Prognostic value of 6-min walk test compared to cardiopulmonary exercise test in patients with severe heart failure.

AIMS: The 6-min walk test (6MWT) and cardiopulmonary exercise test (CPET) are both predictive in heart failure (HFrEF). Although 6MWT substitutes for CPET in HFrEF patients, as submaximal testing may be preferable, its prognostic superiority still needs to be verified, particularly in regard to beta blockers (BBs). We aimed to compare the prognostic role of CPET and 6MWT and investigate whether BB therapy influences the predictive value. METHODS: This is a single-center, retrospective study. Advanced HFrEF patients were followed up for 3 years: events were cardiovascular death or urgent heart transplantation. We analyzed the predictive capacity of CPET and 6MWT in patients, and subdivided according to use of BBs. RESULTS: In a group of 251 HFrEF patients, we found a correlation between meters and peak VO2 (r2 = 0.94). Over the 3-year follow-up, 74 events were recorded. Both CPET and 6MWT variables were correlated with outcome at univariate analysis (meter and VE/VCO2 slope, peak VO2, VO2 at ventilatory anaerobic threshold, percentage predicted of peak VO2), but only percentage predicted of peak VO2 (pppVO2) was an independent predictor. In 103 HFrEF patients on BBs (23 nonsurvivors), neither pppVO2 nor meter were predictive, while in 148 patients not treated with BB (51 with events) pppVO2 was selected as an independent prognostic parameter (P = 0.001). CONCLUSIONS: 6MWT is a valid alternative to CPET, although the percentage of predicted of peak VO2 emerged as the strongest predictor. Nonetheless, our results suggest that both functional derived parameters are not predictive among those patients treated with BBs. Further studies are necessary to confirm these findings.

Cardiovascular disease patients and predictors of length of stay of residential of cardiac rehabilitation. A specific rehabilitation is mandatory in very old patients?

As more adults are living into old age, they are predisposed to cardiovascular disease (CVD) and the demand for cardiac rehabilitation is increasing. We aimed to verify predictors of length of stay (LOS) in young (Y) vs older (O) vs very old (VO) CVD patients, admitted to residential cardiac rehabilitation. Patients' demographic and clinical characteristics at admission, as well as Barthel index (BI), Cumulative Illness Rating Scale (CIRS), comorbidity severity/complexity, NYHA classification, left ventricular ejection fraction (LVEF), physical activity level were compared in Y (≤65 years) vs O (between >65 and <76 years) vs VO patients (with an age of ≥76 years) against LOS. In 5,070 consecutively CVD patients were included; they were 1392 Y (38%) 1944 O (35%) 1334 VO patients (27%) and LOS duration was 16±7, 19±9 and 22±10 days, respectively (p<0.0001). In Y, LOS was linked to BI (p=0.000) and to LVEF (p=0.000) at multivariable analysis with area under ROC curve of 0.82, whereas in O, LOS was associated to gender (p=0.013) CIRS severity (p=0.000), BI (p=0.000), LVEF (p=0.000), and in those VO to gender (p=0.004), BI (p=0.000) and medical infusion (p=0.000) at multivariable with ROC curve of 0.83 and 0.74, respectively. In very old patients, a prolonged LOS is related to extra-cardiac conditions. Therefore, we promote a specific cardiac rehabilitation for these patients.

Cardiopulmonary exercise testing in patients with asymptomatic left ventricular dysfunction: lack of prognostic predictive power of ventilatory variables.

