Benefits of intravenous iron supplementation in heart failure.

Introduction: Iron deficiency (ID) is one of the most frequent comorbidities in patients with heart failure (HF) and is estimated to be present in up to 80% of acute patients regardless of their ejection fraction. Randomized controlled trials have shown that supplementary intravenous iron results in improved clinical outcomes; however, the current understanding of the effects of intravenous iron on morbidity and mortality remains limited. Study and results: The meta-analysis pooled individual participant data from three randomized placebo-controlled trials of ferric carboxymaltose (FCM) in adult patients (n = 4,501) with heart failure and iron deficiency (CONFIRM-HF, AFFIRM-AHF, and HEART-FID). FCM therapy significantly reduced the co-primary composite endpoint of total cardiovascular hospitalizations and cardiovascular death, with a rate ratio (RR 0.86; 95% CI 0.75 to 0.98; p = 0.029). FCM therapy was associated with a 17% relative rate reduction in total cardiovascular hospitalizations (RR 0.83; 95% CI 0.73 to 0.96; p = 0.009) and a 16% relative rate reduction in total heart failure hospitalizations (RR 0.84; 95% CI 0.71 to 0.98; p = 0.025). Lessons learned: The meta-analysis shows that in iron-deficient patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, intravenous ferric carboxymaltose (FCM) is associated with a reduced risk of total cardiovascular hospitalization and cardiovascular mortality. These findings indicate that intravenous FCM should be considered in iron-deficient patients with heart failure and reduced or mildly reduced ejection fractions.

Rurality and race in heart failure risk: Insights from the Southern Community Cohort Study.

INTRODUCTION: Rural-urban health disparities are apparent in the burden of disease and health outcomes, including cardiovascular disease (CVD), specifically heart failure (HF). However, the factors influencing these disparities are not fully understood. Study and results: Among 27,115 participants in the Southern Community Cohort Study (SCCS) (mean age: 54 years (47-65)), 18,647 (68.8%) were black, 8,468 (32.3%) were white, and 20% resided in rural areas. Over a median 13-year follow-up period, 7,542 HF events occurred (rural = 1,865 vs. urban = 5,677). The age-adjusted HF incidence was 29.6 (95% CI, 28.9-30.5) and 36.5 (95% CI, 34.9-38.3) per 1,000 person-years for urban and rural participants, respectively (P < .001). The risk of HF associated with rurality varied by race and sex. Rural black men had the highest risk across all groups (HR, 1.34; 95% CI, 1.19-1.51) (age-adjusted incidence rate: 40.4/1000 person-years (95% CI, 36.8-44.3)) followed by black women (HR, 1.18; 95% CI, 1.08-1.28) and white women (HR, 1.22; 95% CI, 1.07-1.39). Rurality was not associated with HF risk among white men (HR, 0.97; 95% CI, 0.81-1.16). LESSONS LEARNED: This large study shows that rural populations have an increased incidence of HF, which is particularly striking among women and black men, independent of individual-level biological, behavioral, and sociocultural risk factors. It also shows the need for further investigation into the rurality-associated risk of HF, the impact of preventive care utilization on the risk of HF and interpersonal, community, or societal factors that could contribute to rural-urban disparities. This will help to guide public health efforts aimed at HF prevention among rural populations.

Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy.

Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive fatal disease characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TTR) protein in tissues, resulting in cardiomyopathy and heart failure. Approximately 50,000 people have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis globally, leading to poor quality of life and high morbidity, resulting in death within a median of 2 to 6 years after diagnosis. However, data on the prevalence of ATTR-CM is limited and poorly characterized. NTLA-2001, an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum by knocking out the TTR gene, has been shown to be effective, presenting a new therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration has not been yet demonstrated. Study and results: The first-in-human in vivo CRISPR/Cas9 trial of TTR Gene editing by NTLA-2001 in patients with Transthyretin Amyloidosis and cardiomyopathy was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic responses to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis and cardiomyopathy. Twelve subjects received NTLA-2001 (three NYHA I/II subjects at 0.7 mg/kg, three subjects at 1.0 mg/kg, and six NYHA III subjects at 0.7 mg/kg). Serum TTR levels were reduced from the baseline in all subjects (mean>90% after 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA III at 0.7 mg/kg = 94% (1%) maintained through 4-6 months. Two of the 12 patients (16.7%) reported a transient infusion reaction. One patient experienced a grade 3 infusion-related reaction that resolved without any clinical sequelae. Lessons learned: This study showed a significant and consistent reduction in serum TTR protein levels after a single admission, while being generally well tolerated, representing a potential new option for the treatment and improvement of the prognosis of cardiac ATTR amyloidosis. Further research into the long-term safety and efficacy of NTLA-2001, particularly in higher-risk patients, including continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term, is essential. Evaluation of the potential effects of markedly reduced TTR levels on patients' clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential. The analysis of the use of this technology for an array of other diseases is vital.

