Applicability and performance of heart failure prognostic scores in dilated cardiomyopathy: the real-world experience of an Italian referral center for cardiomyopathies.

BACKGROUND: The performance of heart failure (HF) risk models is validated in the general population with HF but in specific aetiological settings, and specifically in dilated cardiomyopathy (DCM), has scarcely been explored. We tested eight of the main prognostic scores used in HF in a large real-world population of patients with DCM. METHODS: We included 784 consecutive DCM patients enrolled, both inpatients and outpatients, enrolled between January 2000 and December 2017. The risk of 1 and/or 3-year all-cause mortality/heart transplantation/durable left ventricular assist device (LVAD) implantation (D/HTx/LVAD) was estimated in our cohort according to the following risk scores SHFM, 3-CHF, CHARM, MAGGIC, GISSI-HF, MECKI, Barcelona Bio-HF, Krakow score and their accuracy calculated through the receiver operator characteristic (ROC) curve analysis. RESULTS: During a median follow-up of 5.8 years (Interquartile Range 3.2-7.6 years), 191 patients (20%) died or underwent HTx/LVAD (158 deaths, 30 heart transplantations, and 3 LVAD implantations). The high missing rate allowed to calculated only four prognostic models (MAGGIC, CHARM, 3-CHF and SHFM). All the scores overestimated the rate of D/HTx/LVAD. The prognostic accuracy was suboptimal for MAGGIC (AUC 0.754) and CHARM (AUC 0.720) scores and only modest for 3-CHF (AUC 0.677) and SHFM (AUC 0.667). CONCLUSIONS: Main prognostic scores for the risk stratification of HF are only partially applicable to real-world patients with DCM. MAGGIC and CHARM scores showed the best accuracy, despite the overestimation of risk. Our findings corroborate the need of specific risk scores for the prognostic stratification of DCM. CLINICAL PERSPECTIVE: What is new? The present study is the largest analysis in literature which investigate how the main existing heart failure prognostic risk scores performed in a real-world of dilated cardiomyopathy population, both in- and outpatients. What are the clinical implications? DCM is a stand-alone model of heart failure, where the performance of multiple heart failure prognostic scores for the risk stratification is quite limited. The need for contemporary, dedicated prognostic scores in this disease is increasingly evident.

How to incorporate left atrial strain in the diagnostic algorithm of left ventricular diastolic dysfunction.

The combination of early trans-mitral inflow and mitral annular tissue Doppler velocities (E/e' ratio) is widely applied to noninvasively estimate left ventricular (LV) filling pressures. However, when E/e' is between 8 and 14 its accuracy decreases substantially. Left atrial (LA) deformation analysis by speckle tracking echocardiography was recently proposed as an alternative approach to estimate LV filling pressures, but its role when E/e' is between 8 and 14 has been under-investigated. We aimed to assess whether LA strain could help to identify elevated filling pressures in patients with E/e' between 8 and 14. Among consecutive non-selected patients who underwent a comprehensive echocardiographic evaluation, we enrolled those with E/e' ratio > 8 and ≤ 14. Exclusion criteria were: organic mitral valve disease or mitral surgery; presence of mitral regurgitation greater than moderate in severity; diseases associated with pre-capillary pulmonary hypertension; and undetectable systolic pulmonary artery pressure (PAP-S). Peak LA longitudinal (PALS) and contraction strain (PACS) values was obtained by averaging all segments, and by separately averaging segments measured in the 4-chamber and 2-chamber views. Seventy-six patients had E/e' > 8 and ≤ 14 and formed the study cohort. Mean age 69 ± 12 years, LV ejection fraction (LVEF) 54.5 ± 11.2%, mean E/e' 11.2 ± 1.9, PAP-S 33 ± 7 mmHg, PALS 31.6 ± 11.7%. PALS was significantly associated to PAP-S after adjustment for LVEF, E/e', septal LV longitudinal shortening velocity (s'), LA volume indexed (p = 0.002) and also for ASE/EACVI diastolic dysfunction classification (p = 0.0002). Furthermore, PALS but not ASE/EACVI diastolic dysfunction grading, resulted independently associated to New York Heart Association (NYHA) class (p = 0.0004). PALS is able to predict increased intra-cardiac pressure and NYHA class in patients characterized by E/e' between 8 and 14. Therefore, we propose that PALS might be incorporated in a simplified diagnostic algorithm based on E/e' classes.

Effects of Aortic Valve Replacement on Left Ventricular Diastolic Function in Patients With Aortic Valve Stenosis.

