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Background C-type natriuretic peptide production by the heart in patients with chronic heart failure has recently been demonstrated by measuring the difference in C-type natriuretic peptide plasma levels between the aortic root and coronary sinus samples. To assess this previous relevant observation, we re-evaluated the cardiac production of C-type natriuretic peptide, thus increasing the total number of patients studied. In light of the difficulty in recruiting patients with these characteristics, this kind of study can be performed with a small number of subjects. Methods Cardiac production of C-type natriuretic peptide was evaluated in a subset (n = 6) of patients, referred to our institute for the evaluation of chronic heart failure. C-type natriuretic peptide was measured in the coronary sinus and in aorta blood collected during right and left heart catheterization using a specific immunometric assay, after solid-phase extraction of plasma samples. Results Significantly higher C-type natriuretic peptide levels were found in the coronary sinus than in aorta blood (7.8 +/- 1.3 versus 6.1 +/- 1.5 pg/ml, P = 0.034) and our results were in accordance with previous ones. Analysing as a whole the data gathered in the two studies, a noteworthy significant increase was observed (n = 15, P = 0.002) between the C-type natriuretic peptide concentrations in the two sites. Conclusions The results of the present study strengthen the hypothesis that C-type natriuretic peptide is produced by the heart in patients with chronic heart failure.

To determine whether skin blood flow is local or takes part in general regulatory mechanisms, we recorded laser-Doppler flowmetry (LDF; left and right index fingers), blood pressure, muscle sympathetic nerve activity (MSNA), R-R interval, and respiration in 10 healthy volunteers and 3 subjects after sympathectomy. We evaluated 1) the synchronism of LDF fluctuations in two index fingers, 2) the relationship with autonomically mediated fluctuations in other signals, and 3) the LDF ability to respond to arterial baroreflex stimulation (by neck suction at frequencies from 0.02 to 0.20 Hz), using spectral analysis (autoregressive uni- and bivariate, time-variant algorithms). Synchronous LDF fluctuations were observed in the index fingers of healthy subjects but not in sympathectomized patients. LDF fluctuations were coherent with those obtained for blood pressure, MSNA, and R-R interval. LDF fluctuations were leading blood pressure in the low-frequency (LF; 0.1 Hz) band and lagging in the respiratory, high-frequency (HF; ∼0.25 Hz) band, suggesting passive “downstream” transmission only for HF and “upstream” transmission for LF from the microvessels. LDF fluctuations were responsive to sinusoidal neck suction up to 0.1 Hz, indicating response to sympathetic modulation. Skin blood flow thus reflects modifications determined by autonomic activity, detectable by frequency analysis of spontaneous fluctuations.

Over the last 5 years, several immunoassay methods for the measurement of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) became commercially available. Recent studies have confirmed the clinical usefulness of measurements of these cardiac natriuretic peptides for the prognostic stratification of patients with congestive heart failure, for the detection of left ventricular systolic and/or diastolic dysfunction, and for the differential diagnosis of dyspnea (1)(2)(3)(4). However, to answer the most urgent requests of current clinical practice and to allow widespread use of BNP and NT-proBNP assays, some key issues had to be solved, such as increasing the sensitivity, precision, and experimental practicability (5). The aim of the present study was to evaluate and compare the analytical and clinical performance of five commercial natriuretic peptide immunoassays. Throughout this report, the values in healthy individuals and patients are reported as the range, median, and 25th and 75th percentiles. We enrolled 172 healthy adults (89 women and 83 men; age range, 16–73 years; median age, 49.0 years; 25th percentile, 38 years; 75th percentile, 58 years). All participants were nonobese (body mass index, 19.4–27.6 kg/m2, 24 kg/m2, 22.8 kg/m2, and 25.6 kg/m2), normotensive (diastolic blood pressure, 60–85 mmHg, 70 mmHg, 70 mmHg, and 80 mmHg; systolic blood pressure, 90–140 mmHg, 120 mmHg, 102.5 mmHg, and 124.5 mmHg), and free from acute or chronic diseases. All participants had main plasma indices (including creatinine, urea nitrogen, glucose, uric acid, albumin, enzymes, electrolytes, and hemoglobin) within the appropriate reference intervals, and normal erythrocyte and leukocyte counts …

We thank Drs Alter1 and Taylor et al2 for their attention on our article and the interesting issues raised. With regard to Dr Alter’s comments, the correlation between late gadolinium enhanced (LGE) detected by contrast-enhanced cardiovascular magnetic resonance and replacement fibrosis seen on histology has been described in several autopsy cases of idiopathic dilated cardiomyopathy.3,4 In 7 explanted idiopathic dilated cardiomyopathy hearts, Gulati et al4 showed an excellent agreement between replacement fibrosis at histopathology and LGE as seen with in vivo cardiovascular magnetic resonance. In our study,5 we disregarded spotty LGE confined to the interventricular septum insertion points because …