AIMS: The indication for cardiopulmonary exercise testing (CPET) in predictive evaluation has been extended beyond chronic heart failure (HF) patients to include asymptomatic left ventricular dysfunction (ALVD) patients, but its prognostic value is still unclear. We aimed to verify if CPET can predict outcome in ALVD and to identify which of the CPET parameters predictive in chronic HF are also effective in ALVD patients. METHODS AND RESULTS: We screened ALVD (LVEF ≤ 40% without HF symptoms) and HF patients for cardiac death, and compared peak oxygen consumption (pVO2), exertional oscillatory ventilation (EOV), and ventilatory response (VE/VCO2 slope) between survivors and non-survivors. Asymptomatic left ventricular dysfunction and HF patients formed the study population (585 ALVD and 695 HF). Both groups had similar male prevalence (98% vs. 98%; P = 0.345) but ALVD patients were younger (52 ± 10 vs. 60 ± 10 years, P = 0.004). Cardiac death was observed in 142 patients (5% of ALVD, 15% of HF). Exertional oscillatory ventilation occurred in 4% of ALVD, whereas VE/VCO2 slope was significantly lower (30 ± 7 vs. 35 ± 4) and pVO2 higher (16 ± 4 vs. 14 ± 3 mL/kg/min) than in chronic HF patients. Asymptomatic left ventricular dysfunction non-survivors had a significantly greater EOV incidence (13% vs. 3%, P = 0.003), lower pVO2 (13 ± 4 vs. 16 ± 3 mL/kg/min P = 0.000) and higher VE/VCO2 slope (33 ± 7 vs. 31 ± 5, P = 0.032). No ventilatory parameter had prognostic value at multivariable analysis in ALVD patients. CONCLUSIONS: Cardiopulmonary exercise testing can predict events in ALVD patients, but the risk stratification relies on different parameters than in HF patients. Further analysis in a multi-centre trial is required to better quantify the predictive impact of CPET risk parameters in ALVD patients.

The Future of Exercise-Based Cardiac Rehabilitation for Patients With Heart Failure.

Cardiac rehabilitation (CR) is a comprehensive program that includes exercise training, titration of medical therapy, lifestyle modification, educational support, and psychosocial assessment. All these components are safe and beneficial resulting in significant improvements in quality of life, functional capacity, mortality, and hospital readmission. Current guidelines support its use in a broad spectrum of cardiac disease. This review focuses on exercise-based CR for heart failure (HF) patients in whom CR is a recommended treatment. Exercise should be prescribed according to a personalized approach, optimizing, and tailoring the rehabilitative program to the patient's characteristics. Specific CR programs are dedicated to older patients, those with HF and preserved ejection fraction, and recipients of cardiac implantable electronic devices or left ventricular assistance device. Telemedicine may increase CR participation and overcome some of the barriers that limit its utilization.

Exertional and nocturnal periodic breathing after successful cardiac transplantation. A case report.

We present a case report of a heart failure patient who underwent cardiopulmonary exercise testing and sleep screening 12 months before and after heart transplantation (HTx). Severe Cheyne-Stokes respiration (CSR) with central sleep apnoea (CSA) was identified either before and after HTx, while periodic breathing during exercise vanished. We suggest that optimization of hemodynamics and medical therapy (low dose of diuretic) did not withdraw the central mechanisms underlying the diathesis for CSR-CSA. While periodic breathing during exercise reversal may support a closer link with an exertional central hemodynamic. This observation indirectly neglects the possible unifying mechanistic background of CSR and periodic breathing, during exercise, in this setting.

Aortic root 3D parametric morphological model from 2D-echo images.

The gold standard for the study of the macro-anatomy of the aortic root are multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging. Both technologies have major advantages and limitations. Although 4D echo is entering the study of the aortic root, 2D echo is the most commonly used diagnostic tool in daily practice. We designed and developed an algorithm for 3D modeling of the aortic root based on measures taken routinely at 2D echocardiography from 20 healthy individuals with normal aortic root. The tool was then translated in 12 patients who underwent both echo and MDCT. The results obtained with the 3D modeling program were quantitatively and qualitatively compared with 3D reconstruction from MDCT. Ad hoc ratios describing the morphology of the aortic root in MDCT and in the 3D model were used for comparison. In 12 patients with aortic root dilatation, the ratios obtained with our model are in good agreement with those from MDCT. Linear correlation for both long axis and short axis ratios was strong. The 3D modeling software can be easily adopted by cardiologists routinely involved in clinical evaluation of the pathology of the aortic root. The tool is easy to apply, does not require additional costs, and may be used to generate a set of data images for monitoring the evolution of the morphology and dimension of the aortic root, flanking the 3D MDCT and MR that remain the gold standard tools.