The afterload increase imposed by severe aortic valve stenosis (AS) creates concentric left ventricular (LV) remodeling and diastolic dysfunction (DD), which are both markers of poor clinical outcome. Ideally, a correctly timed surgery for isolated AS can reverse the LV remodeling. However, data on LV DD after aortic valve replacement (AVR) are sparse and contrasting. Aims of the study are to define the markers of a favorable evolution of the DD at follow-up. Patients with severe isolated AS, scheduled for AVR were prospectively enrolled. Transthoracic echocardiography with DD assessment was performed before surgery, and at 12 months after surgery. Global LV longitudinal and circumferential strain, peak atrial longitudinal and contraction strain (PALS, PACS) were obtained at baseline. LV septal biopsy to assess fibrosis was performed at the time of AVR. Sixty-seven patients were enrolled, age 72 ± 8 years, 66% female, ejection fraction 61 ± 8%, E/e' 13 ± 6, PALS 23 ± 7%. Normal estimated left atrial pressure was detected in 19/67 (28%) versus 43/67 (64%) at follow-up (p <0.0001). In the 37 patients with biopsy available, fibrosis was 24 ± 12%. PALS and AS severity were correlated with LV fibrosis (R2 = 0.19; p = 0.006, and R2 = 0.15; p = 0.02, respectively). PALS (odds ratio: 1.19 [1.05 to 1.41], p = 0.02) and PACS (odds ratio: 1.24 [1.06 to 1.50], p = 0.006) were the only baseline noninvasive parameters independently associated with normal left atrial pressure at follow-up. Mean follow-up time was 791 ± 245 days, and 8 (12%) patients had cardiovascular events (death, hospital admission due to heart failure or ischemic disease, and onset of atrial fibrillation). Myocardial fibrosis (p = 0.05), baseline PALS (p = 0.004), and PACS (p = 0.03) were associated with cardiovascular events. In conclusion, LV diastolic function generally improves after AVR for severe AS. Baseline PALS, PACS, and LV fibrosis were related to the DD and clinical outcome at follow-up; these parameters might cue a better diastolic response to the afterload correction.

Is TAVI superior to surgery in high-risk patients? Insight into the concept of individual risk assessment.

The prevalence of aortic valve stenosis (AS) is growing in developed countries because its prevalence increases with age. A growing number of elderly patients are currently referred to specialized centres to be evaluated for potential therapeutic strategies. Indeed, two techniques are nowadays able to treat high-risk AS patients: TAVI and surgical replacement (AVR). It is the purpose of the present review to summarize current knowledge on safety and efficacy of AVR and TAVI in high-risk patients; to focus on some aspects of recently published guidelines; to emphasize the growing importance of pre-operative individual risk assessment, which is considered the real crucial point for patient selection and trial's comparisons. Indeed, it is worth of noting that currently adopted risk-scores do not show satisfactory performances. Accordingly, it becomes of utmost importance to investigate several baseline but still neglected patients' characteristics (e.g. frailty, functional status, co-morbid conditions, etc.), as well as their pathogenetic relationships with interventional results and follow-up prognosis. All these items are emphasized in the present review. Finally, we have tried to anticipate future scenarios in terms of both ongoing clinical trials and improvements of risk-scores.

Tobacco smoke affects expression of peroxisome proliferator-activated receptor-gamma in monocyte/macrophages of patients with coronary heart disease.

BACKGROUND AND PURPOSE: Tobacco smoke represents a relevant risk factor for coronary heart disease (CHD). Although peroxisome proliferator-activated receptor (PPAR)gamma activation reduces inflammation and atherosclerosis, expression of PPARgamma in cells and its modulation by smoking are poorly investigated. We previously reported that monocyte/macrophages from healthy smokers exhibited an enhanced constitutive expression of PPARgamma. Here, we evaluated PPARgamma expression and basal cytokine release in monocytes and monocyte-derived macrophages (MDMs) from 85 CHD patients, classified by their smoking habit (smokers, non-smokers and ex-smokers), and assessed the role of PPARgamma ligands in this context. EXPERIMENTAL APPROACH: PPARgamma protein was detected by Western blot and semi-quantified by PPARgamma/beta-actin ratio; cytokine release was measured by elisa and nuclear factor-kappaB (NF-kappaB) translocation by electrophoretic mobility shift assays. KEY RESULTS: As compared to the other groups, MDMs from smoker CHD patients exhibited a reduced PPARgamma/beta-actin ratio and an increased spontaneous release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6, but with no major variations in monocytes. In cells from selected CHD patients, rosiglitazone inhibited TNF-alpha release and NF-kappaB translocation induced by phorbol-12-myristate 13-acetate. The selective PPARgamma antagonist GW9662 reversed these effects, with some variations related to smoking habit. CONCLUSIONS AND IMPLICATIONS: In CHD patients, exposure to tobacco smoke profoundly affected PPARgamma expression, and this was related to levels of secretion of pro-inflammatory cytokines. MDMs from CHD smokers showed the lowest PPARgamma expression and released more inflammatory cytokines. Moreover, rosiglitazone's ability to inhibit cytokine release and its reversal by GW9662 clearly indicated PPARgamma involvement in these changes in CHD patients.

