Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine.

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .

Cardiac Extracellular Matrix Hydrogel Enriched with Polyethylene Glycol Presents Improved Gelation Time and Increased On-Target Site Retention of Extracellular Vesicles.

Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs-PEG-cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs-PEG-cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.

Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats.

AIM: The aim is to assess the effects of CDCs on heart structure, function, gene expression, and systemic parameters in aged rats. Diastolic dysfunction is characteristic of aged hearts. Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated. METHODS AND RESULTS: We compared intra-cardiac injections of neonatal rat CDCs to vehicle (phosphate-buffered saline, PBS) in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs (CDC-XO) from paediatric donors. Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed, P < 0.05). Telomeres in heart cells were longer in CDC-transplanted animals (P < 0.0001 vs. PBS). Cardiosphere-derived cells attenuated hypertrophy by echo (P < 0.01); histology confirmed decreases in cardiomyocyte area (P < 0.0001) and myocardial fibrosis (P < 0.05) vs. PBS. Cardiosphere-derived cell injection improved diastolic dysfunction [lower E/A (P < 0.01), E/E' (P = 0.05), end-diastolic pressure-volume relationship (P < 0.05) compared with baseline), and lowered serum brain natriuretic peptide (both P < 0.05 vs. PBS). In CDC-transplanted old rats, exercise capacity increased ∼20% (P < 0.05 vs. baseline), body weight decreased ∼30% less (P = 0.05 vs. PBS) and hair regrowth after shaving was more robust (P < 0.05 vs. PBS). Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group (P < 0.05 for each, all vs. PBS). Young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture. CONCLUSION: Young CDCs rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers.

The use of the CNIC-Polypill in real-life clinical practice: opportunities and challenges in patients at very high risk of atherosclerotic cardiovascular disease - expert panel meeting report.

Although the cardiovascular (CV) polypill concept is not new and several guidelines state that a CV polypill should be considered an integral part of a comprehensive CV disease (CVD) prevention strategy, there are still some barriers to its implementation in the real-world setting, mainly in secondary CV prevention. As the CNIC-polypill is the only one approved for secondary CV prevention in patients with atherosclerotic CVD in 27 countries worldwide, a panel of four discussants and 30 participants from 18 countries conveyed in a virtual meeting on April 21, 2022, to discuss key clinical questions regarding the practical use of the CNIC-Polypill and barriers to its implementation.Data presented showed that, although the use of the CV polypill is not explicitly mentioned in the current 2021 European Society of Cardiology guidelines on CVD prevention, it may be used in any patient for secondary CVD prevention tolerating all their components to improve outcomes through different aspects. The favourable results of the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial now reinforce this recommendation. The panellists presented algorithms on how to switch from any baseline regimen when starting treatment with the CNIC-polypill in different situations, including patients with hypertension, dyslipidaemia, and a previous CV event; at discharge after a cardiovascular event; in chronic ischemic conditions; and in cases of polypharmacy. The panellists and expert discussants did agree that available studies conducted so far with the CNIC-polypill demonstrate that it is as efficacious as the monocomponents, equipotent drugs, or other therapies; reduces the risk of experiencing recurrent major CV events; improves medication adherence; reduces health care costs and resources compared to patients treated with loose drugs; and the patients prefer it over the multipill strategy.In conclusion, the data presented by the participants provided the evidence behind the use of the CNIC-polypill to help fulfil the goal of encouraging its adoption by physicians.

Endothelial dysfunction in patients with angina and non-obstructed coronary arteries is associated with an increased risk of mayor cardiovascular events. Results of the Spanish ENDOCOR registry.