Background— In idiopathic dilated cardiomyopathy, there are scarce data on the influence of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance on left ventricular (LV) remodeling. Methods and Results— Fifty-eight consecutive patients with idiopathic dilated cardiomyopathy underwent baseline clinical, biohumoral, and instrumental workup. Medical therapy was optimized after study enrollment. Cardiovascular magnetic resonance was used to assess ventricular volumes, function, and LGE extent at baseline and 24-month follow-up. LV reverse remodeling (RR) was defined as an increase in LV ejection fraction ≥10 U, combined with a decrease in LV end-diastolic volume ≥10% at follow-up. ΔLGE extent was the difference in LGE extent between follow-up and baseline. LV-RR was observed in 22 patients (38%). Multivariate regression analysis showed that the absence of LGE at baseline cardiovascular magnetic resonance was a strong predictor of LV-RR (odds ratio, 10.857 [95% confidence interval, 1.844–63.911]; P =0.008) after correction for age, heart rate, New York Heart Association class, LV volumes, and LV and right ventricular ejection fractions. All patients with baseline LGE (n=26; 45%) demonstrated LGE at follow-up, and no patient without baseline LGE developed LGE at follow-up. In LGE-positive patients, there was an increase in LGE extent over time ( P =0.034), which was inversely related to LV ejection fraction variation (Spearman ρ, −0.440; P =0.041). Five patients showed an increase in LGE extent >75th percentile of ΔLGE extent, and among these none experienced LV-RR and 4 had a decrease in LV ejection fraction ≥10 U at follow-up. Conclusions— In patients with idiopathic dilated cardiomyopathy, the absence of LGE at baseline is a strong independent predictor of LV-RR at 2-year follow-up, irrespective of the initial clinical status and the severity of ventricular dilatation and dysfunction. The increase in LGE extent during follow-up was associated with progressive LV dysfunction.

Background Ventilatory impairment is known to occur in patients with heart failure (HF). Alveolar volume (VA) is measured by the dilution of an inert gas during a single breath-hold maneuver. Such measurement is sensitive to ventilatory disturbances. We conducted a prospective, observational study to establish the prognostic value of VA in systolic HF. Methods We studied 260 consecutive patients who were hospitalized for systolic HF. All patients were evaluated under stable clinical conditions, before hospital discharge. Lung function studies included spirometry and determination of the lung diffusing capacity for carbon monoxide (DLCO) by the single-breath method. We also measured the cardiothoracic ratio on frontal chest radiographs, and the circulating levels of N-terminal pro-hormone of B-type natriuretic peptide (NT-proBNP). The hazard ratio (HR) of death was estimated with Cox regression, and the percentiles of survival time with Laplace regression. For survival analysis, VA was categorized as 0.5, NT-proBNP, persistent atrial fibrillation, DLCO, COPD comorbidity, use of beta-blockers and angiotensin converting enzyme inhibitors, the HR decreased to 1.9 but remained statistically significant (p = 0.039). Two percent of the patients with VA

The “clogged pipe” analogy of coronary artery disease (CAD) is questioned as a conceptual model to interpret symptoms, evaluate prognosis, and guide therapy in ischemic patients [(1,2)][1]. Clinical studies indicate that most cardiac events occur in patients who have angiographically mild

Background Recent studies suggested that there are marked systematic differences among BNP immunoassays. In this study we compared the BNP data and clinical results obtained with different immunoassays, including a new method (ST-AIA-PACK, TOSOH Corporation). Methods BNP was measured on plasma-EDTA samples of healthy subjects (HS, n = 126) and patients with heart failure (HF, n = 31 NYHA I, II; n = 46 NYHA III, IV) using the ST-AIA-PACK and the Triage Biosite (Beckman Coulter) methods. Control samples distributed in the CardioOrmoCheck external quality assessment were also measured with TOSOH and the most used BNP immunoassays in Italy. Results TOSOH method showed a good correlation (R = 0.976; n = 327) but a mean bias (− 46.9%) compared to Triage Biosite. On the base of the results obtained in 10 samples of the CardioOrmoCheck study, TOSOH method showed a strict agreement with ADVIA Centaur, while it underestimated BNP in comparison with Triage (− 52.5%) and ARCHITECT methods (− 39.4%). The agreement of ST-AIA-PACK and Triage Biosite methods for classification of HF patients was tested using 100 ng/L of BNP; the positive agreement between methods was 65%, overall agreement was 73%. Conclusions Our results confirm that there are marked differences in measured values among commercial methods for BNP assay.

We assessed GGT fractions correlates and their reference values in the Offspring Cohort of the Framingham Heart Study.Correlates of GGT fractions were assessed by multivariable regression analysis in 3203 individuals [47% men, mean age (SD): 59 (10) years]. GGT fractions reference values were established by empirical quantile analysis in a reference group of 432 healthy subjects [45% men, 57 (10) years].Fractional GGT levels were higher in men than in women (P0.0001). In both sexes, fractions were associated with: triglycerides were associated with b-GGT, alcohol consumption with m-, s- and f-GGT. C-reactive protein with m- and s-GGT, while plasminogen activator inhibitor-1 with b- and f-GGT. Body mass index, blood pressure, glucose and triglycerides correlated with b- and f-GGT. In comparison with the reference group [b-GGT/s-GGT median (Q1-Q3): 0.51 (0.35-0.79)U/L], subjects affected by cardiovascular disease or diabetes showed no change of b/s ratio [0.52 (0.34-0.79)U/L, 0.57 (0.40-0.83)U/L, respectively]. The b/s ratio was higher in presence of metabolic syndrome [0.61 (0.42-0.87)U/L, P0.0001], while lower in heavy alcohol consumers [0.41 (0.28-0.64)U/L, P0.0001].Metabolic and cardiovascular risk markers are important correlates of GGT fractions, in particular of b-GGT.