The Aswan Rheumatic heart disease reGIstry: rationale and preliminary results of the ARGI database.

Background: Rheumatic Heart Disease (RHD) remains a major cause of valvular heart disease related mortality and morbidity in low- and middle-income countries, with significant variation in characteristics and course of the disease across different regions. However, despite the high disease burden, there is sparse region-specific data on demographics, disease characteristics and course in treated and untreated patients to guide policy. Methods: The ARGI database is a hospital-based registry in a tertiary referral national centre (Aswan Heart Centre, AHC) in which all patients with the diagnosis of RHD are being included. The mode of presentation, including baseline clinical and echocardiographic characteristics (as well as other imaging modalities), biomarkers and genetics are being documented. Treatment modalities and adherence to treatment is being recorded and patients are followed up regularly every 6 and/or 12 months, or more frequently if needed. Discussion: This study shows for the first time an in-depth analysis of the severity and phenotype of disease in Egyptian patients presenting with RHD as well as the progression with time and provides a platform for further comparisons of regional differences in these details as well as their causes. The ARGI database will be of help in achieving the objectives of the Cairo Accord aiming at eradication of RF and RHD.

Lessons from a pre-specified meta-analysis of sodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure: Time for new clinical recommendations.

INTRODUCTION: Cardiovascular disease remains the leading cause of death worldwide with heart failure (HF) being one of the significant contributors to morbidity and mortality. The incidence of HF with preserved ejection fraction (HFpEF) is increasing, especially in young adults making it a growing public health matter. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the development, progression, and mortality of heart failure in patients with reduced EF regardless of patients' diabetes status but their clinical benefits in patients with heart failure and preserved ejection fraction are less well-established. Recent trials have shown reductions in cardiovascular death and heart failure events in patients with mildly reduced or preserved ejection fraction (EF), although with uncertainty around the consistency of clinical benefits across the classes and therapeutic effects. Study and Results: The meta-analysis used data from trials on patients with mildly reduced or preserved EF (DELIVER and EMPEROR-Preserved), reduced EF (DAPA-HF and EMPEROR-Reduced), and those hospitalized (SOLOIST-WHF). The endpoints evaluated included a composite of time to cardiovascular (CV) death or first hospitalization for heart failure, cardiovascular death, all-cause death, first and recurrent heart failure hospitalizations, and urgent heart failure visits (not requiring hospitalization). Among 12251 participants in the DELIVER and EMPEROR-Preserved trials, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalization for HF (HR 0.80 [95% CI 0.73-0.87]) with consistent reductions in both components: cardiovascular death (HR 0.88 [95% CI 0.77-1.00]) and first hospitalization for HF (HR 0.74 [95% CI 0.67-0.83]). In the broader analysis of the five trials with a total of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalization for HF (HR 0.77 [95% CI 0.72-0.82]), cardiovascular death (0.87 [0.79-0.95]), first hospitalization for heart failure (HR 0.72 [95% CI 0.67-0.78]), and all-cause mortality (HR 0.92 [95% CI 0.86-0.99]). These treatment effects for each of the studied endpoints were consistently observed across all five trials and across the HF subgroups, including those on mildly reduced or preserved ejection fraction. LESSONS LEARNED: SGLT2 inhibitors significantly reduce the risk of mortality and worsening of heart failure and improve patient symptoms and overall health status across the full spectrum of ejection fraction. SGLT2 inhibitors should be considered foundational therapy in all patients with heart failure, irrespective of LVEF or care setting. The results presented propose an update of the recommendations for the pharmacological treatment of heart failure, to prioritize the use of SGLT2 inhibitors in patients across the full EF spectrum. Future investigations should include the long-term benefits of the use of SGLT2 inhibitors among the different HF subgroups, including the performance of SGLT2 inhibitors in those excluded from the current heart failure trials.

