Device Interventions for Heart Failure.

Despite remarkable advances in drug therapy for heart failure (HF), the residual HF-related morbidity, mortality, and hospitalizations remain substantial across all HF phenotypes, and significant proportions of patients with HF remain symptomatic despite optimal drug therapy. Driven by these unmet clinical needs, the exponential growth of transcatheter interventions, and a recent shift in the regulatory landscape of device-based therapies, novel device-based interventions have emerged as a potential therapy for various phenotypes of HF. Device-based interventions can overcome some of the limitations of drug therapy (eg, intolerance, nonadherence, inconsistent delivery, and recurrent and long-term cost) and can target some HF-related pathophysiologic pathways more effectively than drug therapy. This paper reviews the current evolving landscape of device-based interventions in HF and highlights critical points related to implementation of these therapies in the current workflow of HF management.

Sodium-glucose cotransporter-2 inhibitors in heart failure: Potential decongestive mechanisms and current clinical studies.

Congestion is a key pathophysiological feature of heart failure (HF) syndrome that drives most of the clinical manifestations of acute HF and is related with poor quality of life and outcomes. Therefore, safe and effective decongestion is an important therapeutic target in the management of acute HF and despite the use of guideline-recommended loop diuretics, adequate decongestion is not always achieved in patients with acute HF. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to provide clinical benefits across a broad spectrum of patients with HF, including consistent reduction in the risk of acute HF episodes. While the exact mechanisms underlying these benefits remain a matter of debate, a growing body of evidence suggests that effective decongestion may be partly responsible, especially in the setting of acute HF. In this review, we discuss the potential decongestive mechanisms of SGLT-2 inhibitors, such as osmotic diuresis, natriuresis, preservation of glomerular filtration and facilitation of interstitial drainage, which can collectively translate into effective and safe decongestion. Furthermore, we provide a comprehensive review of up-to-date clinical data of SGLT-2 inhibitor use in the acute HF population.

Role of the Renal Lymphatic System in Heart Failure.

PURPOSE OF REVIEW: The lymphatic system plays a major but overlooked role in maintaining fluid homeostasis. Given the unique fluid homeostasis functions of the kidneys, dysregulation of the renal lymphatic system underlies the development of self-propagating congestive pathomechanisms. In this review, we outline the roles of the renal lymphatic system in heart failure (HF). RECENT FINDINGS: Studies have uncovered several pathomechanisms involving the renal lymphatic system in congestive states, such as impaired interstitial draining by the renal lymphatic system, impaired structure and valves of renal lymphatics, lymphatic-induced increase in renal reabsorption of water and sodium, and development of albuminuria with proteinuria-induced renal lymphangiogenesis. These self-propagating mechanisms result in "renal tamponade" with manifestations of cardiorenal syndrome and inappropriate renal response to diuretics. Dysregulation of the renal lymphatic system is integral to the development and progression of congestion in HF. Targeting renal lymphatics may provide a novel pathway to treat intractable congestion.

Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis.

AIMS: There is considerable variability in the effect of intravenous iron on hard cardiovascular (CV)-related outcomes in patients with heart failure (HF) in randomized controlled trials (RCTs). We use a meta-analytic approach to analyse data from existing RCTs to derive a more robust estimate of the effect size of intravenous iron infusion on CV-related outcomes in patients with HF. METHOD AND RESULTS: PubMed/Medline was searched using the following terms: ('intravenous' and 'iron' and 'heart failure') from inception till 6 November 2022 for RCTs comparing intravenous iron infusion with placebo or standard of care in patients with HF and iron deficiency. Outcomes were the composite of CV mortality and first hospitalization for HF; all-cause mortality; CV mortality; first hospitalization for HF; and total hospitalizations for HF. Random effects risk ratio (RR) with 95% confidence intervals (CIs) were calculated. Ten RCTs with a total of 3438 patients were included. Intravenous iron resulted in a significant reduction in the composite of CV mortality and first hospitalization for HF [RR 0.0.85; 95% CI (0.77, 0.95)], first hospitalization for HF [RR 0.82; 95% CI (0.67, 0.99)], and total hospitalizations for HF [RR 0.74; 95% CI (0.60, 0.91)] but no statistically significant difference in all-cause mortality [RR 0.95; 95% CI. (0.83, 1.09)] or CV mortality [OR 0.89; 95% CI (0.75, 1.05)]. CONCLUSIONS: Intravenous iron infusion in patients with HF reduces the composite risk of first hospitalization for HF and CV mortality as well as the risks of first and recurrent hospitalizations for HF, with no effect on all-cause mortality or CV mortality alone.

