Search

Aims: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). Methods and results: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow‐up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between‐group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase‐7 (MMP‐7), galectin‐4 (GAL4), plasminogen activator inhibitor 1 (PAI‐1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP‐7, neurotrophin‐3 (NT3), pulmonary surfactant‐associated protein D (PSPD), and lower plasma tumour necrosis factor‐related activation‐induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. Conclusions: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes. [ABSTRACT FROM AUTHOR]

Aims: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF. Methods and results: An individual‐patient‐data meta‐analysis of three randomized trials (HOMAGE, Aldo‐DHF, and TOPCAT) was performed comparing spironolactone (9–12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e′ ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo‐DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo‐DHF, and 134 (13.6%) from TOPCAT. The pooled‐cohort patient's median age was 71 (66–77) years and 39% were women. Median LAVi was 29 (24–35) ml/m2, LVMi 100 (84–118) g/m2, IVS thickness 12 (10–13) mm, E/e′ ratio 11 (9–13), and LVEF 64 (59–69)%. Spironolactone reduced LAVi by −1.1 (−2.0 to −0.1) ml/m2 (p = 0.03); LVMi by −3.6 (−6.4 to −0.8) g/m2 (p = 0.01); IVS thickness by −0.2 (−0.3 to −0.1) mm (p = 0.01); E/e′ ratio by −1.3 (−2.4 to −0.2) (p = 0.02); and increased LVEF by 1.7 (0.8–2.6)% (p < 0.01). No treatment‐by‐study heterogeneity was found except for E/e′ ratio with a larger effect in Aldo‐DHF and TOPCAT (interaction p < 0.01). Conclusions: Spironolactone improved cardiac structure and function of patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Procollagen type I C‐terminal propeptide (PICP) and procollagen type III N‐terminal propeptide (PIIINP) are markers reflecting collagen synthesis in cardiac fibrosis. However, they may be influenced by the presence of non‐cardiac comorbidities (e.g. ageing, obesity, renal impairment). Understanding the associations between markers of collagen synthesis and abnormalities of cardiac structure and function is important to screen for myocardial fibrosis and monitor the antifibrotic effect of medications. Methods and results: The HOMAGE (Heart 'OMics' in AGEing) trial showed that spironolactone decreased serum PICP concentrations and improved cardiac remodelling over 9 months in a population at risk of developing heart failure (HF). We evaluated the associations between echocardiographic variables, PICP, PIIINP and galectin‐3 at baseline and during the course of the trial. Among 527 individuals (74 ± 7 years, 26% women), median serum concentrations of PICP, PIIINP and galectin‐3 were 80.6 μg/L (65.1–97.0), 3.9 μg/L (3.1–5.0), and 16.1 μg/L (13.5–19.7), respectively. After adjustment for potential confounders, higher serum PICP was significantly associated with left ventricular hypertrophy, left atrial enlargement, and greater ventricular stiffness (all p < 0.05), whereas serum PIIINP and galectin‐3 were not (all p > 0.05). In patients treated with spironolactone, a reduction in serum PICP during the trial was associated with a decrease in E/e′ (adjusted‐beta = 0.93, 95% confidence interval 0.14–1.73; p = 0.022). Conclusions: In individuals at high risk of developing HF, serum PICP was associated with cardiac structural and functional abnormalities, and a decrease in PICP with spironolactone was correlated with improved diastolic dysfunction as assessed by E/e′. In contrast, no such associations were present for serum PIIINP and galectin‐3. [ABSTRACT FROM AUTHOR]

Aims: The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C‐terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C‐terminal telopeptide to matrix metalloproteinase‐1 ratio (CITP:MMP‐1), associated with high collagen cross‐linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP‐1 and spironolactone on cardiac function in the HOMAGE trial. Methods and results: Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP‐1 was used as an indirect measure of collagen cross‐linking. Higher baseline CITP:MMP‐1 (i.e. lower collagen cross‐linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP‐1 (estimated lowest collagen cross‐linking) [mean differencesspiro/control: −1.77 (95% confidence interval, CI −2.94 to −0.59) and −2.52 (95% CI −4.46 to −0.58) mL/m2; interaction pacross‐tertiles = 0.005; interaction pthird tertile = 0.008] with a similar trend for N‐terminal pro‐B‐type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross‐linking tertile [mean differencesspiro/control: −0.47 (95% CI −0.66 to −0.28) and −0.31 (95% CI −0.59 to −0.04) ng/L; interaction pacross‐tertiles = 0.09; interaction pthird tertile < 0.001]. Conclusions: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross‐linking (indirectly assessed by serum CITP:MMP‐1). [ABSTRACT FROM AUTHOR]