Background Peripheral and central chemoreflex sensitivity, assessed by the hypoxic or hypercapnic ventilatory response (HVR and HCVR, respectively), is enhanced in heart failure (HF) patients, is involved in the pathophysiology of the disease, and is under investigation as a potential therapeutic target. Chemoreflex sensitivity assessment is however demanding and, therefore, not easily applicable in the clinical setting. We aimed at evaluating whether common clinical variables, broadly obtained by routine clinical and instrumental evaluation, could predict increased HVR and HCVR. Methods and results 191 patients with systolic HF (left ventricular ejection fraction—LVEF—

Reverse remodeling (R2) in non-ischemic dilated cardiomyopathy (NIDCM) is associated with reduced morbidity, improved quality of life and survival. There is still scarce knowledge on predictors of R2, relevant for guide to treatment and device implantation. We aimed to identify predictors of R2

We evaluated the performance and diagnostic accuracy of an electrochemiluminescence immunoassay (ECLIA) method for N-terminal pro-B-type natriuretic peptide (NT-proBNP) in healthy persons and in patients with cardiac disease, and then compared the results obtained with the ECLIA method with results from IRMA methods for BNP and atrial natriuretic peptide (ANP). We studied 58 healthy individuals [mean (SD) age, 58 (8) years; 19 women and 39 men] and 148 consecutive patients [mean age, 64 (13) years; range, 20–80 years; 47 women and 101 men] with cardiomyopathy, admitted to the Department of Cardiovascular Medicine of our Institute. The study was done from November 2001 to October 2002. All healthy participants were nonobese, normotensive, and free from acute diseases, and all denied the use of any drug during the 4 weeks before the study. All had normal values for the main plasma indices and nonpathologic erythrocyte and leukocyte counts and urine analysis. In all of the participants, a complete cardiologic examination, including electrocardiogram and echocardiographic investigation (left ventricular ejection fraction >55%), was performed; in patients >50 years of age, an effort stress test was …

Recent studies reported that many different biochemical forms of B-type-related peptides circulate in human blood. In particular, a significant amount of the prohormone peptide (i.e., proBNP108) can be detected in plasma of patients with heart failure. These data indicate that the posttranslational maturation processing of the B-type natriuretic peptide (BNP) precursor may not be efficient in heart failure. The aim of this chapter is to describe the biochemical pathways of proBNP108 maturation and to discuss the pathophysiological relevance of alteration of the posttranslational maturation mechanisms in heart failure. An impaired cardiac endocrine function was proposed to explain the altered electrolyte and fluid homeostasis occurring in chronic heart failure. Recent studies demonstrated that a great part of BNPs assayed by immunoassay methods in healthy subjects and in patients with cardiovascular disease is devoid of biological activity. These findings suggest that an alteration in posttranslational maturation of BNP precursor may promote the resistance to biological action of BNP in patients with heart failure at a prereceptor level. These studies also open a new and more complex scenario regarding the circulating BNPs. The active hormone (i.e., BNP1-32) may be produced even in vivo from the circulating precursor proBNP108 by plasma enzyme degradation, such as the soluble form of corin, possibly able to process the circulating intact precursor of natriuretic hormones. As a future perspective, the simultaneous measurement of the proBNP1-108 and the active peptide BNP1-32 with more specific methods could allow a more accurate estimation of both production/secretion of B-type-related peptides from cardiomyocytes and the true activity of the cardiac endocrine function.

Objectives We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables. Background HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty. Methods Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041days (range 4–5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant. Results Six variables (hemoglobin, Na + , kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO 2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754–0.852) at 1year, 0.789 (0.750–0.828) at 2years, 0.762 (0.726–0.799) at 3years and 0.760 (0.724–0.796) at 4years. Conclusions This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC.

Lamin A/C ( LMNA ) gene mutation, identified in 10% of familial dilated cardiomyopathy (DCM) patients, is associated with an increased risk of sudden cardiac death (SCD), which may be the first clinical manifestation ([1][1]). Myocardial fibrosis (MF) has been identified in the hearts of LMNA

Cardiopulmonary exercise test (CPT) has a prominent value in assessing clinical severity in chronic heart failure (HF) patients. Reduced free triiodothyronine (fT3) plasma level is associated with a more severe disease and prognosis. The aim of this study was to evaluate the relationship between low fT3 plasma level and reduced exercise capacity in chronic HF, and to determine the influence of a low T3 status in subsets of patients with different functional impairment.240 HF patients (79% males; age 62 ± 12 years, mean ± standard deviation; left ventricular ejection fraction, EF, 30 ± 9%) underwent a CPT, clinical and neurohormonal characterization (assay for plasma brain natriuretic peptide, BNP, norepinephrine, aldosterone, renin activity, fT3, free T4, thyroid-stimulating hormone). At multivariate analysis in the whole population, age, gender and BNP level were independently associated with peak VO2, whereas in patients with severe functional impairment (peak VO214 ml/min/kg) fT3 resulted independently related to peak VO2, together with gender and BNP. When patients with peak VO214 ml/min/kg were divided according to fT3 levels, patients with low T3 syndrome showed reduced exercise capacity and worse ventilatory efficiency.BNP and fT3 are independently associated with exercise capacity in severely compromised HF patients.