INVICTUS: Vitamin K antagonists remain the standard of care for rheumatic heart disease-associated atrial fibrillation.

INTRODUCTION: Rheumatic heart disease (RHD) remains a major healthcare problem. Atrial fibrillation (AF) is the commonest sustained arrhythmia in RHD, leading to major complications and morbidity in a young population. Currently, anticoagulation with vitamin K antagonists (VKA) is the mainstay of therapy for the prevention of thromboembolic adverse events. However, effective use of VKA remains challenging, especially in developing countries, showing a need for alternatives. Novel oral anticoagulants (NOACs), including rivaroxaban, could form a safe and effective alternative to fulfil a major unmet need in RHD patients with AF. However, until recently, no data was available for the use rivaroxaban in patients with rheumatic heart disease associated AF. Study and Results: The INVICTUS trial was conducted to assess efficacy and safety of once-daily rivaroxaban compared with a dose-adjusted VKA for the prevention of cardiovascular events in patients with RHD-associated AF. A total of 4531 patients (age: 50.5 ± 14.6 years) were followed for 3.1 ± 1.2 years in which 560/2292 patients in the rivaroxaban group and 446/2273 in the VKA group had a primary-outcome adverse event. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the VKA group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P <0.001). A higher incidence of death occurred in the rivaroxaban group than in the VKA group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. LESSONS LEARNED: The INVICTUS trial shows that Rivaroxaban is inferior to Vitamin K-antagonists in patients with RHD associated AF as VKA therapy led to a lower rate of ischemic and lower mortality due to vascular causes, without significantly increasing the rate of major bleeding. The results support current guidelines, which recommend vitamin K antagonist therapy for the prevention of stroke in patients with RHD associated AF.

EMMY: The continued expansion of clinical applications of SGLT2 inhibitors.

Introduction: Myocardial infarction (MI) is a challenging clinical and public health problem and is a leading cause of morbidity and mortality worldwide. Heart failure (HF) is a common sequela of acute myocardial infarction (AMI), with an incidence of up to 40% among hospitalized patients and has important implications for treatment and prognosis. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as empagliflozin, have been shown to reduce the risk of hospitalization and cardiovascular mortality in patients with symptomatic HF and have therefore been included in the European and American heart failure guidelines. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking. Study and Results: The EMMY trial was conducted to assess the safety and efficacy of empagliflozin in patients with acute myocardial infarction (AMI). A total of 476 patients with AMI were randomly assigned to empagliflozin (10 mg) or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. NT-proBNP reduction was significantly greater in the empagliflozin group (-15% after adjusting for baseline NT-proBNP, gender, and diabetes status (P = 0.026)). Absolute left-ventricular ejection fraction improvement was 1.5% (P = 0.029) greater, mean E/e' reduction was 6.8% (P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (P = 0.0003) and 9.7 mL (P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for HF (3 in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups. Lessons learned: The EMMY trial shows that early use of the SGLT2 inhibitor empagliflozin after acute myocardial infarction (MI) improves natriuretic peptide levels and markers of cardiac function and structure supporting the use of Empagliflozin in HF related to a recent MI.

Secondary analysis of REPRISE III trial: The Lotus valve's persistence after withdrawal.

INTRODUCTION: Aortic stenosis (AS) is the leading heart valve disease in developed countries, often caused by calcific degeneration. In low-and-middle-income countries, it's primarily due to RHD. Prevalence of AS increases with age and up to 22.8% of those affected over the age of 75. While surgical aortic valve replacement is standard treatment for AS, many older individuals are not ideal candidates. Transcatheter aortic valve replacement (TAVR) offers an alternative. The REPRISE III trial showed the Lotus valve outperformed the CoreValve/EvolutR TAVR valves in various metrics over 2 years. Despite its success and over 10,000 implantations, the Lotus valve was pulled from the market, highlighting the need to understand its long-term outcomes. Study and results: In the REPRISE III trial, the long-term outcomes of TAVR using the Lotus valve were compared to the CoreValve/EvolutR over 5 years across 55 global centers. Of the participants, 581 (95.7%) used the Lotus valve and 285 (93.4%) used CoreValve/EvolutR. Event rates for all-cause mortality were similar between the groups, but the Lotus valve group had lower rates of disabling stroke and pacemaker implantation. The Lotus valve showed a higher aortic gradient but lower effective orifice area. Additionally, the Lotus valve had reduced mild PVL, valve malpositioning, and the need for a second valve. Both groups showed comparable long-term improvements in heart and cardiomyopathy assessments. LESSONS LEARNED: The REPRISE III analysis highlights the favourable long-term outcomes of the Lotus valve and CoreValve/EvolutR for high-risk surgical patients. These findings underscore the importance of ongoing management post-valve procedure and the potential advantages of the Lotus valve design. Further studies comparing these valves to surgery will inform aortic stenosis management and potentially expand TAVR indications. The future goal is to develop a tissue-engineered living heart valve to improve survival and quality of life.