BACKGROUND: Coronary endothelial dysfunction and vasospasm are potential causes of ischemia in patients without obstructive coronary stenoses (INOCA). OBJECTIVE: To evaluate the prevalence of endothelial dysfunction and the clinical profile of patients with INOCA in Spain, as well as to identify the predictors and the prognostic impact of endothelial dysfunction in this scenario. METHODS: A total of 438 consecutive patients with INOCA in whom the acetylcholine test was performed were prospectively enrolled. Patients were followed up at 1 and 2 years. RESULTS: Mean age was 62 ± 11 years with 60% female. Clinical presentation comprised 52.6% angina at rest, 61.2% exertional angina, and 31.7% dyspnea. There were no major complications of the acetylcholine test. Endothelial dysfunction was observed in 198 (45%) of patients, with severe vasoconstriction (defined as over 70% constriction), being observed in 101 (23%). Multivariable regression analysis showed that endothelial dysfunction was predicted by the presence of exertional angina (OR 2.2; CI95%1.01-2.55; p = 0.02), prior coronary disease (OR 2.46; CI95% 1.57-3.89; p < 0.01), and coronary intramyocardial bridging (2.35; CI95% 1.02-5.60; p = 0.04). Patients with endothelial dysfunction presented with worsening angina compared to those without endothelial dysfunction (25.6% vs. 12.8%) and also presented with increased levels of minimal effort angina (40% vs. 26,7%, p = 0.03) more frequently during the follow up than those without endothelial dysfunction. Endothelial dysfunction was also an independent predictor of the occurrence of myocardial infarction or unstable angina at one year (OR 2.85, CI 95% 1.01-9.25; p = 0.03). CONCLUSIONS: Endothelial dysfunction is present in almost half of patients with INOCA and is associated with worsening symptoms, as well as with a higher rate of adverse events.

Rejuvenating effects of young extracellular vesicles in aged rats and in cellular models of human senescence.

Rejuvenation of an old organism was achieved in heterochronic parabiosis experiments, implicating different soluble factors in this effect. Extracellular vesicles (EVs) are the secretory effectors of many cells, including cardiosphere-derived cells (CDCs) with demonstrated anti-senescent effect. 1. To determine the role of EVs (versus other blood fractions) on the rejuvenating effect of the young blood. 2. To evaluate the anti-aging properties of therapeutically administered EVs secreted by young-CDCs in an old organism. Neonatal blood fractioned in 4 components (whole blood, serum, EV-depleted serum and purified EVs) was used to treat old human cardiac stromal cells (CSPCs). CDCs were generated from neonatal rat hearts and the secreted CDC-EVs were purified. CDC-EVs were then tested in naturally-aged rats, using monthly injections over 4-months period. For validation in human samples, pediatric CDC-EVs were tested in aged human CSPCs and progeric fibroblasts. While the purified EVs reproduced the rejuvenating effects of the whole blood, CSPCs treated with EV-depleted serum exhibited the highest degree of senescence. Treatment with young CDC-EVs induce structural and functional improvements in the heart, lungs, skeletal muscle, and kidneys of old rats, while favorably modulating glucose metabolism and anti-senescence pathways. Lifespan was prolonged. EVs secreted by young CDCs exert broad-ranging anti-aging effects in aged rodents and in cellular models of human senescence. Our work not only identifies CDC-EVs as possible therapeutic candidates for a wide range of age-related pathologies, but also raises the question of whether EVs function as endogenous modulators of senescence.

Predictive value of advanced glycation end products for the development of post-infarction heart failure: a preliminary report.

BACKGROUND: Since post-infarction heart failure (HF) determines a great morbidity and mortality, and given the physiopathology implications of advanced glycation end products (AGE) in the genesis of myocardial dysfunction, it was intended to analyze the prognostic value of these molecules in order to predict post-infarction HF development. METHODS: A prospective clinical study in patients after first acute coronary syndrome was conducted. The follow-up period was consisted in 1 year. In 194 patients consecutively admitted in the coronary unit for myocardial infarct fluorescent AGE levels were measured. The association between glycaemic parameters and the development of post-infarction HF were analyzed in those patients. Finally, we identified the variables with independent predictor value by performing a multivariate analysis of hazard ratio for Cox regression. RESULTS: Eleven out of 194 patients (5.6%) developed HF during follow-up (median: 1.0 years [0.8 - 1.5 years]). Even though basal glucose, fructosamine and glycated haemoglobin were significant predictive factors in the univariate analysis, after being adjusted by confounding variables and AGE they lost their statistical signification. Only AGE (Hazard Ratio 1.016, IC 95%: 1.006-1.026; p<0,001), together with NT-proBNP and the infarct extension were predictors for post-infarction HF development, where AGE levels over the median value 5-fold increased the risk of HF development during follow-up. CONCLUSIONS: AGE are an independent marker of post-infarction HF development risk.