Quantitative expression of the mutated lamin A/C gene in patients with cardiolaminopathy.

OBJECTIVES: The authors sought to investigate the gene and protein expression in Lamin A/C (LMNA)-mutated dilated cardiolaminopathy (DCM) patients (DCM(LMNAMut)) versus LMNA-wild-type DCM (DCM(LMNAWT)), and normal controls (CTRL(LMNAWT)). BACKGROUND: Dilated cardiolaminopathies are clinically characterized by high arrhythmogenic risk and caused by LMNA mutations. Little is known regarding quantitative gene expression (QGE) of the LMNA gene in blood and myocardium, as well as regarding myocardial expression of the lamin A/C protein. METHODS: Using the comparative ΔΔCT method, we evaluated the QGE of LMNA (QGE(LMNA)) in peripheral blood and myocardial RNA from carriers of LMNA mutations, versus blood and myocardial samples from DCM(LMNAWT) patients and CTRL(LMNAWT) individuals. After generating reference values in normal controls, QGE(LMNA) was performed in 311 consecutive patients and relatives, blind to genotype, to assess the predictive value of QGE(LMNA) for the identification of mutation carriers. In parallel, Lamin A/C was investigated in myocardial samples from DCM(LMNAMut) versus DCM(LMNAWT) versus normal hearts (CTRL(LMNAWT)). RESULTS: LMNA was significantly underexpressed in mRNA from peripheral blood and myocardium of DCM(LMNAMut) patients versus DCM(LMNAWT) and CTRL(LMNAWT). In 311 individuals, blind to genotype, the QGE(LMNA) showed 100% sensitivity and 87% specificity as a predictor of LMNA mutations. The receiver-operating characteristic curve analysis yielded an area under the curve of 0.957 (p < 0.001). Loss of protein in cardiomyocytes' nuclei was documented in DCM(LMNAMut) patients. CONCLUSIONS: The reduced expression of LMNA gene in blood is a novel potential predictive biomarker for dilated cardiolaminopathies with parallel loss of protein expression in cardiomyocyte nuclei.

Diagnostic work-up and risk stratification in X-linked dilated cardiomyopathies caused by dystrophin defects.

OBJECTIVES: We sought to describe the diagnostic work-up, phenotype, and long-term evolution of dilated cardiomyopathy (DCM) associated with Dystrophin (DYS) defects. BACKGROUND: X-linked DCM associated with DYS defects can be clinically indistinguishable from other types of DCM. METHODS: The series comprises 436 consecutive male patients diagnosed with DCM. Patients underwent endomyocardial biopsy (EMB). Genetic testing employed multiplex polymerase chain reaction and multiple ligation dependent probe assay for deletions and direct sequencing of the 79 exons and flanking regions of the gene for point mutations or small rearrangements. RESULTS: We identified DYS defects in 34 of 436 patients (7.8%) (onset age 34 ± 11 years, age range 17 to 54 years); 30 had proven X-linked inheritance. The 2 phenotypes included DCM with mild skeletal myopathy and/or increased serum creatine phosphokinase (n = 28) or DCM only (n = 6). The EMB showed defective dystrophin immunostain. The DYS defects consisted of 21 in-frame deletions and 11 out-of-frame deletions as well as 1 stop and 1 splice-site mutation. During a median follow-up of 60 months (interquartile range: 11.25 to 101.34 months) we observed 17 events, all related to heart failure (HF) (median event-free survival: 83.5 months). Eight patients (23%) underwent transplantation, and 9 (26%) died of HF while waiting for transplantation. Eight patients received an implantable cardioverter-defibrillator, although none had device intervention during a median follow-up of 14 months (interquartile range: 5 to 25 months). No patient died suddenly, suffered syncope, or developed life-threatening ventricular arrhythmias. CONCLUSIONS: DYS-related DCM should be suspected in male patients with increased serum creatine phosphokinase (82%) and X-linked inheritance. The disease shows a high risk of end-stage HF but a lower risk of life-threatening arrhythmias.