Transcatheter device closure of patent ductus arteriosus by exclusive venous access under echocardiographic guidance without angiography.

INTRODUCTION: The standard transcatheter technique to profile the patent ductus arteriosus requires arterial access through the femoral artery and is associated with arterial complications, longer fluoroscopic time, contrast volume, and longer hospital stay. AIM OF THE STUDY: To compare exclusive transvenous access with the standard procedures for patent ductus arteriosus closure and evaluate whether exclusive venous approach is a safe and effective alternative. METHODS: A total of 320 patients were included. A detailed echocardiographic evaluation of the duct morphology was performed. Patients were classified into group 1 included patients who underwent exclusive femoral venous access, without any injections of contrast media and group 2 included patients who underwent arterial and venous access. RESULTS: Arterial access was achieved in 210 (65.6%). Successful closure of patent ductus arteriosus was achieved in 109 (99.1%) patients in group 1 and in 203 (96.7%) patients in group 2. The patent ductus arteriosus was large and was referred for surgical closure in one patient from group 1 and 7 patients from group 2. Residual patent ductus arteriosus was seen in 6 cases from group 1 (5.4%) and 12 patients from group 2 (5.7%). None of the cases in group 1 had vascular complications, while vascular complications were seen in 20 cases, all of them in group 2 (9.5%). Nonvascular complications were seen in one patient from group 1 (0.9%) and 15 patients in group 2 (7.1%). The procedure time and fluoroscopy times were less in patients with exclusive transvenous access. CONCLUSION: Patent ductus arteriosus device closure without arterial access can be accomplished safely and effectively.

Community-based prevalence of rheumatic heart disease in rural Ethiopia: Five-year follow-up.

BACKGROUND: As little is known about the prevalence and clinical progression of subclinical (latent) rheumatic heart disease (RHD) in sub-Saharan Africa, we report the results of a 5 year follow-up of a community based, echocardiographic study of the disease, originally carried out in a rural area around Jimma, Ethiopia. METHODS: Individuals with evidence of RHD detected during the baseline study as well as controls and their family members were screened with a short questionnaire together with transthoracic echocardiography. RESULTS: Of 56 individuals with RHD (37 definite and 19 borderline) in the original study, 36 (26 definite and 10 borderline) were successfully located 57.3 (range 44.9-70.7) months later. At follow-up two thirds of the definite cases still had definite disease; while a third had regressed. Approximately equal numbers of the borderline cases had progressed and regressed. Features of RHD had appeared in 5 of the 60 controls. There was an increased risk of RHD in the family relatives of borderline and definite cases (3.8 and 4.0 times respectively), notably among siblings. Compliance with penicillin prophylaxis was very poor. CONCLUSIONS: We show the persistence of echocardiographically demonstrable RHD in a rural sub-Saharan population. Both progression and regression of the disease were found; however, the majority of the individuals who had definite features of RHD had evidence of continuing RHD lesions five years later. There was an increased risk of RHD in the family relatives of borderline and definite cases, notably among siblings. The findings highlight the problems faced in addressing the problem of RHD in the rural areas of sub-Saharan Africa. They add to the evidence that community-based interventions for RHD will be required, together with appropriate ways of identifying active disease, achieving adequate penicillin prophylaxis and developing vaccines for primary prevention.

The "Cairo Accord"- Towards the Eradication of RHD: An Update.