Recent studies reported that many different biochemical forms of B-type-related peptides circulate in human blood. In particular, a significant amount of the prohormone peptide (i.e., proBNP108) can be detected in plasma of patients with heart failure. These data indicate that the posttranslational maturation processing of the B-type natriuretic peptide (BNP) precursor may not be efficient in heart failure. The aim of this chapter is to describe the biochemical pathways of proBNP108 maturation and to discuss the pathophysiological relevance of alteration of the posttranslational maturation mechanisms in heart failure. An impaired cardiac endocrine function was proposed to explain the altered electrolyte and fluid homeostasis occurring in chronic heart failure. Recent studies demonstrated that a great part of BNPs assayed by immunoassay methods in healthy subjects and in patients with cardiovascular disease is devoid of biological activity. These findings suggest that an alteration in posttranslational maturation of BNP precursor may promote the resistance to biological action of BNP in patients with heart failure at a prereceptor level. These studies also open a new and more complex scenario regarding the circulating BNPs. The active hormone (i.e., BNP1-32) may be produced even in vivo from the circulating precursor proBNP108 by plasma enzyme degradation, such as the soluble form of corin, possibly able to process the circulating intact precursor of natriuretic hormones. As a future perspective, the simultaneous measurement of the proBNP1-108 and the active peptide BNP1-32 with more specific methods could allow a more accurate estimation of both production/secretion of B-type-related peptides from cardiomyocytes and the true activity of the cardiac endocrine function.

Background: Brain natriuretic peptide (BNP) predicts exercise performance and exercise training may modulate BNP and its N-terminal portion (NT-pro-BNP), we therefore conducted an individual patient analysis of exercise training effects on BNP and NT-pro-BNP. Aims: To use an individual patient meta-analysis to relate changes in BNP, NT-pro-BNP, and peak VO2; to link these changes to volume parameters of exercise training programmes (intensity etc.); and to identify patient characteristics likely to lead to greater improvements in BNP, NT-pro-BNP, and peak VO2. Design: Individual patient meta-analysis. Methods: A systematic search was conducted of Medline (Ovid), Embase.com, Cochrane Central Register of Controlled Trials, and CINAHL (until July 2008) to identify randomized controlled trials of aerobic and/or resistance exercise training in systolic heart failure patients measuring BNP and/or NT-pro-BNP. Primary outcome measures were change in BNP, NT-pro-BNP, and peak VO2. Subanalyses were conducted to identify (1) patient groups that benefit most and (2) exercise programme parameters enhancing favourable changes in primary outcome measures. Results: Ten randomized controlled studies measuring BNP or NT-pro-BNP met eligibility criteria, authors provided individual patient data for 565 patients (313 exercise and 252 controls). Exercise training had favourable effects on BNP (−28.3%, p 2 (17.8%, p 2 change. Conclusion: Exercise training has favourable effects on BNP, NT-pro-BNP, and peak VO2 in heart failure patients and BNP/NT-pro-BNP changes were correlated with peak VO2 changes.

BACKGROUND Essential hypertension is characterized by both increased oxidative stress and sympathetic traffic. Experimental studies have shown that reactive oxygen species can modulate autonomic activity. OBJECTIVE The aim of this study was to determine whether acute administration of the antioxidant vitamin C modifies sympathetic nerve activity in essential hypertension. DESIGN Thirty-two untreated patients with essential hypertension and 20 normotensive subjects received vitamin C (3 g intravenously in 5 min) or vehicle. Heart rate, noninvasive beat-to-beat blood pressure, and muscle sympathetic nerve activity (microneurography) were monitored at baseline and up to 20 min after the infusion. Spectral analysis of RR interval variability and spontaneous baroreflex sensitivity were also computed. RESULTS Vitamin C infusion significantly lowered blood pressure in hypertensive patients but not in normotensive subjects (maximal changes in systolic blood pressure: -4.9 ± 10.1 compared with -0.7 ± 4.0 mm Hg, respectively; P < 0.05). Moreover, muscle sympathetic nerve activity was significantly reduced after vitamin C infusion in hypertensive patients (from 53.3 ± 12.2 to 47.4 ± 11.5 bursts/100 heart beats; P < 0.01) but not in healthy subjects (from 42.0 ± 10.1 to 42.7 ± 11.8 bursts/100 heart beats; NS). On the contrary, in 16 hypertensive patients, sodium nitroprusside in equidepressor doses induced a significant increase in muscle sympathetic nerve activity compared with vitamin C (+10.0 ± 6.9 bursts/100 heart beats). Sympathovagal balance and spontaneous baroreflex sensitivity were restored during vitamin C infusion in hypertensive subjects. CONCLUSIONS These results indicate that acute administration of vitamin C is able to reduce cardiovascular adrenergic drive in hypertensive patients, which suggests that oxidative stress is involved in the regulation of sympathetic activity in essential hypertension.

Recent studies demonstrated that large amounts of the pro-hormone peptide of brain natriuretic peptide (proBNP) can be detected in plasma of healthy subjects and in particular of patients with heart failure. As a result, a great part of B-type natriuretic peptides measured in patients with cardio-vascular disease may be devoid of biological activity. These findings stimulated the set up of specific immunoassay methods for the measurement of the intact proBNP peptide. The aim of this review article is to discuss the methodological characteristics and the possible clinical relevance of specific immunoassay methods for the measurement of the proBNP peptide. From an analytical point of view, a fully automated immunoassay of proBNP has some theoretical advantages (e.g., a more stable molecule with higher molecular weight than the derived peptides) compared to the active hormone BNP. Recent studies supported the concept that the precursor proBNP might be actually considered a circulating prohormone, which can be cleaved by specific plasma proteases in BNP, the active hormone, and NT-proBNP, an inactive peptide. The peripheral processing of circulating proBNP could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening new perspectives in the treatment of heart failure (e.g., by studying drugs inducing the cleavage of the prohormone into active BNP). Furthermore, as a future perspective, the specific assay in the same plasma sample of the intact precursor proBNP and of the biologically active peptide BNP, could allow a more accurate estimation of the production/secretion of B-type related peptides from cardiomyocytes and of the global cardiac endocrine function.

