Pulmonary Arterial Hypertension in the Elderly: Peculiar Features and Challenges for a Proper Phenotyping Approach.

(1) Introduction. Although pulmonary arterial hypertension (PAH) usually affects young people with a low cardiovascular risk profile, progressive epidemiologic changes have been providing a codified phenotype of elderly subjects with PAH and increased risk predictors for left heart disease. We therefore conducted a systematic review to describe the current knowledge and characteristics of elderly individuals with PAH and further insights concerning their prognostic outcomes and therapeutic response. (2) Methods. A search was conducted in PubMed, Embase, and Cochrane Library for publications evaluating the epidemiology, diagnostic work-up, and treatment of PAH in elderly subjects. (3) Among the 74 publications initially retrieved, 16 full-text articles were selected for the present systematic review. Compared to their younger counterparts, elderly individuals with PAH showed greater clinical deterioration, reduced exercise capacity, and worse prognostic outcomes, as well as less response to PAH-targeted therapy and higher rates of PAH drug discontinuation. (4) Conclusions. Demographic changes over time contributed to define a peculiar PAH phenotype in elderly patients, with an increased burden of cardiovascular comorbidities and distinctive features compared to young patients. Further investigations are needed in order to better clarify the nosologic criteria, and management in this subset population.

Impact of structural similarity on the accuracy of retention time prediction.

Quantitative Structure-Retention Relationships offer a valuable tool for de-risking chromatographic methods in relation to newly formed or hypothetical compounds, arising from synthetic processes or formulation activities. They can also be used to identify optimal separation conditions, or in support of structural elucidation. In this contribution, we provide a systematic study of the relationship between the accuracy of the retention model, the size of the training set and its structural similarity to the predicted compound. We compare structural similarity expressed either on a fingerprint basis (e.g., Tanimoto index), or by Euclidean distance calculated from of subset of molecular descriptors. The results presented indicate that accurate and predictive models can be built from a small dataset containing as few as 25 compounds, provided that the training set is structurally similar to the test compound. When the training set contains compounds selected by minimizing the Euclidean distance calculated from 3 descriptors most correlated with the retention time, root mean square error of 0.48 min and correlation coefficient of 0.9464 were observed for the test sets of 104 compounds. Moreover, these models meet the Tropsha predictivity criteria. These findings potentially bring the prediction of retention times within the practical reach of pharmaceutical analysts involved in chromatographic method development. We also present an optimisation approach to select algorithm settings in order to minimize the prediction error and ensure model predictivity.

Treatment with neurohormonal inhibitors and prognostic outcome in pulmonary arterial hypertension with risk factors for left heart disease.

BACKGROUND: Despite major advances in pharmacologic treatment, patients with pulmonary arterial hypertension (PAH) still have a considerably reduced life expectancy. In this context, chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH, thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target. AIM: To evaluate the application and prognostic effect of neurohormonal inhibitors (NEUi) in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease. METHODS: We analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1, 2005 to October 31, 2018. Patients on beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi non-recipients. RESULTS: Complete data were available for 57 PAH subjects: 27 of those (47.4%) were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients. NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients. Additionally, NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients (56.7% vs 25.9%, log-rank P = 0.020). CONCLUSION: The above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival. Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

Venous Congestion and Systemic Hypoperfusion in Cardiorenal Syndrome: Two Sides of the Same Coin.

A wide range of comorbidities play a pivotal role in worsening outcomes and increasing mortality risk in patients with heart failure (HF). Among them, renal dysfunction has been recognized as a highly prevalent prognostic variable, with a strong impact on prognosis, length of hospital stay and need for intensive care. In this context, recent evidence has pointed out the relevance of both systemic hypoperfusion and venous congestion on the imbalance of renal function as well as on the conditioning the pathophysiological crosstalk between heart and kidneys through a wide range of haemodynamic and biochemical pathways. This narrative review aims to investigate the intricate interplay between impaired systemic perfusion and venous congestion in cardiorenal syndrome, as well as their haemodynamic and biochemical implications for renal damage in HF.

A systematic review on focal takotsubo syndrome: a not-so-small matter.