Aims  To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results  Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P  = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P  < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P  < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P  = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P  < 0.0001) were reduced in those assigned spironolactone. Conclusions  Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Aims: Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial., Methods: In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current sub-study included 113 controls and 114 patients assigned spironolactone (~70% on beta-blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within-group changes over time (follow-up minus baseline) and between-group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data., Results: Irrespective of randomization, the resting HR and CHR did not change from baseline to follow-up, with the exception of a small decrease in the HR immediately post-exercise (-3.11 b.p.m.) in controls at Month 9. In within-group analyses, HR decline over the 5 min post-exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between-group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post-exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles., Conclusions: Spironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta-blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom-limited exercise capacity in patients prone to developing heart failure because of coronary heart disease., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

At the dawn of "metaclinical medicine" era, shared decision-making represents the overcoming of modern medicine guidelines and classical medicine experience. The patient's life plan, the doctor's health plan, the scientist's evidence-based plan, the administrator's plan and the beliefs of the society for healthcare options should be integrated into the shared decision-making process to avoid patient's unrealistic expectations, doctor's self-referential and defensive medicine, the science without compassion of the scientist, the administered medicine of the politician, the herd mentality of artificial intelligence. For a doctor who must evaluate according to science and conscience, it becomes difficult to make decisions about a patient who thinks that there can be "no decisions about me without me". It risks being a pure declamatory statement in the absence of clinical knowledge and the associated concept of probability. The idea of moving from informed consent to shared probability is convenient for both the doctor and the patient but not for litigation professionals. Even in metaclinical medicine, clinical decision support systems, if well governed, would facilitate the choice of the best treatment according to the definition of absolute risk reduction and the number of patients to be treated to avoid an event, leaving it up to the doctor-patient relationship the narrative and the choice of the most appropriate treatment, which also requires taking care of the emotional and compassionate aspects.

Aims: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect., Methods and Results: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041)., Conclusion: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

In type 1 diabetes mellitus and in symptomatic and critical hyperglycemic states, insulin is a lifesaving drug; however, its value in long-term type 2 diabetes therapy, which represents more than 90% of diabetes, has not been assessed. This happens despite the fact that, in randomized studies on type 2 diabetes, insulin is used in two-thirds of cases when intensive hypoglycemic treatment is needed and in half of the patients when treatment is the standard one. This is a major issue from a clinical, economic and social-health organization point of view as insulin therapy is expensive and needs a complex organization. Observational and retrospective studies from the scientific literature show that in this type of diabetes insulin treatment is associated with increased cardiovascular and all-cause mortality. It is not clear whether this is due to a greater severity of the clinical picture, to the therapeutic target of blood glucose that may induce hypoglycemia, or to the intrinsic pharmacological activity of the drug that beyond reducing hyperglycemia can cause hypoglycemia, water retention, weight gain and hyperinsulinemia with proatherogenic effects. In particular, in patients with heart failure at high cardiovascular risk or with high insulin resistance, these clues are supported by meaningful data. Although there is no definitive evidence (the so-called "smoking gun") from randomized controlled trials, the high degree of suspicion induces the preferential choice of other drugs such as sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and metformin beyond avoiding glycemic targets that induce hypoglycemia, especially in frail, elderly patients, or patients with cardiovascular diseases. These drugs, for their proven efficacy and the easy use within an outpatient setting (that favors their prescription and improves the inertia of the doctor and the adherence of patients), could help a more effective treatment of patients, both for quality and life expectancy beyond mere glycemic control.

Background: Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The "Heart OMics in AGEing" (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial., Methods: Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes., Results: Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05)., Conclusions: Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status.  Trial registration NCT02556450., (© 2021. The Author(s).)