67±6%), while in DCM patients LV end-diastolic volume (102±17 ml/m2) and ejection-fraction (49±5%) were worse than both controls and LM carriers (p

The prognostic role of specific biomarkers of the renin-angiotensin-aldosterone system and sympathetic activation pathways in heart failure has never been investigated in populations with current evidence-weighted treatment. To establish whether the plasma renin activity (PRA), among several neurohormonal biomarkers, is able to predict cardiac events in a population of patients with heart failure on up-to-date treatment, we selected 996 consecutive patients with systolic left ventricular dysfunction (ejection fraction50%, mean age 65 ± 13 years), who underwent a complete clinical and humoral characterization and were then followed up (median 36 months, range 0 to 72) for cardiac death and appropriate implantable cardioverter device shock. We recorded 170 cardiac deaths and 27 shocks. On Cox multivariate analysis, only ejection fraction (hazard ratio 0.962, 95% confidence interval 0.938 to 0.986), N-terminal pro-brain natriuretic peptide (NT-proBNP; hazard ratio 1.729, 95% confidence interval 1.383 to 2.161) and PRA (hazard ratio 1.201, 95% confidence interval 1.024 to 1.408) were independent predictors of cardiac death. Receiver operating characteristic curve analysis identified a cutoff value for PRA of 2.30 ng/ml/hour that best predicted cardiac mortality. Independent predictors of PRA were ejection fraction, functional class, sodium, potassium, NT-proBNP, norepinephrine, aldosterone, C-reactive protein, and medical therapy. The association of high NT-proBNP and high PRA identified a subgroup (22% of the study population) with the greatest risk of cardiac death. In conclusion, PRA resulted an independent prognostic marker in patients with systolic heart failure additive to NT-proBNP level and ejection fraction. PRA might help to select those patients needing an enhanced therapeutic effort, possibly targeting incomplete renin-angiotensin-aldosterone system blockade.

Lack of increase in left ventricular (LV) stroke volume (SV) during low-dose dobutamine stress (LDD) is attributed to exhausted cardiac contractile reserve in failing heart. However, the role of the afterload and preload in SV changes is underestimated. The aim of the study was to investigate the effects of LDD on preload reserve and afterload in patients with non-ischemic heart failure.58 patients (age 62 years) underwent LDD (up to 20μg/kg/min) using cardiac magnetic resonance.LV-SV increased by 27% in 24 patients (p0.001) (SV+), while decreased by 19% in 22 patients (p0.001) (SV-). The LDD-to-rest reduction in preload, as defined by LV end-diastolic volume (EDV), was more pronounced in SV- than SV+ (24% and 8% respectively, p0.05). The LLD-to-rest increase in systolic blood pressure to LV end systolic volume ratio, an index of LV contractility, was higher but not statistically different in SV+ in comparison to SV- (70% vs 48%, p=ns). Systemic vascular resistance during LDD tended to be higher in SV- (23%, p=ns), while it was significantly reduced in SV+ (9.5%, p0.011), whereas arterial elastance (Ea) increased in SV- (30%, p0.001) but decreased in SV+ (0.5%, p=0.04). At multivariable regression models LV-EF, LV-EDV and Ea significantly contributed to LV-SV changes in all patients. Also among SV+ and SV- LV-EDV and Ea revealed significant contribution to LV-SV change.At similar contractile reserve response, the lack of LDD-induced increase in LV-SV, can be related to reduced preload reserve as well as to increased afterload.

Patients with hepatic cirrhosis frequently show idiopathic hyperventilation at rest, despite no concomitant cardiopulmonary disease. The aim of the study was to determine whether altered chemosensitivity either to hypoxia or hypercapnia could underlie inappropriate hyperventilation in cirrhotic patients.We consecutively recruited 30 biopsy proven cirrhotic patients equally distributed in the three Child's classes A, B and C (age 54 ± 8 years, mean ± SD). All patients underwent evaluation of chemosensitivity to hypoxia and to hypercapnia and blood sampling for brain natriuretic peptide, norepinephrine and progesterone, besides full clinical characterization. We also recruited 10 age- and gender-matched healthy controls (age 55 ± 7 years).Overall, 18 patients (60%) showed an increased chemosensitivity to carbon dioxide (CO(2)), while 8 patients (27%) showed enhanced chemosensitivity to hypoxia. Child's class C patients had lower arterial partial pressure of CO(2) (PaCO(2)), higher rest ventilation, increased chemosensitivity to hypercapnia, plasma level of norepinephrine and serum progesterone levels when compared to class A patients and controls (all p0.05). Rest ventilation was positively related to pH (R = 0.41, p = 0.023), chemosensitivity to hypercapnia (R = 0.54, p = 0.002), and progesterone (R = 0.53, p = 0.016) and negatively to PaCO(2) (R = 0.61, p0.001), but not to hemoglobin level and chemosensitivity to hypoxia. Chemosensitivity to hypercapnia was positively related to PaCO(2) (R = 0.74, p0.001), serum progesterone (R = 0.50, p = 0.016), and to plasma norepinephrine (R = 0.57, p = 0.004).Enhanced chemosensitivity to hypercapnia was found in more decompensated cirrhotic patients and was associated with sympathetic overactivity and elevated serum progesterone, likely representing a key mechanism underlying the "unexplained" hyperventilation observed in such patients.