A novel activity for substance P: stimulation of peroxisome proliferator-activated receptor-gamma protein expression in human monocytes and macrophages.

BACKGROUND AND PURPOSE: Substance P (SP) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) play important roles in different inflammatory conditions and are both expressed in human monocytes and macrophages. However, it is not known whether or not they interact. This study was undertaken to evaluate the effects of SP on PPAR-gamma protein expression in monocytes and macrophages (MDMs: monocyte-derived macrophages) from healthy smokers and non-smokers. EXPERIMENTAL APPROACH: PPAR-gamma protein was detected by western blot and quantified by calculating the ratio between PPAR-gamma and beta-actin protein expression. Constitutive tachykinin NK(1) receptor expression in monocytes and MDMs from healthy smokers and non-smokers was evaluated by western blot. Cytokine release was evaluated by ELISA. KEY RESULTS: In the concentration range 10(-10)-10(-6) M, SP stimulated PPAR-gamma protein expression in monocytes and MDMs, being more effective in cells from healthy smokers. Moreover, in these cells there was a constitutively increased expression of NK(1) receptors. SP-induced expression of the PPAR-gamma protein was receptor-mediated, as it was reproduced by the NK(1) selective agonist [Sar(9)Met(O(2))(11)]SP and reversed by the competitive NK(1) antagonist GR71251. SP-induced maximal effects were similar to those evoked by 15-deoxy-Delta(12,14)-prostaglandin J(2); an endogenous PPAR-gamma agonist, and were significantly reduced by a PPAR-gamma antagonist. NK(1) and PPAR-gamma agonists exerted opposite effects on TNF-alpha release from monocytes and MDMs. CONCLUSIONS AND IMPLICATIONS: Enhancement of PPAR-gamma protein expression represents a novel activity for SP, which could contribute to a range of chronic inflammatory disorders.

The role of nitric oxide in the peripheral vasoconstriction caused by human placental lactogen in anaesthetized pigs.

Regional intra-arterial infusion of human placental lactogen in anaesthetized pigs has been shown to cause coronary, renal and iliac vasoconstriction by antagonizing the vasodilatory effects of beta2-adrenergic receptors. Since nitric oxide is known to modulate or mediate beta2-adrenergic effects, the present study was planned in the same experimental model to determine the role of nitric oxide in the above vascular responses to human placental lactogen. In eight pigs anaesthetized with sodium pentobarbitone, changes in anterior descending coronary, left renal and left internal iliac blood flow caused by intra-arterial infusion of human placental lactogen at constant heart rate and arterial blood pressure were assessed using electromagnetic flowmeters. Intra-arterial infusion of the human placental lactogen caused decreases in coronary, renal and iliac blood flow which, respectively, averaged 16.7, 8.1 and 12.2% of the baseline values. The role of nitric oxide in this response was studied in the same pigs by repeating the experiments, after measured blood flows had returned to baseline values, following intra-arterial administration of N(omega)-nitro-L-arginine methyl ester (L-NAME). The subsequent intra-arterial infusion of human placental lactogen did not cause any significant changes in measured blood flows, even when performed after reversing the increase in arterial blood pressure and coronary, renal and iliac resistance caused by L-NAME with continuous intravenous infusion of papaverine. These results indicate that the coronary, renal and iliac vasoconstriction caused by human placental lactogen, known to involve antagonism of beta2-adrenergic vasodilatory effects, was mediated by inhibition of nitric oxide release.

Human placental lactogen decreases regional blood flow in anesthetized pigs.

In 22 pigs anesthetized with sodium pentobarbitone, changes in blood flow caused by infusion of human placental lactogen into the left renal, external iliac, and anterior descending coronary arteries were assessed using electromagnetic flowmeters. In 17 pigs, infusion of human placental lactogen whilst keeping the heart rate and arterial pressure constant decreased coronary, renal and iliac flow. In 5 additional pigs, increasing the dose of human placental lactogen produced a dose-related decrease in regional blood flow. The mechanisms of the above response were studied in 15 of the 17 pigs by repeating the experiment of infusion. The human placental lactogen-induced decrease in regional blood flow was not affected by blockade of cholinergic receptors (5 pigs) or of alpha-adrenergic receptors (5 pigs), but it was abolished by blockade of beta2-adrenergic receptors (5 pigs). The present study showed that intra-arterial infusion of human placental lactogen primarily decreased coronary, renal and iliac blood flow. The mechanism of this response was shown to be due to the inhibition of a vasodilatory beta2-adrenergic receptor-mediated effect.