A focal contraction pattern in takotsubo syndrome (TTS) is considered rare. Due to its peculiar presentation, which includes segmental left ventricular (LV) regional wall motion abnormalities (RWMA), the focal TTS pattern may be hardly differentiable from other entities, such as myocarditis or myocardial infarction. We performed a comprehensive systematic literature review researching for works in English published in Journals indexed in Embase, available online for consultation, using the following keywords (in Title and/or Abstract): ("takotsubo" OR "broken heart" OR "apical ballooning" OR "stress cardiomyopathy") AND ("focal" OR "atypical" OR "variant" OR "segments"). Thirty-three papers were retrieved: 17 case reports, 6 case series, and 10 population studies-with a total of 166 focal TTS patients. Prevalence of focal TTS ranged between 0.1% and 14% (pooled mean: 2.8%). Mean age of onset (58 years), gender distribution (80% of females), and type of triggers appeared similar to those reported in typical TTS. RWMA more frequently involved the interventricular septum and the anterolateral LV segments, with often preserved LV ejection fraction. In the majority of focal TTS reports that included adequate ECG information (n = 13), abnormalities were localized and not diffuse, always matching RWMA, and in 3 cases, reciprocal changes were observed. No in-hospital nor long-term deaths were reported. The focal TTS contraction pattern may be more prevalent than currently reported. Though possibly presenting with similar demographic background compared with typical TTS, the focal variant might be characterized by peculiar ECG modifications and better prognosis.

Structure Driven Prediction of Chromatographic Retention Times: Applications to Pharmaceutical Analysis.

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. The results presented here indicate that retention models based on Quantitative Structure Retention Relationships can be used for de-risking methods used in pharmaceutical analysis and for the identification of optimal conditions for separation of known sample constituents from postulated/hypothetical components. The prediction of retention times for hypothetical components in established methods is highly valuable as these compounds are not usually readily available for analysis. Here we discuss the development and optimization of retention models, selection of the most relevant structural molecular descriptors, regression model building and validation. We also present a practical example applied to chromatographic method development and discuss the accuracy of these models on selection of optimal separation parameters.

Frequency, predictors and prognostic impact of implantable cardioverter defibrillator shocks in a primary prevention population with heart failure and reduced ejection fraction.

AIMS: The role of the implantable cardioverter defibrillator (ICD) in primary prevention real-world population is debated. We sought to evaluate the incidence, predictors and prognostic impact of ICD shocks in consecutive heart failure patients implanted for primary prevention at our tertiary institution. METHODS AND RESULTS: We retrospectively selected a sample of 497 patients (mean age 64.8 years, 82.1% men, average left ventricular ejection fraction, LVEF, 27.1%). At long-term follow-up (median time 70.4 months), total mortality was 40.8%, and 16.5% of patients had received at least one appropriate shock (3.12%/year). Inappropriate shock [odds ratio (OR) 1.93, 95% confidence interval (95% CI) 1.08-3.47; P = 0.027] and length of follow-up (1 year, OR 1.01, 95% CI 1.00-1.01; P = 0.0031) were associated with the occurrence of appropriate shock, whereas atrial fibrillation (OR 2.65, 95% CI 1.55-4.51, P < 0.001), length of follow-up (1-year OR 1.01, 95% CI 1.00-1.01, P < 0.001) and appropriate shock (OR 1.93, 95% CI 1.08-3.47, P = 0.027) were associated with the occurrence of inappropriate shock. Neither appropriate nor inappropriate shock independently increased mortality risk, whereas older age (hazard ratio 1.05; 95% CI 1.04-1.07; P < 0.001), atrial fibrillation (hazard ratio 2.25; 95% CI 1.67-3.02; P < 0.001) and lower LVEF (hazard ratio 0.97; 95% CI 0.94-0.99; P = 0.004) did. CONCLUSION: Incidence of shocks in real-world primary prevention ICD recipients might be lower than expected, and the association between ICD shocks and prolongation of survival is not as clear-cut as might be perceived. Further investigations from larger real-world samples are warranted.

Alzheimer's Disease and Cardiovascular Disease: A Particular Association.

METHODS: This review is based on the material obtained via MEDLINE (PubMed), EMBASE, and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease," combined with "cardiovascular disease," "hypertension," "dyslipidaemia," "diabetes mellitus," "atrial fibrillation," "coronary artery disease," "heart valve disease," and "heart failure." Out of the 1,328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed. Among the 681 remaining studies, 98 were included in our research material on the basis of the following inclusion criteria: (a) the community-based studies; (b) using standardized diagnostic criteria; (c) reporting raw prevalence data; (d) with separate reported data for sex and age classes. RESULTS: While AD and CVD alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of vascular factors on these diseases. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being hypoperfusion and emboli, atherosclerosis, and the fact that, in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs. CONCLUSIONS: AD and CVD are frequently associated. Further studies are needed in order to understand the effect of CVD and its risk factors on AD in order to better comprehend the effects of subclinical and clinical CVD on the brain. Finally, we need to clarify the impact of the underlying hypothesized mechanisms of this association and to investigate gender issues.

PCSK9 inhibitors for treating hypercholesterolemia.

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.

An Emerging Cardiovascular Disease: Takotsubo Syndrome.

