.003 vs. baseline; p = 0.02 vs. 7 days). CONCLUSION: CRT induces a significant change in T vector magnitude, azimuth, and elevation after resumption of spontaneous ventricular activation after 7 days from implantation. While further changes in T vector angle were not observed, after 2 months of CRT a significant decrease of paced T vector magnitude and a significant increase of spontaneous T vector magnitude were observed.

May TGFBR1 act also as low penetrance allele in Marfan syndrome?

Marfan syndrome, a human disease involving cardiovascular and skeletal apparatuses and ocular and central nervous systems, is associated to mutations in FBN1 gene; heterozygous mutations in TGFBR2 and TGFBR1 genes were found associated to MFS type 2, characterized by the presence of skeletal and cardiovascular major criteria and absence of eye major criterion. We screened the TGFBR1 gene in 46 Marfan patients in whom mutations in FBN1 and TGFBR2 genes were excluded and the analysis of Ex1 was extended to additional 114 Marfan patients and 237 controls. We detected two potentially pathological sequence variants: the TGFBR1 6Ala allele whose frequency was higher in the group of Marfan patients (0.13) than in the controls (0.08) (p=0.013; OR=1.69) and an insertion of 20 nucleotides in the 5'UTR that turned out to be a familial silent rare polymorphism. We hypothesize that TGFBR1 sequence variants may act not only as major, but also as low penetrance alleles of the clinical phenotype in Marfan syndrome.

Vascular and connective tissue features in 5 Italian patients with homocystinuria.

Homocystinuria is a metabolic disorder associated with defects in genes encoding for methionine metabolism enzymes. Vascular and connective tissue manifestations such as deep venous thrombosis, ectopia lentis and skeletal alterations are the major clinical features. We investigated the clinical manifestations of 5 Italian homocystinuric patients, performed mutation screening analysis on cystationine beta-synthase (CBS) gene and searched for genotype/phenotype correlations. We detected mild cardiovascular and skin connective tissue stigmas in these patients, never reported in homocystinuric patients before. We found 1 novel and 7 known mutations. Our patients carried no other mutation associated with venous thrombosis. Our data stress the importance of extending the clinical investigation for connective tissue manifestations in homocystinuric patients to all the organs/systems involved in Marfan syndrome, also suggesting long term follow-ups for cardiovascular manifestations.

Effects of cardiac resynchronization therapy on systemic inflammation and neurohormonal pathways in heart failure.

BACKGROUND: The effect of cardiac resynchronization therapy (CRT) on systemic inflammation and neurohormonal alterations associated with heart failure is not well characterized. Accordingly, we aimed to assess the long term effects of CRT on systemic inflammation and neurohormonal factors in heart failure patients. METHODS AND RESULTS: In 47 HF patients (NYHA III-IV) we evaluated, at baseline and after one year of CRT: TNF-alpha, TNF soluble receptors (sTNFR1 and sTNFR2), insulin-like growth factor-1alpha (IGF-1alpha), adiponectin, norepinephrine, pro-atrial natriuretic peptide (pro-ANP), N-terminal-pro-brain natriuretic peptide (NT-proBNP) and angiotensin II, NYHA functional class, quality of life (the Minnesota Living with Heart Failure questionnaire), a 6-minute walk test and an echocardiogram. Long-term CRT decreased activation of renin-angiotensin system (RAS) only in patients with reverse remodelling. It failed to prevent a decline in adiponectin levels, regardless of reverse remodelling. NT-proBNP remained unchanged in patients with reverse remodelling, whereas its levels increased in those without reverse remodelling. IGF-1alpha increased with CRT, whereas CRT had no effect on pro-ANP and inflammatory markers. CONCLUSIONS: Long-term CRT is associated with decreased RAS activation and stabilization of NT-proBNP in heart failure patients with reverse remodelling. Long-term CRT, with or without reverse remodelling, does not affect systemic inflammation and fails to prevent a decline in adiponectin.

Tissue Doppler and strain imaging: a new tool for early detection of cardiac amyloidosis.

Using traditional echocardiography, the diagnosis of cardiac amyloidosis (CA) is often only possible in advanced stage when recommended therapies may have adverse effects. The aim of our study was to evaluate whether additional information can be derived from Tissue and strain Doppler imaging (TDI and SDI). Forty patients with systemic amyloidosis and 24 healthy subjects underwent traditional, tissue and strain Doppler echocardiography. Patients were classified having CA if mean wall thickness (mT), was half of the sum septum and posterior wall thickness, was > or =12 mm. The following parameters were evaluated: peak early diastolic velocity (Em) as index of ventricular relaxation, mitral E-wave to Em ratio (E/Em) as index of left ventricular (LV) filling pressure and mean LV strain peak curves (mSt) as global long-axis contraction index. In non cardiac amyloidosis (NCA), both Em and mSt were lower than in age matched controls (p < 0.01, p < 0.05, respectively) and higher than in CA (p < 0.01 and p < 0.01, respectively). Both Em and mSt were related to mT (p < 0.001). A significant (p < 0.01) nonlinear relation was observed between plasma terminal of pro B-natriuretic peptide and mT, Em, E/Em and mSt. TDI and SDI are able to detect amyloid myocardial involvement in such an early stage that cannot be evidenced by using traditional echocardiography.