The relationship between work rate (WR) and its tolerable duration (tLIM) has not been investigated at high altitude (HA). At HA (5050 m) and at sea level (SL), six subjects therefore performed symptom-limited cycle-ergometry: an incremental test (IET) and three constant-WR tests (% of IET WRmax, HA and SL respectively: WR1 70 ± 8%, 74 ± 7%; WR2 86 ± 14%, 88 ± 10%; WR3 105 ± 13%, 104 ± 9%). The power asymptote (CP) and curvature constant (W′) of the hyperbolic WR–tLIM relationship were reduced at HA compared to SL (CP: 81 ± 21 vs. 123 ± 38 W; W′: 7.2 ± 2.9 vs. 13.1 ± 4.3 kJ). HA breathing reserve (estimated maximum voluntary ventilation minus end-exercise ventilation) was also compromised (WR1: 25 ± 25 vs. 50 ± 18 l min−1; WR2: 4 ± 23 vs. 38 ± 23 l min−1; WR3: −3 ± 18 vs. 32 ± 24 l min−1) with near-maximal dyspnea levels (Borg) (WR1: 7.2 ± 1.2 vs. 4.8 ± 1.3; WR2: 8.8 ± 0.8 vs. 5.3 ± 1.2; WR3: 9.3 ± 1.0 vs. 5.3 ± 1.5). The CP reduction is consistent with a reduced O2 availability; that of W′ with reduced muscle–venous O2 storage, exacerbated by ventilatory limitation and dyspnea.

Renal denervation is a emerging treatment in patients with resistant arterial hypertension. Neurohromonal activation (catecholaminergic and renin angiotensin aldosterone systems) play an important role in hypertensive patients; B-type cardiac natriuretic peptides have been demonstrated as useful

Dysregulation of baro-, ergo- and chemoreflex in patients with heart failure (HF) elicits autonomic imbalance associated with parasympathetic withdrawal and increased adrenergic drive to the heart, and contributes to worsening arrhythmic burden and haemodynamics. Hence, on top of guideline-recommended medical therapy, all visceral feedbacks have been considered in HF patients as additional targets; baroreflex activation therapy for baroreceptors (Sabbah et al. 2011), physical training for muscle metaboreceptors (Piepoli et al. 1996), and, recently, carotid body (CB) denervation for chemoreceptors (Marcus et al. 2014). In particular, increased peripheral (PC) and central chemoreceptor (CC) sensitivity is frequently observed in HF patients. This phenomenon, is recognized as an independent prognostic marker in HF (Ponikowski et al. 2001; Giannoni et al. 2009), being associated with autonomic imbalance, adrenergic activation, and with ventilatory instability (Cheyne–Stokes respiration); therefore, it has been proposed as a therapeutic target (Paton et al. 2013). Schultz and colleagues have investigated the causal link between HF and PC sensitivity. They first showed an increase in PC sensitivity (Sun et al. 1999) in a rabbit pacing-induced HF model, probably due to reduced CB perfusion and suppression of outward voltage-gated K+ currents, deriving from altered carbon monoxide/nitric oxide and angiotensin-II signalling in glomus cells (Schultz & Marcus, 2012). They also showed that an increase in PC activity leads to adrenergic activation in normoxia, reversible after pure oxygen inhalation, and to a higher sympathetic response to hypoxia (Sun et al. 1999). Finally, they showed the reversibility, after bilateral cryoablation of CB, of the several negative correlates of overactive PCs, again in the rabbit pacing-induced HF model (Marcus et al. 2014). Indeed, bilateral CB ablation was found to decrease baseline ventilation and the hypoxic ventilatory response to a level lower than in sham animals. The baseline renal sympathetic nerve activity (RSNA) and the hypoxia-related RSNA response showed a similar behaviour after CB ablation. These effects on adrenergic outflow and ventilation were followed by a decrease in arrhythmias and ventilatory instability. Finally, although no effect on left ventricular ejection fraction was reported, reduced diastolic and systolic volumes were found in CB-ablated compared to sham HF rabbits. The paper by Marcus et al. (2014) is indeed an interesting advance in research on feedback control, though it raises some methodological and conceptual questions. First, ventricular pacing used to produce HF could potentially increase the arrhythmic risk (Gardiwal et al. 2008), leading to the overestimation of the positive effect of CB ablation on rhythm stability. More importantly, pacing takes up to 4 weeks to induce HF, so it should be considered as a subacute model of HF rather than a chronic model, able to induce haemodynamic compromise, sensed by PCs (Schultz & Marcus, 2012), but less likely to be associated with significant neurohormonal activation and with the global feedback resetting seen in the chronic scenario. This caveat may hamper the direct extension of the findings by Marcus and colleagues to the clinical setting of chronic HF. Second, PCs are commonly considered the only sensors of hypoxia available in the body, and also an ‘emergency valve’, quickly activated in conditions of asphyxia, with hypoxia and hypercapnia simultaneously present. Although both carotid and aortic bodies function as PCs, with interspecies differences, CBs act as the main hypoxia sensors in humans (Prabhakar & Peng, 2004). Moreover, in contrast to animal studies, failure to restore the hypoxic ventilatory response from aortic bodies after long-term CB removal has been described in humans with asthma (Prabhakar & Peng, 2004). Therefore, an irreversible bilateral surgical CB demolition seems far from desirable, especially in HF patients, when in acute life-threatening conditions, such as, pulmonary oedema or cardiogenic shock, the adrenergic and ventilatory response linked to hypoxia may instead be necessary. Bilateral CB ablation may also increase arterial carbon dioxide by reducing baseline ventilation, and reduce pH (unfortunately not measured in the experiments of Marcus et al. 2014), which seems undesirable, too, since maintenance of pH homeostasis and oxygen availability at the tissue level is the primary purpose of the chemoreflex system (Blain et al. 2010). In conclusion, monolateral CB surgery, as already tested in mice (Del Rio et al. 2013), or, alternatively, a reversible pharmacological/non-pharmacological CB modulation could succeed in blunting the negative effects of PC overactivity, without affecting its physiological function, with a net long-term positive effect on survival.