Gender Differences and Outcomes of Hypoattenuated Leaflet Thickening (HALT) Following Transcatheter Aortic Valve Replacement: A Meta-analysis of Randomized and Cohort Studies.

Subclinical leaflet thrombosis is characterized by hypoattenuated leaflet thickening (HALT) after transcatheter aortic valve replacement (TAVR) on computed tomography. However, given the low incidence of HALT after TAVR, the clinical significance of HALT is still being investigated. We sought to generate a more reliable estimate of the risk factors and adverse outcomes associated with HALT after TAVR by pooling data from randomized trials and cohort studies. PubMed/Medline database was systematically searched from inception until November 24, 2021, using the following terms: ("hypoattenuated leaflet thickening" and "transcatheter aortic valve replacement") and ("Subclinical leaflet thrombosis" and "transcatheter aortic valve replacement"). A random effects model meta-analysis was conducted using Mantel-Haenszel odds ratios (ORs) and the associated 95% confidence intervals (CIs), mean difference and the associated 95%. Ten studies with a total of 1462 patients were included, with follow-up ranging between 4 months and 3 years. HALT occurred in 14.4% of the patients undergoing TAVR. HALT was not associated with increased risk of stroke/TIA (OR 1.38; 95% CI [0.61-3.11]; I2=0%) or increased risk of all-cause mortality (OR 0.67; 95% CI [0.25-1.80]; I2=0). HALT was associated with a greater post-procedural mean aortic valve gradient (mean difference 2.31 mmHg; 95% CI [0.27, 4.35]; I2=71%). Interestingly, there was a trend of higher risk of HALT in men (OR 1.37; 95% CI [0.82-2.30]; I2=44%) while there was a trend towards lower risk of HALT in the presence of CKD (OR 0.76; 95% CI [0.49-1.19]; I2=0%); these trends did not reach statistical significance. This meta-analysis shows that the occurrence of HALT following TAVR is associated with a greater post-procedural mean aortic valve gradient but no excess risk of death or cerebrovascular events. The clinical significance of this higher post-procedural mean aortic valve gradient is uncertain and requires further investigations.

Association of Non-Alcoholic Fatty Liver Disease With in-Hospital Outcomes in Primary Heart Failure Hospitalizations With Reduced or Preserved Ejection Fraction.

Recent studies focusing on the prevalence, characteristics, and outcomes of primary heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) in non-alcoholic fatty liver disease (NAFLD) are sparse. We sought to assess these using a nationally-representative population. We used the 2016-2018 National Inpatient Sample database to study the prevalence, characteristics, clinical risk profiles, morbidity, mortality, cost, and resource utilization among primary HFpEF and HFrEF hospitalizations with and without NAFLD. In the period from January 1, 2016, to December 31, 2018, there were 3,522,459 admissions of patients aged ≥18 years with a diagnosis of primary HF. Of these, 82,585 (2.3%) hospitalizations had secondary diagnosis of NAFLD. Admissions with NAFLD and HFrEF were associated with higher rates of in-hospital mortality (aOR 1.84, CI 1.66-2.04, P < 0.001) compared to admissions of HFrEF without NAFLD. Similarly, hospitalizations with HFpEF-NAFLD were associated with higher rates of in hospital mortality (aOR 1.65 CI 1.43-1.9, P < 0.001) compared to HFpEF admissions without NAFLD. Pressors use, cardiogenic shock, AKI with or without dialysis use, cardiac arrest, LOS and hospitalization cost were higher in admissions of HFrEF and HFpEF with NAFLD compared to those without NAFLD. In-hospital mortality, was higher in primary HFrEF and HFpEF admissions with NAFLD compared to without NAFLD. Physicians must be aware of the worse clinical outcomes of HFrEF and HFpEF in patients with NAFLD. Further clinical research is needed to address the knowledge gap and treatment options available for the patients with HF and NAFLD.

Influence of Iron Deficiency on Clinical and Haemodynamic Parameters in Pulmonary Arterial Hypertension Cohorts.