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2).

OBJECTIVE: To evaluate the prevalence and phenotype of smooth muscle alpha-actin (ACTA2) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD). DESIGN: Observational study of ACTA2 mutations in TAAD. SETTING: Centre for Inherited Cardiovascular Diseases. PATIENTS: A consecutive series of 100 patients with TAAD. Exclusion criteria included genetically confirmed Marfan syndrome, Loeys-Dietz type 2, familial bicuspid aortic valve and Ehlers-Danlos type IV syndromes. INTERVENTIONS: Multidisciplinary clinical and imaging evaluation, genetic counselling and testing of ACTA2, and family screening. MAIN OUTCOME MEASURES: Prevalence of ACTA2 mutations and corresponding phenotypes. RESULTS: TAAD was familial in 43 cases and sporadic in 57 cases. Five mutations in the familial TAAD group (12%) were identified that were absent in controls. The known p.Arg149Cys and the novel p.Asp82Glu, p.Glu243Lys and p.Val45Leu mutations affected evolutionarily conserved residues. The IVS4+1G>A mutation was novel. Of 14 affected relatives, 13 were carriers of the mutation identified in the corresponding proband while one deceased relative had no genetic test. Type A dissection was the first manifestation of aortic aneurysm in four probands and occurred unexpectedly in five relatives. The aortic aneurysm was age dependent and absent in mutated children. Of nine patients who had acute dissection, five died following surgery. At dissection, the size of the aortic aneurysm ranged from 40 mm to 95 mm. Extravascular, ocular, skeletal, nervous and pulmonary traits were variably associated with TAAD, with iris flocculi being most common. CONCLUSIONS: Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections.

When should cardiologists suspect Anderson-Fabry disease?

Anderson-Fabry disease is a lysosomal storage disorder caused by α-galactosidase defects and progressive intracellular accumulation of globotriaosylceramide. The disease can be specifically treated with enzyme replacement therapy. Hemizygous men and heterozygous women can develop cardiac disease. Whereas men experience the most severe clinical phenotype, clinical presentation in women varies from asymptomatic to severely symptomatic. The characteristic cardiac phenotype is left ventricular hypertrophy mimicking sarcomeric hypertrophic cardiomyopathy or hypertensive heart disease. Early or prehypertrophy cardiac involvement may escape detection, unless electrocardiographic clues are present. The cardiac markers that raise suspicion of Anderson-Fabry disease include a short PR interval without a δ wave and a prolonged QRS interval, supraventricular and ventricular arrhythmias, and concentric left ventricular hypertrophy. Extracardiac features include renal failure, corneal deposits, and nervous, gastrointestinal, and cutaneous manifestations. Useful family data include cardiac and extracardiac traits in relatives and absence of male-to-male transmission. Symptoms are subtle, and the interval between the onset of symptoms and diagnosis may be as long as 20 years. As such, the diagnosis is typically late. Endomyocardial biopsy shows optically empty myocytes on light microscopy and dense osmiophilic bodies constituted of globotriaosylceramide on electron microscopy. Alpha-galactosidase A activity is reduced in hemizygous men but not in heterozygous women. Genetic testing is the gold standard for the diagnosis. In conclusion, a correct and timely diagnosis offers the possibility of disease-specific treatment that leads to sustained clinical benefits for cardiac and noncardiac signs and symptoms.

Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations.