Variations in platelet proteins associated with ST-elevation myocardial infarction: novel clues on pathways underlying platelet activation in acute coronary syndromes.

OBJECTIVE: Our aim in this study was to provide novel information on the molecular mechanisms playing a major role in the unwanted platelet activation associated with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We compared the platelet proteome of 11 STEMI patients to a matched control group of 15 stable chronic ischemic cardiopathy patients. In addition, we did a prospective study to follow the STEMI patients over time. Proteins were separated by high-resolution 2D gel electrophoresis, identified by mass spectrometry, and validated by Western blotting. Platelets from STEMI patients on admission displayed 56 protein spot differences (corresponding to 42 unique genes) compared with the control group. The number of differences decreased with time during the patients' follow-up. Interestingly, the adapter protein CrkL and the active form of Src (phosphorylated in Tyr418) were found to be upregulated in platelets from STEMI patients. Major signaling pathways related to the proteins identified include integrin, integrin-linked kinase, and glycoprotein VI (GPVI) signaling. Interestingly, a study on an independent cohort of patients showed a higher degree of activation of GPVI signaling in STEMI patients. CONCLUSIONS: CrkL, the active form of Src, and GPVI signaling are upregulated in platelets from STEMI patients.

Cardiovascular Diseases in the Digital Health Era: A Translational Approach from the Lab to the Clinic.

Translational science has been introduced as the nexus among the scientific and the clinical field, which allows researchers to provide and demonstrate that the evidence-based research can connect the gaps present between basic and clinical levels. This type of research has played a major role in the field of cardiovascular diseases, where the main objective has been to identify and transfer potential treatments identified at preclinical stages into clinical practice. This transfer has been enhanced by the intromission of digital health solutions into both basic research and clinical scenarios. This review aimed to identify and summarize the most important translational advances in the last years in the cardiovascular field together with the potential challenges that still remain in basic research, clinical scenarios, and regulatory agencies.

Practical Decision Algorithms for the Use of the Cardiovascular Polypill in Secondary Prevention in Europe.

The main objective of cardiovascular disease (CVD) prevention is to reduce morbidity and mortality. Despite recommendations on evidence-based pharmacological treatment and lifestyle changes, the control of CV risk factors such as hypertension or dyslipidaemia is not optimal. The use of a CV polypill, including guideline-recommended drugs, as a baseline therapy, may contribute to improving risk factors control either by improving the treatment adherence or by the synergistic effect of its components. The CNIC-Polypill is the first CV polypill approved in Europe as an effective strategy for secondary prevention, which contains acetylsalicylic acid, atorvastatin (in two optional doses), and ramipril (in three optional doses) in a single pill. The present practical clinical document aims to provide a guide for patient management after an acute coronary syndrome (ACS) or with chronic CVD (CCVD) with a strategy based on the CNIC-Polypill, also considering the need to add other therapies for a personalized treatment. The most suitable clinical scenarios for the CNIC-Polypill use are discussed: (a) in patients after an ACS at discharge, (b) in patients with CCVD (chronic coronary syndrome, stroke, or peripheral artery disease) with uncontrolled low-density lipoprotein cholesterol (LDL-c) and/or blood pressure levels and (c) in patients with CCVD with well-controlled risk factors to simplify treatment and reduce polypharmacy in the context of CCVD prevention.

The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development.

Biological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action. Development of potency assays for cell-based products consists in understanding the pathophysiology of the disease, identifying potential mechanisms of action (MoA) to counteract it and finding the most suitable cell-based product that exhibits these MoA. When applied, the potency assay needs to correlate bioactivity of the product, via a measurement related to the MoA, with treatment efficacy. However, in the cardiovascular field, the process faces several challenges and high requirements.

[#CienciaenelParlamento: the need for a parliamentary office of science and technology advice]. / #CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico.

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain.

Insights into therapeutic products, preclinical research models, and clinical trials in cardiac regenerative and reparative medicine: where are we now and the way ahead. Current opinion paper of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine.

Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting.