The pathophysiologic role of enhanced chemosensitivity to carbon dioxide and/or hypoxia has been underscored in several cardiovascular diseases, including heart failure. In the early stages of this syndrome, the chemoreflex acts as a compensatory mechanism. Later on, however, it contributes to sustain the sympathetic activation, with detrimental effects on cardiovascular function and prognosis.

C-type natriuretic peptide (CNP) plasma levels are extremely low and a pre-analytical phase is necessary to assay plasma CNP concentrations. Amino-terminal CNP (NT-proCNP) circulates at higher concentrations than CNP, allowing a direct assay and the use of smaller amounts of plasma. Aim of this study was to evaluate the analytical performance of a direct NT-proCNP assay and to measure its plasma levels in heart failure (CHF), diabetes and chirrosis patients. NT-proCNP and CNP were measured in 130 CHF, 19 patients with diabetes, 24 with hepatic cirrhosis and 73 controls. Plasma NT-proCNP was higher in all the clinical conditions studied (controls:45.5 ± 1.84 pg/ml, CHF:67.09 ± 7.36, diabetes:51.5 ± 5.75 cirrhosis:78.4 ± 19.9; p = 0.034, p = 0.04 controls vs. CHF and cirrhosis, respectively) and in CHF NT-proCNP concentration showed a significant increase as a function of clinical severity. By comparison of ROC curves, CNP assay resulted better associated with disease than NT-proCNP assay in all the different clinical conditions probably due to different release and clearance. The determination of NT-proCNP adds a piece of information to better understanding the molecular mechanisms at the basis of CNP action in different diseases. Due to its higher analytical feasibility, this determination could become widespread in clinical biochemistry laboratories and serve as a complementary marker of disease conditions.

Cardiomiopathy and hypereosinophilia: a post-partum case. A case of cardiomyopathy and hyperoesinophilia observed soon after delivery is reported. A wide spectrum of different clinical entities characterized by peripheral hyperoesinophilia, tissue infiltration and eosinophil-mediated organ damage is referred to as hypereosinophilic syndrome and their distinction is often challenging. Cardiac involvement is frequent in such these syndromes and worsens prognosis. A prompt recognition and therapy of the underlying disease and of its peripheral expression, as in the following case, may improve patients' outcome.

Mutations in the lamin A/C gene (LMNA) are known to be involved in several diseases such as Emery–Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and dilated cardiomyopathies with conduction disease, with considerable phenotype heterogeneity. Here we report on a novel autosomal dominant mutation in LMNA in two direct relatives presenting with different clinical phenotypes, characterized by severe life-threatening limb-girdle muscle involvement and cardiac dysfunction treated with heart transplantation in the proband, and by ventricular tachyarrhythmias with preserved cardiac and skeletal muscle function in her young son. To our knowledge, this is the first report of a duplication in the LMNA gene. The two phenotypes described could reflect different clinical stages of the same disease. We hypothesize that early recognition and initiation of therapeutic manoeuvres in the younger patient may retard the rate of progression of the cardiomyopathy.

Introduction In thalassemia patients heart failure remains the main cause of mortality. High cardiac output state due to chronic anaemia is a significant determinant of cardiomyopathy, in particular in thalassemia intermedia (TI) patients (a moderate form, not transfusion dependent). Hypoxia and volume overload are known stimuli for plasma N-terminal fragment of proBNP (NT-proBNP) raise. Nevertheless, NT-proBNP role in clinical management of thalassemia patients has not been fully investigated.

Survival of patients with systolic heart failure (HF) may be influenced by the presence of chronic atrial fibrillation (AF) and circulating concentrations of B-type natriuretic peptides. In this study, we sought to assess the prognostic value of chronic AF in comparison to those of amino-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels and of echocardiographic parameters among HF patients of the entire study population and in those with AF.Plasma NT-proBNP levels and echocardiography were prospectively assessed in 489 patients with chronic systolic HF (LV ejection fractionor=45%) in sinus rhythm or AF (16%). Follow-up duration was 26+/-15 months.Patients with AF were older (p0.0001), had a worse NYHA class (p=0.002) and higher NT-proBNP levels (p0.0001) than those in sinus rhythm. Presence of AF (HR [hazards ratio]: 2.01, p=0.013) and plasma NT-proBNP (HR: 3.05, p0.0001) were the only independent predictors of all-cause mortality. At receiver operating characteristic analyses, the threshold level for outcome prediction of NT-proBNP was higher in patients with AF (3883 pg/ml) than in patients in sinus rhythm (1653 pg/ml). Multivariate analysis performed in patients with HF and AF showed that plasma NT-proBNP was the most important predictor of death after statistic adjustment for age.Chronic AF and NT-proBNP independently predicted the outcome of patients with HF. The threshold level of NT-proBNP for outcome prediction was different in patients with AF with respect to those in sinus rhythm. NT-proBNP was the most important independent predictor of all-cause mortality in HF patients with AF.

Introduction Cardiac complications are the main cause of morbidity and mortality in thalassemia major (TM). In particular, thalassemic cardiomyopathy include forms with right involvement difficult to detect by usual approach, whereas early diagnosis could permit early treatment and improvement in prognosis. Plasma N-terminal fragment of proBNP (NT-proBNP) concentration holds a known value in asymptomatic cardiac patients, too, but its usefulness in the management of TM has not been fully investigated.