BACKGROUND: The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS. METHODS: The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48. CONCLUSION: The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

Transcriptomic and proteomic analysis in the cardiovascular setting: unravelling the disease?

Whole gene expression analysis through microarray technologies revolutionized the manner of identifying changes in biological events and complex diseases, such as cardiovascular settings. These new methodologies may scan up to 35 000 transcripts at once rather than screening a small amount of genes one at a time. The ability of microarrays to provide a broad insight into the disease process directly within the tissues provides a unique insight into the intracellular perturbations of the cell organization and function and sheds an entirely unique new perspective on the heart failure process. Commonalities and differences at the molecular level will identify critical pathways of pathogenesis, and response to therapy, or both: indeed, gene expression profiling holds tremendous promise for classifying clinical phenotypes, developing prognostic predictors and, most importantly, providing novel unbiased insights into the mechanisms underlying heart disease and, eventually, novel causative genes. On the contrary, established proteomic technologies, together with the new alternative strategies currently under evaluation (i.e. metabolomics), are now making possible the translation of data obtained on the bench to the daily clinical routine with the discovery of new diagnostic/prognostic biomarkers (such as troponin for ACS and BNP for congestive heart failure) and the identification of new therapeutic approaches for combating heart diseases. Finally, genomic studies (including transcriptomics) together with proteomics should not represent a challenge for who is going to win the final battle, but rather they should provide a setting in which together and in a complementary fashion the final fight against heart disease can be won.

Long-term outcome and risk stratification in dilated cardiolaminopathies.

OBJECTIVES: The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies. BACKGROUND: Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases. METHODS: Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype. RESULTS: Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for >or=10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death. CONCLUSIONS: Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

Clinical and therapeutical follow-up of HIV-associated pulmonary hypertension: prospective study of 10 patients.

OBJECTIVE: To determine the clinical course and prognosis of pulmonary hypertension (PH) in HIV-infected patients in comparison with a group of PH patients without HIV infection. The secondary objective was to ascertain whether more powerful antiretroviral treatments (highly active antiretroviral therapy) could modify the course of PH in HIV-infected patients. DESIGN: Patients with PH and HIV (HIV-PH, group 1) and patients without HIV (PPH, group 2) were prospectively followed. SETTING: A tertiary care institution. PATIENTS: Group 1 included 10 patients, and group 2 included 25 patients. INTERVENTIONS: In group 1, HIV infection was staged according to Centers for Disease Control and Prevention (CDC) classification when patients entered the study, and was re-staged every fourth month. In both groups, PH functional classes and right heart catheterization (RHC) were determined at baseline. RESULTS: In group 1, one of 10 patients was assigned to New York Heart Association (NYHA) class II, seven patients to NYHA class III, and two patients to NYHA class IV. CDC stages ranged from A1 (three patients) to C3 (one patient). No patient showed progression of HIV disease during follow-up. By May 2001, six patients had died. The median survival by the time of RHC was 15.1 months. Causes of death were heart failure in three cases, sepsis in two, and suicide in one case. In seven patients, epoprostenol was started; three patients survived and four died. The cause of death was heart failure in one patient, suicide in one, non-catheter-related sepsis in one patient and catheter-related sepsis in the last patient. In group 2, 11 patients out of 25 were assigned to NYHA class II, 11 patients to NYHA class III, and three patients to NYHA class IV. RHC was not statistically different in the two groups. By May 2001, nine of 25 patients died and one underwent a double-lung transplant. The median survival from the time of RHC was 6.86 months. Cumulative survival rates by RHC were not statistically different (hazard ratio close to 1). CONCLUSIONS: In HIV-infected patients, the onset of PH adversely affects the prognosis at any stage of infection. Clinically adverse progression of PH is not correlated with HIV initial stage and evolution. Moreover, prognosis in patients with sporadic or familial PPH and in patients with HIV-PH with similar RHC is so similar as to strengthen the concept that pulmonary vascular disease overshadows the overall clinical problem in HIV-infected patients.