The MUSIC Risk score: a simple method for predicting mortality in ambulatory patients with chronic heart failure.

AIMS: The prognosis of chronic heart failure (CHF) is extremely variable, although generally poor. The purpose of this study was to develop prognostic models for CHF patients. METHODS AND RESULTS: A cohort of 992 consecutive ambulatory CHF patients was prospectively followed for a median of 44 months. Multivariable Cox models were developed to predict all-cause mortality (n = 267), cardiac mortality (primary end-point, n = 213), pump-failure death (n = 123), and sudden death (n = 90). The four final models included several combinations of the same 10 independent predictors: prior atherosclerotic vascular event, left atrial size >26 mm/m(2), ejection fraction < or =35%, atrial fibrillation, left bundle-branch block or intraventricular conduction delay, non-sustained ventricular tachycardia and frequent ventricular premature beats, estimated glomerular filtration rate <60 mL/min/1.73 m(2), hyponatremia < or =138 mEq/L, NT-proBNP >1.000 ng/L, and troponin-positive. On the basis of Cox models, the MUSIC Risk scores were calculated. A cardiac mortality score >20 points identified a high-risk subgroup with a four-fold cardiac mortality risk. CONCLUSION: A simple score with a limited number of non-invasive variables successfully predicted cardiac mortality in a real-life cohort of CHF patients. The use of this model in clinical practice identifies a subgroup of high-risk patients that should be closely managed.

[Erectile dysfunction as a marker of silent cardiovascular disease in type-2 diabetic patients in Spain. The DIVA (DIabetes and VAscular disease) study]. / Disfunción eréctil como marcador de vasculopatía en la diabetes mellitus tipo 2 en España. Estudio DIVA.

BACKGROUND AND OBJECTIVES: Erectile dysfunction (ED) is a sign of vascular disease in type 2 diabetic patients. The present subanalysis of the DIVA Registry, whose main objective was to estimate the prevalence of clinical vascular disorder and silent vascular disorder, as well as risk factors in type 2 diabetic patients treated in Spain, aims to analyze the relationship between those data and the prevalence of ED in these patients. PATIENTS AND METHODS: A total of 2444 type 2 diabetic patients (56% male; mean age 65.2 years) attended by 387 cardiologists and endocrinologists at ambulatory care were included. RESULTS: Coronary heart disease was present in 37% of the patients, cerebrovascular disease in 12%, and peripheral arterial disease in 13%. Forty percent of male patients had ED (according to the IIEF criteria), although in this group, as compared to those patients without ED, the prevalence of cardiovascular disease and signs of subclinical vascular disorder (microalbuminuria and abnormal ankle/brachial index (ABI)) was higher. The only independent predictor of ED was left ventricular hypertrophy (OR 5.2; 95% CI: 1.1-24.1; P=.03), with the ABI <0,9 being of borderline significance (OR 5.9; 95% CI: 0.9-39.9; P=.06). Poor glycemic and lipemic control (P<.05 in both cases) as well as cerebrovascular and peripheral arterial disease (P<.01 in both cases) and renal dysfunction (P<.001) were all more frequent among patients with severe ED. CONCLUSIONS: Forty percent of diabetic patients suffer from ED. The results of this study suggest that ED may be considered as an atherosclerosis marker and could be included in algorithms for risk stratification and subclinical vascular disorder detection.

Why and when do patients with heart failure and normal left ventricular ejection fraction die? Analysis of >600 deaths in a community long-term study.