Background We investigated the relationship between nonsustained ventricular tachycardia (NSVT) and left ventricular (LV) dilatation, function, remodeling, and scar tissue extent in patients with previous myocardial infarction (MI). Methods and Results Eighty-two patients (ages 64 ± 10 years) with first previous MI were referred for 24-hour electrocardiogram recording and cine and delayed enhancement (DE) cardiac magnetic resonance (CMR). LV volumes, ejection fraction, systolic wall thickening, sphericity index, and core and peri-infarctual areas of scar tissue by CMR were evaluated. LV dilatation was observed in 39 patients. Episodes of NSVT were recorded in 32 patients: 23 with LV dilatation and 9 without. In the entire population, NSVT was related to ejection fraction, LV volumes, LV mass, and sphericity index; end-systolic volume (P = .001) resulted in the only independent predictor at multivariate analysis. In patients without LV dilatation, the occurrence of NSVT was only positively related with percentage of contracting segments with DE (P = .008). Conversely, in patients with LV dilatation, increase in LV mass (P = .020) and end-systolic volume (P = .038) were independent predictors of NSVT. Conclusions Necrotic and viable myocardium coexistence within the same wall segments predicted occurrence of NSVT in patients without LV dilatation, whereas LV mass and end-systolic volume were predictors of NSVT in those with LV dilatation.

The search for the presence of Cheyne-Stokes respiration should be introduced into the routine diagnostic process in heart failure patients, owing to its clinical and prognostic implications. The analysis of this specific alteration of the respiratory pattern could contribute both to the understanding of its pathophysiological role, and to the discovery of specific treatments for heart failure patients, characterized by poor prognosis, despite optimal conventional treatment.

The described report deals with the case of a patient with diagnosis of ischemic-hypertensive cardiomyiopathy based on the history of angina and inducible myocardial ischemia with normal coronary arteries. However, after cardiac magnetic resonance, the typical amyloidotic pattern is found and the final diagnosis of multiple myeloma is made at osteomedullary biopsy.

Background Over the last 50 years left bundle branch block (LBBB) has been defined as homophasic (concordant: cLBBB) or heterophasic (discordant: dLBBB) when associated with a positive or negative T wave in leads I and V5-V6, respectively. LBBB is recognized as an adverse prognostic factor in heart failure (HF). The prevalence and clinical significance of cLBBB and dLBBB in HF patients are unknown. Methods and Results A total of 897 consecutive systolic HF patients (age 65 ± 13 years, left ventricular ejection fraction [LVEF], 34 ± 10%) underwent clinical characterization, electrocardiographic evaluation for LBBB diagnosis and classification, and follow-up for cardiac events (median 37 months, range 1-84). LBBB was diagnosed in 232 patients (26%), cLBBB in 71 (31%), and dLBBB in 161 (69%). The dLBBB patients were older than those with cLBBB, and presented with lower LVEF, greater left ventricular telediastolic diameter and left ventricular mass index, higher level of brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, renin activity, and norepinephrine (all P < .05). At Kaplan-Meier analysis, LBBB (P = .003) and dLBBB (P = .036) were associated with a worse prognosis when the composite end point of sudden death and implantable cardioverter defibrillator shock was considered. Conclusions In systolic HF, dLBBB is associated with a worse clinical, neurohormonal, and prognostic profile. LBBB classification could represent a useful tool in routine clinical evaluation.

Renal function is known to be a strong predictor of cardiovascular prognosis, and cardiorenal disease is increasingly investigated in medical research. In this study, we tested the hypothesis that a single combined cardiorenal scintigraphy examination with the perfusion tracer (99m)Tc-tetrofosmin is feasible and may allow the simultaneous investigation of cardiac and renal pathology in cardiovascular patients.Thirty patients scheduled for dual-day gated SPECT also gave their informed consent for a renal acquisition after a single injection of 370 MBq of (99m)Tc-tetrofosmin, at rest (30 patients) or with adenosine (21 patients), and to undergo an additional standard renal study with the glomerular tracer (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) (74 MBq) after 1 wk (24 patients). Kidney images and renograms were obtained. Renal uptake index, expressed as the percentage ratio of kidney counts cumulated over the second minute after injection to the administered dose, was calculated as a functional renal parameter. Time to peak activity and separate kidney percentage uptake (as the percentage contribution of each kidney to total renal uptake) were also calculated.Compared with (99m)Tc-DTPA, (99m)Tc-tetrofosmin provided better-quality kidney images, with a higher uptake index (13.17% +/- 4.76% vs. 8.33% +/- 2.45%, P0.001) and with comparable separate kidney percentage uptake and times to peak activity. (99m)Tc-tetrofosmin uptake index was significantly lower in the patients who were more compromised according to renal and cardiovascular functional parameters, and correlated with (99m)Tc-DTPA uptake index (r = 0.77, P0.001), serum creatinine (r = 0.59, P0.005), log brain natriuretic peptide N-terminal levels (r = -0.65, P0.005), myocardial and carotid intima-media wall thickness (for both, r = -0.61, P0.005), and the Doppler index of renal vascular resistance (r = -0.60, P0.005). In the 21 patients who underwent the provocative test, adenosine induced a significant decrease in renal (99m)Tc-tetrofosmin uptake index (from 14.12% +/- 4.50% to 11.81% +/- 3.33%, P0.005) suggesting a decrement in renal perfusion or function.(99m)Tc-tetrofosmin cardiorenal scintigraphy is feasible at low cost as a single-shot study and may allow both the evaluation of renal morphology and renograms during a cardiac study and the calculation of renal functional parameters.