Takotsubo syndrome (TTS) is a recently identified cardiac disease, which is far from being completely known. The aims of this narrative review are to provide a better understanding of the pathophysiological features of TTS and to update clinical findings in order to improve the management of subjects affected by this syndrome (according to the most recent consensus papers issued by the international scientific societies). We based our search on the material obtained via PubMed up to April 2019. The terms used were "Takotsubo Syndrome and Takotsubo cardiomyopathy" in combination with "heart failure, pathophysiology, complications, diagnosis, and treatment." TTS is a reversible form of ventricular dysfunction usually characterized by akinesia of the apex in the absence of obstructive coronary artery disease. In its initial phase, TTS may be indistinguishable from AMI and is usually triggered by a sudden emotional/physical stressor which abruptly increases catecholamine levels. However, the mechanisms by which catecholamines or other unidentified molecules can cause myocardial dysfunction is unknown. In-hospital stay may be hampered by various life-threatening complications, while data on long-term survival remain scarce and unclear. Furthermore, TTS may sometimes recur. We believe that TTS is clearly a much more complex condition than previously thought. Much remains to be discovered about its pathophysiologic mechanisms, the role of the link between the heart and brain and that of triggering factors and gender, and the reasons why this syndrome displays different phenotypes and sometimes recurs. Undoubtedly, preliminary evidence from pathophysiological studies (mainly genetic studies) has shown promising advances. However, prospective randomized clinical trials are still needed in order to identify and to tailor the best medical treatments for TTS patients.

Clinical Characteristics and Long-Term Mortality Rate in Female Patients with Takotsubo Syndrome Compared with Female Patients with ST-Elevation Acute Myocardial Infarction: A Retrospective Study from a Single Center.

BACKGROUND: Takotsubo syndrome (TTS) is characterized by acute transient, stress-induced, left ventricular systolic dysfunction, generally presenting with apical ballooning. It can mimic an acute coronary syndrome, but with a milder increase in cardiac enzymes and without culprit coronary artery disease on angiography. Data on long-term follow-up and survival in patients with TTS, compared with patients with ST-elevation myocardial infarction (STEMI), are scarce. PURPOSE: To assess all-cause mortality rate and survival in a consecutive series of female patients with TTS compared with age- and sex-matched STEMI patients on long-term follow-up. METHODS AND RESULTS: We collected data of 65 TTS female patients (TTS group) with a mean age of 73.42 ± 11.35 years from 2001 to 2013. Collection of follow-up information was concluded for all patients in 2016. To compare the mortality and survival of TTS patients with those of the STEMI population, we used data from our STEMI Registry, a prospective registry of 7446 STEMI patients admitted from 2001 to 2013 to our cath-lab for primary percutaneous coronary intervention (p-PCI). From the registry, we selected 104 STEMI patients (STEMI group) comparable to our TTS group in terms of age (mean age of 72.33 ± 11.92 years) and sex. On follow-up examination after a median of 1000 days, the TTS group had a lower all-cause mortality rate than the STEMI group (7.69% versus 23.08%). This difference was statistically different between the two groups (log-rank test, p value = 0.03). CONCLUSIONS: In our study, TTS and STEMI patients displayed a statistically significant difference in long-term survival. Specifically, the TTS group had a lower mortality rate than the STEMI group. This seems to suggest that TTS and STEMI are two different clinical entities with two different clinical outcomes.

Causes and impact on survival of underuse of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in heart failure.

Guidelines recommend angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) for treatment of heart failure with reduced ejection fraction (HFrEF), but these medications are underprescribed in clinical practice. We reviewed the records of HF patients receiving a first visit in a tertiary outpatient clinic from January 1st 2004 to May 31st 2015, and selected those with a serum creatinine concentration (sCr) available at both the first and last visit and < 3.5 mg/dL at baseline, and a left ventricular ejection fraction (LVEF) < 50% at the first visit. Of 570 eligible patients, 92 (16.1%) never received ACEi/ARB. Compared to ACEi/ARB users, never-users were older, more often women, had higher sCr and lower systolic blood pressure, were less commonly on beta-blocker, and had more frequently anemia. Current or prior cancer also tended to be more common in ACEi/ARB never-users. ACEi/ARB users displayed an improvement in LVEF by ≥ 10% of the baseline value more often than ACEi/ARB never-users (33.7% vs. 20.7%, respectively, P = 0.01), whereas no difference in percent variation of sCr levels was found between the two groups (8.2% vs. 3.1%, respectively; P = 0.13). Over a median follow-up of 56 months (range 1-137 months), 215 (37.7%) patients died. After multiple adjustments, ACEi/ARB never-use was associated with an almost twofold increased risk of all-cause mortality (HR 1.97, 95%CI 1.39-2.80). ACEi/ARB underuse in HFrEF is a standing issue with dramatic prognostic consequences. Efforts are needed to eliminate perceived contraindications to these drugs and ensure their implementation in real-life cardiology.