BACKGROUND: Iron deficiency (Fedef) has been shown to be common in patients with group 1 or pulmonary arterial hypertension (PAH). Several studies have shown a negative impact of Fedef on clinical and haemodynamic parameters of the disease, but data from individual studies have not been strong enough to lead to incorporation of the finding of Fedef into prognostic or therapeutic algorithms. The goal of this meta-analysis was to combine data from available studies to better define any associations between Fedef and established variables of prognostic importance in PAH. METHODS: A literature search identified nine studies with extractable data relevant to the study questions. The impact of Fedef upon the following parameters was evaluated: 6-minute walk distance (6MWD), WHO-functional class, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, echocardiography, and findings from right heart catheterisation (RHC). Pooled results were reported as mean difference or risk difference with 95% confidence intervals utilising a random effects modeling approach. RESULTS: Fedef in the PAH population was common (47% of cases) and was associated with cardiovascular dysfunction (lower tricuspid annular plane systolic excursion [TAPSE], elevated NT-proBNP, and lower mixed venous oxygen saturation) and with reduction in functional capacity (lower 6MWD and higher functional class). CONCLUSION: This meta-analysis strengthens the relationships between Fedef and several markers of poor outcome in PAH. Fedef in patients with PAH warrants further scrutiny and merits consideration as a cause of clinical deterioration. Even though causation and longitudinal relationships between Fedef and PAH could not be identified, effect of Fedef on factors that affect disease prognosis is noteworthy and worthy of more focussed studies.

Device Therapy for Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with few options for effective pharmacologic therapies. Numerous device-based approaches to HFpEF therapy have emerged, which aim to treat the clinical and pathophysiologic features common to the varied causes of this syndrome. This review summarizes the current landscape of device therapy in HFpEF with a focus on structural interventions, such as left-to-right atrial shunts; cardiac contractility modulation; autonomic modulation, such as baroreflex activation therapy and splanchnic nerve modulation; and respiratory modulation, such as phrenic nerve stimulation.

Sodium-glucose Cotransporter 2 Inhibitors and Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a systemic disorder with cardiovascular manifestations; due to its complex and multifactorial pathophysiological mechanisms, no effective pharmacologic treatment has been identified to date. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated potentially favorable effects on NAFLD incidence and progression in preclinical and clinical studies. This review summarizes the evidence from preclinical and human studies supporting the use of SGLT2 inhibitors in NAFLD and proposes several mechanisms that may drive these favorable effects (ie, increasing insulin sensitivity, decreasing intrahepatic fat accumulation and lipotoxicity, decreasing oxidative stress and endoplasmic reticulum (ER) stress, improving autophagy, and inhibiting apoptosis).

Diaphragmatic Function in Cardiovascular Disease: JACC Review Topic of the Week.

In addition to the diaphragm's role as the primary respiratory muscle, it also plays an under-recognized role in cardiac function. It serves as a pump facilitating venous and lymph return, modulating left ventricular afterload hemodynamics and pericardial pressures, as well as regulating autonomic tone. Heart failure (HF) is associated with diaphragmatic changes (ie, muscle fiber atrophy and weakness, increased ratio of type I to type II muscle fibers, and altered muscle metaboreflex) that lead to diaphragmatic dysfunction with subsequent symptomatic manifestations of HF. Herein, it is proposed that targeting the diaphragm in patients with HF via inspiratory muscle training or device-based stimulation can provide a novel treatment pathway for HF. Reviewed are several potential mechanisms through which therapies targeting the diaphragm can be beneficial in HF (ie, improving preload reserve, atrial and ventricular synchrony, and metaboreflex activity; reducing pericardial restraint; and restoring diaphragm strength).

Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study.

Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39-1.51), with more pronounced associations among patients who were younger (P-interaction = 0.003), White (P-interaction = 0.005), or who had established cardiovascular disease (P-interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure.

Trends and Characteristics of Hospitalizations in Patients With Heart Transplant.

There is limited data regarding the leading causes of hospitalization among heart transplant (HT) recipients and the characteristics of these hospitalizations. We conducted a retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004, and December 31, 2018, which included hospitalized adults ≥18 years with a history of HT. Primary outcomes were the 10 most common primary causes of hospitalizations, clinical characteristics, inpatient mortality, length of stay, and inflation-adjusted care costs. We divided the study population in two period (2004-2014 and 2016-2018) to report the most common causes of hospitalizations. We identified a total of 209,771 weighted hospitalizations with a history of HT between January 1, 2004, and December 31, 2018. Between 2004 and 2014, pneumonia (6.21%), acute or unspecified renal failure (4.94%), complication of device, implant or graft (4.66%), sepsis (4.56%), and congestive heart failure (2.94%) were the most common causes of hospitalizations for HT recipient. Between 2016 and 2018, sepsis (9.03%), acute or unspecific renal failure (6.27%), complication of device, implant or graft (5.16%), pneumonia (4.92%), and complications of surgical procedure or medical device (3.86%) were the most common causes of hospitalizations for HT recipient. Sepsis had the highest inpatient mortality accounting for 11.32% of inpatient mortality in the 2004-2014 period and 6% in the 2016-2018 period. In summary, infections, acute renal failure, and other transplant complications are the leading causes of hospitalization among HT recipients. Sepsis carries the highest inpatient mortality.

Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.