BACKGROUND: The aim of the study was to examine the causes of the death of patients with heart failure (HF) and evaluate the differences in this respect between patients with and without depression of left ventricular ejection fraction (LVEF). METHOD: All patients hospitalized with HF between 1995 and 2002 in the cardiology service of a tertiary hospital were assessed. LVEF was evaluated by echocardiography during hospitalization and was considered normal when it was > or =50%. After a mean follow-up time of 3.7 +/- 2.8 years, 615 cases had terminated in death. RESULTS: The most common cause was refractory HF, both in the whole group (39%) and in both the subgroups defined with respect to LVEF (normal and depressed). There was no statistically significant difference between the normal and depressed subgroups as regard the distribution of deaths, although the depressed group showed a somewhat greater incidence of sudden death (21% as against 16% in the normal group) and a somewhat smaller incidence of death due to refractory HF (37% as against 47%). However, in the depressed LVEF group, the cumulative risk of death due to acute myocardial infarction in the first 1.5 years first increased rapidly and then more slowly, whereas the reverse pattern was held in the normal left ventricular systolic function group, in which it was the cumulative risks of death from noncardiovascular or vascular noncardiac causes that initially increased more rapidly than later. CONCLUSIONS: The spectrum of causes of death among patients with HF who have been hospitalized is independent of LVEF in the long term. In the short term, there are differences between patients with normal LVEF and depressed LVEF as regard the dynamics of the risks of death from acute myocardial infarction, noncardiac vascular causes, and noncardiovascular causes. These results may help orient the short-term and long-term management of HF, especially for patients with normal LVEF, for whom there is still no well-established consensus strategy.

Association of blood pressure and its evolving changes with the survival of patients with heart failure.

OBJECTIVE: The association between low blood pressure (BP) levels and increased mortality has been established in several studies of heart failure (HF). Although many drugs administered to these patients decrease BP, the relationship between changes in BP and survival has not been investigated. Nor have previous analyses distinguished among different forms of death. We investigated the influence of baseline BP and changes in BP during a 1-year period on the survival of patients with HF, distinguishing among sudden cardiac death, nonsudden cardiac death, and noncardiac death. We also identified the possible relationship with the baseline values of and changes in other clinical and treatment variables, including pharmacologic treatments. METHOD AND RESULTS: A total of 1062 patients with chronic HF included in the Spanish National Registry of Sudden Death (mean age of 64.5 +/- 11.8 years, 72% were men, and 21% were in New York Heart Association class III with a mean left ventricular ejection fraction of 36.7% +/- 14.2%) were prospectively investigated for a mean of 1.9 +/- 0.6 years. A multivariable Cox proportional hazards model adjusting for clinical and therapeutic variables showed an independent association between low baseline systolic blood pressure (SBP) and nonsudden cardiac death (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.93-0.98), but changes in SBP during the following year did not influence survival, regardless of the baseline SBP level (P = .55). Contrariwise, baseline diastolic BP was not associated with mortality, but an increase in diastolic BP during the following year showed a borderline independent significant association with lower nonsudden cardiac death (HR 0.90, 95% CI 0.82-1.00). Treatment with angiotensin-converting enzyme inhibitors or beta-blockers at baseline was also associated with lower nonsudden cardiac mortality, as was an increase in left ventricular ejection fraction during the following year (HR 0.69, 95% CI 0.51-0.93; P = .015). CONCLUSION: Among patients with stable HF, low SBP is associated with a greater risk of nonsudden cardiac death. The change in SBP during a 1-year period has no prognostic value. Because the beneficial effects of drugs associated with increased survival (in this study, angiotensin-converting enzyme inhibitors and beta-blockers) thus seem to be independent of their effects on BP, changes in BP should probably not influence the decision to use such drugs or continue their administration.

Innovative Strategies in Heart Failure: Present and Future.

Heart failure (HF) is a progressively debilitating disease that considerably decreases the life expectancy and quality of life. It has become an important area of focus since it remains one of the most common reasons for admission in patients over the age of 65. Importantly, the incidence of HF has not declined within the past 20 years, but the survival after onset has increased in younger patients and men. This has been in part due to the growing interest in therapies that may decrease morbidity, mortality, along with the substantial health care expenditures associated with the disease. It can be said that over the past 50 years, there have been three distinct eras relating to HF management; a) the non-pharmacologic era, focused its treatments on fluid restriction; b) the pharmacologic era, marked by the increased use of inotropes and diuretics and the discovery of vasodilators, and the posterior discovery of medications relating to neurohormonal pathways; c) the device era, with the discovery, acceptance, and increased use of implantable cardioverter defibrillators, cardiac resynchronization therapy (CRT), and left ventricular assist devices (LVADs) among others. A new forth era could be about to arrive, with the advent of regenerative therapies. In this review article will discuss new therapeutic discoveries as well as provide insight into future therapies.