Background: The request for informed consent to join a clinical trial often creates mistrust and hesitation in the patient who should be enrolled. In our study, we evaluated the reasons for refusing to participate in a clinical trial., Methods: In the last 10 years of cardiovascular clinical research, we asked an informed consent to 2586 patients for intervention studies. Overall, 59% agreed to join clinical trials, 40% refused. The 1% initially accepted and then withdrew the consent. Those who refused were more frequently women, relatively younger (mean age 62 ± 5 vs 74 ± 9 years) and had a higher level of education and income. We asked all these patients who refused to answer a brief questionnaire about the reasons for rejection., Results: Of 1031 patients, 629 (61%), accepted to answer the interview; 176 (28%) answered they refused on relatives', friends' or other doctors' advices, or after Internet searches; 157 (25%) answered they did not agree about how the trials were carried out (double-blind control procedure, use of placebo); 126 (20%) did not trust official medicine; 63 (10%) could not guarantee their presence at the follow-up visits; 69 (11%) did not want to undergo additional medical examinations; 31 (5%) had previous bad research experiences (feeling like a guinea pig); 7 (about 1%) refused for other reasons., Conclusions: Recruitment into clinical research studies is still a major challenge. Patients, due to a prevailing humanistic culture, are not fully aware of the importance of participation in clinical research, which is sometimes considered as exclusive economic or prestige interest. In our experience, people who refused participation in the trials were younger, with a high level of education and income, more frequently women. The researcher's task is to motivate the patient by emphasizing that participating in a study means being the actors of a treatment choice and that one is a guinea pig when taking untested therapies.

Background: In patients with diabetic or stress hyperglycemia hospitalized for acute cardiovascular disease, the occurrence of hypoglycemia increases the risk of mortality and morbidity without this being counterbalanced by a reduction in events related to a tighter glycemic control. The guidelines on this topic agree in excluding intensive treatment, but are very discordant in recommending a conventional (<180 mg/dl) or milder (<200 mg/dl) blood glucose control., Methods: In 1256 hyperglycemic patients (mean age 74 ± 12 years) admitted to the medical intensive care unit (MICU) for acute coronary syndrome or acute heart failure, we adopted a nurse-led protocol of mild blood glucose control with subcutaneous administration of insulin, called "BBC200" (basal-bolus correction insulin regimen with glycemic target <200 mg/dl), with the aim at maintaining average blood glucose <200 mg/dl and an indication for intravenous insulin only for blood glucose >350 mg/dl. A retrospective analysis was carried out for assessing the occurrence of hypoglycemic episodes (blood glucose <70 mg/dl) and therapeutic failure (persistent hyperglycemia with values >240 mg/dl)., Results: Mean blood glucose was 261 ± 72 mg/dl on admission and 173 ± 50 mg/dl during treatment. Five patients (0.2%) required intravenous insulin infusion. There was only one case of severe hypoglycemia (≤40 mg/dl) due to an error of administration, and 2 cases of moderate hypoglycemia (41-70 mg/dl), with a total hypoglycemia rate of 0.24%. Transient therapeutic failure occurred in 27% of cases., Conclusions: In MICU hyperglycemic patients, the simple, intuitive and economical "BBC200" protocol could lead to a hypoglycemic risk very close to zero (0.24%), with a significant reduction in hypoglycemia-related clinical events and a modest increase in persistent hyperglycemic phenomena.

We performed a comprehensive review of the scientific literature on the use of digoxin in heart failure and atrial fibrillation. In congestive heart failure (CHF) there is only one randomized trial with a statistical sample sufficiently large. In this trial (DIG trial), which enrolled patients with systolic left ventricular dysfunction in sinus rhythm, digoxin had a neutral action on mortality and modestly reduced the overall need of hospitalization. The study was conducted in the pre-beta-blocker era and, therefore, it has a doubtful application to the current clinical context. There are no randomized trials on atrial fibrillation, either with or without heart failure. Several observational and retrospective studies and meta-analysis have shown an association between the use of digoxin and increased mortality about 20%. Both in the European and American guidelines, even in class I recommendations, evidence is not supported by randomized or observational trials, but just by experts' opinions. Digoxin use in CHF and atrial fibrillation is related to the physician's clinical judgment, based more on consolidated custom that on established scientific evidence. In our opinion, this therapy should be withdrawn until new randomized controlled trials will provide evidence of its efficacy. Two trials have been planned to this aim. Also the issue of toxicity threshold is still unresolved; digoxinemia values should be <1 ng/ml if digoxin is used, to avoid overdosing and toxicity with increased mortality.