Tissue plasminogen activator antigen is strongly associated with myocardial infarction in young women.

Women who develop acute myocardial infarction (AMI) at a young age have fewer classical risk factors and less coronary stenosis than older women. In this rare population, it is plausible that a heightened hemostatic system may play an important mechanistic role in thrombus formation and in the development of AMI. We chose to investigate whether or not there is an association between premature AMI and the plasma concentrations of five hemostatic measurements that had been previously established as risk factors for AMI, and of the inflammation marker C-reactive protein (CRP). Women who had survived AMI at the age of 45 years or less (n = 141) were drawn from those admitted to 125 Italian coronary care units over a 3-year period. In them, and in an equal number of controls, plasma levels of immunoreactive tissue plasminogen activator (tPA), plasminogen activation inhibitor 1 (PAI-1), von Willebrand factor (VWF), fibrinogen, D-dimer and CRP were measured. Higher levels of VWF, fibrinogen, CRP and tPA were associated with AMI. After adjustment for both classical and hemostatic risk factors, only tPA maintained an independent association with AMI: the odds ratios (taken as an index of relative risk) for tPA values in the middle and higher tertiles were 2.86 (CI 1.63-5.02) and 8.18 (CI 2.66-25.20), respectively. In conclusion, there is a strong association between non-fatal AMI and increased plasma levels of tPA antigen. This finding is thought to be the expression of a reduced rather than enhanced fibrinolytic activity.

Clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h) and late (>4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction.

AIMS: We examined the clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h) and late (>4 h) presentation treated by primary angioplasty or thrombolytic therapy for acute myocardial infarction. METHODS AND RESULTS: We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n=1302) vs thrombolytic therapy (n=1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (<2 h), intermediate presentation (2-4 h), and late presentation (>or=4 h). At 30 days the combined rate of death, non-fatal reinfarction and stroke in patients presenting early was 5.8% in the angioplasty group vs 12.5% in the thrombolysis group, in patients with intermediate presentation, 8.6% vs 14.2%, respectively, and in patients presenting late 7.7% vs 19.4%, respectively. With increasing time from symptom onset to presentation, all major adverse cardiac event rates show a trend to a larger increase in the thrombolysis group compared to the angioplasty group, both at 30 days and at 6 months after the acute event. CONCLUSIONS: Major adverse cardiac event rates are lower after angioplasty compared to thrombolysis, irrespective of time to presentation. With increasing time to presentation major adverse cardiac event rates increase after thrombolysis but appear to remain relatively stable after angioplasty.

In-stent restenosis.

Even after optimal immediate results, restenosis still occurs in a relevant percentage of patients after stent implantation. This disappointing outcome has strong clinical and socio-economical implications and has become a major target of research in cardiology. The conceptual difference between the mere resolution of the restenotic lesion and the understanding of the mechanisms of restenosis creates a dichotomy between daily practice in the catheterization laboratory and questions raised in the research laboratory that commonly divides people (clinicians and researchers) and budgets (industries and academic institutions). As a consequence, efforts are aimed at treating the consequences of unsuccessful stenting on the one hand, and to understand the causes of excessive neointimal proliferation on the other. However, the commitment of researchers and the large clinical experience accumulated in these years are by-products of the symbiosis between manufacturers and scientists, and it seems as though the fight against restenosis is about to be won with the further setting-up of adequate means that act effectively on the target, even though it has not been clearly understood or identified. Such a pragmatic position, although possibly effective, should remind us that the ancient peoples used natural medicines to cure diseases that they never understood.

Pulmonary artery hypertension in adult patients with symptomatic valvular aortic stenosis.