Rheumatic heart disease (RHD) is the most common cause of acquired heart disease in children and young adults. It continues to be prevalent in many low- and middle-income countries where it causes significant morbidity and mortality. Following the 2017 Cairo conference "Rheumatic Heart Disease: from Molecules to the Global Community," experts from 21 countries formulated an approach for addressing the problem of RHD: "The Cairo Accord on Rheumatic Heart Disease." The Accord attempts to set policy priorities for the eradication of acute rheumatic fever (ARF) and RHD and builds on a recent series of policy initiatives and calls to action. We present an update on the recommendations of the Cairo Accord and discuss recent progress toward the eradication of RHD, including contributions from our own Aswan Rheumatic Heart Disease Registry (ARGI).

Cardiovascular adverse events in pregnancy: A global perspective.

Pregnant women with heart disease are vulnerable to many adverse cardiovascular events (AE). AEs during and after pregnancy continue to be important causes of maternal mortality and morbidity worldwide, with huge variations in burden in different countries and regions. These AEs are classified as having direct or indirect causes, depending on whether they are directly caused by pregnancy or due to some pre-existing disease and/or non-obstetric cause, respectively. The risks continue throughout pregnancy and even after childbirth. Apart from immediate complications during pregnancy, there is increasing evidence of a significant link between several events and the risk of cardiovascular disease (CVD) later in life. A significant number of pregnancy-related deaths caused by cardiovascular disease are preventable. This prevention can be realized through increasing awareness of cardiovascular AE in pregnancy, coupled with the application of strategies for prevention and treatment. Knowledge of the risks associated with CVD and pregnancy is of extreme importance in that regard. We discuss the global distribution of cardiovascular maternal mortality, adverse events during and after pregnancy, their predictors and risk stratification. In addition, we enumerate possible solutions, particularly the role of cardio-obstetric clinics.

Thrombosis of mechanical mitral valve prosthesis during pregnancy: An ongoing "saga" in need of comprehensive solutions.

Emergency treatment for thrombosed mechanical valve prothesis during pregnancy is not uncommon in low- and middle-income countries. The presence of a mechanical valve continues to be an important cause of maternal morbidity and mortality. There is a pressing need for increasing awareness and feasible solutions for this huge problem. We here describe four patients who needed emergency treatment for thrombosis of mechanical valve prothesis during pregnancy and review the evolving comprehensive strategies for dealing with this issue.

Prevalence and prognostic value of echocardiographic screening for rheumatic heart disease.

Objective: Rheumatic heart disease (RHD) remains a major health problem in many low-income and middle-income countries. The use of echocardiographic imaging suggests that subclinical disease is far more widespread than previously appreciated, but little is known as to how these mild forms of RHD progress. We have determined the prevalence of subclinical RHD in a large group of schoolchildren in Aswan, Egypt and have evaluated its subsequent progression. Methods: Echocardiographic screening was performed on 3062 randomly selected schoolchildren, aged 5-15 years, in Aswan, Egypt. Follow-up of children with a definite or borderline diagnosis of RHD was carried out 48-60 months later to determine how the valvular abnormalities altered and to evaluate the factors influencing progression. Results: Sixty children were initially diagnosed with definite RHD (19.6 per 1000 children) and 35 with borderline disease (11.4 per 1000); most had mitral valve disease. Of the 72 children followed up progression was documented in 14 children (19.4%) and regression in 30 (41.7%) children. Boys had lower rates of progression while older children had lower rates of regression. Functional defects of the valve even in the presence of structural features were associated with lower rates of progression and higher rates of regression than structural changes. Conclusions: RHD has a high prevalence in Egypt. Although a high proportion of the abnormalities originally detected persisted at follow-up, both progression and regression of valve lesions were demonstrated.

Disease appearance and evolution against a background of climate change and reduced resources.

Global health continues to face increasing challenges owing to a variety of reasons that include the almost constant changes in disease appearance and evolution. Most, but not all, of these changes affect low-income countries and are influenced by climate change. Tracking the recent and anticipated changes in the demographics and global distribution of these changes is essential for evolving effective new methods for dealing with the problems. The recent recognition by the United Nations of the importance of non-communicable diseases is a major positive step. For the sake of this paper, the following diseases were chosen: dengue and malaria, to highlight the role of climate change on vector-borne diseases. Drug-resistant tuberculosis illustrates the role of globalization and reduced resources on disease evolution. The continuing rise in cardiovascular mortality and morbidity, particularly in resource-poor countries is largely attributed to lack of preventive and therapeutic measures against such conditions as hypertension, diabetes, atherosclerosis and congenital heart disease as well as neglected diseases, of which Chagas and rheumatic heart disease will be discussed further.