Pulmonary hypertension (PH) has been reported in patients with valvular aortic stenosis (AS) and has been found to be associated with a more severe clinical picture and a poor prognosis after aortic valve replacement. The aim of this study was to assess the prevalence of PH in adult patients with symptomatic AS undergoing cardiac catheterization, and to evaluate the relation between pulmonary artery (PA) systolic pressure and hemodynamic and clinical variables to further clarify the pathogenetic mechanisms. We assessed right-sided heart hemodynamics during cardiac catheterization in 388 patients with symptomatic isolated or predominant AS. PA systolic pressure between 31 and 50 mm Hg was used to define mild to moderate PH, whereas PA systolic pressure >50 mm Hg was used to define severe PH. PA systolic pressure showed no significant difference according to age and sex, although it was significantly higher in patients in New York Heart Association functional classes III and IV and in patients with coexistent systemic hypertension than in the others. PH was absent in 136 patients (35%, group 1), mild to moderate in 196 patients (50%, group 2), and severe in 58 patients (15%, group 3). Only the prevalence of overt heart failure was significantly higher in group 3 patients. AS severity was similar among the 3 groups, and PA systolic pressure showed no relation to aortic valve area in the entire population. Also, a poor correlation was found between PA pressure and left ventricular (LV) ejection fraction (r = -0.28), with several patients having moderate or severe PH despite a preserved LV systolic function. PA systolic pressure significantly correlated with LV end-diastolic pressure (r = 0.50) and with PA wedge pressure (r = 0.84). Furthermore, transpulmonary pressure gradient, an index of resistance across the pulmonary vascular bed (obtained as the difference between PA mean and PA wedge pressure), was significantly higher in patients with PH, especially in those with a marked increase in PA systolic pressure, suggesting a reactive component of PH.

Angiographic follow-up after coronary implantation of the Multilink stent: a prospective observation.

BACKGROUND: A growing variety of coronary stents is becoming available on the market. Results of randomized trials may be difficult to apply to less selected patients, and experience with every device cannot be obtained in every center. Detailed information about the immediate and long-term results achieved with one device can be a helpful reference for interventional cardiologists. The aim of this study was to test the applicability and the clinical and angiographic results, both immediate and at 6 months, of the Multilink coronary stent in a cohort of unselected patients undergoing coronary angioplasty. METHODS: From March 1997 to June 1998 coronary angioplasty was performed in 391 patients in our center, with the use of stents in 339 patients. RESULTS: Three hundred and seventeen Multilink stents were successfully implanted in 295 lesions in 277 patients; an acute coronary syndrome was present in 209 cases (75%), and lesion types B2 and C accounted for 30% of lesions. In 7 cases (2.4%) the Multilink stent did not cross the lesion, and another device was implanted. Subacute stent occlusion occurred in 1 patient (0.36%) after primary angioplasty. After 6 months from the procedure, clinical follow-up data were available for 252 out of 254 patients: none had died, and angina or myocardial ischemia occurred in 25 patients (9.9%). A control angiogram was performed in 239 out of 254 patients (94%) at 178 +/- 34 days. Restenosis occurred in 44/239 patients (18.4%) and in 48/247 lesions (19.4%). In patients with vs without restenosis the original lesion was longer (p = 0.009), and diabetes mellitus was more frequent (p = 0.002), as was the use of multiple stents (p = 0.005). In single 15, 25 and 35 mm long stents restenosis occurred in 13.9, 15.5 and 46.2% of cases, respectively (p = NS). CONCLUSIONS: The Multilink stent showed a low rate of subacute occlusion (0.36%) and could be used safely also in patients with acute coronary syndromes. The use of a single, 15 or 25 mm long Multilink stent was associated with a low angiographic recurrence rate (14-16%).

Morphological analysis of atherosclerotic plaque retrieved by coronary atherectomy.

The development of atherectomy catheters and their use in clinical practice during percutaneous revascularization procedures permitted the analysis of the pathophysiology of obstructive coronary disease in vivo. The various clinical presentations of coronary disease are related to distinct morphological aspects of the culprit coronary stenosis as assessed by angiography, angioscopy or intravascular ultrasound imaging. Analysis of plaque fragments revealed the underlying histopathology. Restenotic lesions following various mechanical interventions have been studied in detail both in native coronary arteries and in bypass conduits. The biological reaction to implantation of endovascular stents involves inflammation around the stent wires as well as smooth muscle cell proliferation. Specific processes such as nitric oxide production or the activity of intramural proteases can be characterized and contribute to identify targets for future pharmacological therapy.

Experiences with primary angioplasty without on site-cardiac surgery.

Growing evidence suggests that primary angioplasty is superior to thrombolysis for the treatment of acute myocardial infarction, in particular in some high-risk subsets. The performance of primary angioplasty in centres without on-site cardiac surgery may extend the availability of this effective reperfusion therapy. This will benefit in particular those patients who would not be treated otherwise. Optimal primary angioplasty requires a high level of logistic organization, operator expertise, and commitment of the whole team. The outcome does not depend on the presence or absence of surgeons on site. In fact, feasibility, safety and efficacy of primary angioplasty are similar in both types of centres when high standards of care are guaranteed.