PURPOSE OF REVIEWWith the failure of multiple trials to identify a successful therapy for heart failure with preserved ejection fraction (HFpEF), attention has shifted to defining specific phenotypes ...within the HFpEF spectrum in an effort to develop a targeted approach to treatment. Here we summarize the most recent studies investigating the pathophysiology and clinical features of HFpEF, and discuss recent clinical trials in the context of developing treatments that look toward the underlying cause of this disorder.
RECENT FINDINGSAdvances in basic science and clinical research have further characterized HFpEF, identifying multiple pathophysiological mechanisms that ultimately lead to exercise intolerance and volume overload. The success of small studies focused on specific subsets of the HFpEF population has promoted the concept that there may not be one treatment strategy that can universally be applied to HFpEF.
SUMMARYHFpEF is associated with significant morbidity and mortality and accounts for approximately half of patients with chronic heart failure. HFpEF is a complex disease, encompassing a diverse cohort of patients and marked by the presence of multiple etiological mechanisms. The failure to develop successful therapies for the management of HFpEF may be because of inadequate standardization of the HFpEF diagnosis, overly broad inclusion criteria and inadequate differentiation of disease subtypes. Given the heterogeneity among patients with HFpEF, much of the current research is focused on understanding of pathophysiology and identifying disease phenotypes that may respond to a targeted treatment approach. Several newer approaches, including neprilysin inhibition and device therapy, offer promise for a new era of HFpEF treatment.
Our objective was to analyze the development of aortic insufficiency in patients who received central aortic valve repair when undergoing continuous-flow left ventricular assist device implantation.
...We conducted a retrospective review of patients who underwent HeartMate II or 3 (Abbott Lab) implantation between 2004 and 2022. Ninety-four patients were excluded from analysis for history of aortic valve procedures, a bicuspid aortic valve, baseline trace aortic insufficiency, or other concomitant aortic valve procedure. Patients who had ≥ mild aortic insufficiency had concomitant aortic valve repair. Clinical characteristics, serial echocardiograms, and outcomes were determined.
Of the 656 patients who underwent HeartMate II or 3 implantation, 105 patients (59 HeartMate II and 46 HeartMate 3) met study criteria. Median age was 68 years 60-74 years, 91.4% n=96 were male, 54.4% n=56 were white, and 68.6% n=72 received support as destination therapy. Preoperative aortic insufficiency degree was 54.3% (n=57) mild, 23.8% (n=25) mild-to-moderate, 20.0% (n=21) moderate, 1.0% (n=1) moderate-to-severe, 1.0% (n=1) severe. In hospital mortality was 5.7% n=6. Freedom from ≥ moderate aortic insufficiency was 96.4% (95%CI: 92.5%-100%), 93.3% (95%CI: 87.6%-99.2%), and 91.0% (95%CI: 84.1%-98.5%) at 1-year, 2-year, and 3-year post-implantation, respectively. One HeartMate II patient experienced severe aortic insufficiency and was treated with a heart transplant. Three-year survival was 63.4% 95%CI: 52.9%-75.9%.
Central aortic valve repair may be an effective technique to mitigate aortic insufficiency in HeartMate II and 3. A larger cohort study with longer duration of follow up is warranted to further investigate the clinical impact.
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Thromboembolic events (TEs) are common adverse events with continuous-flow left ventricular assist devices (LVADs). Left atrial appendage occlusion (LAAO) is commonly performed at the time of a ...cardiac operation. The effect of LAAO on TEs in LVAD patients remains unknown.
All patients receiving a first LVAD implantation between January 2013 and January 2014 were reviewed. TEs included device thrombosis and ischemic cerebrovascular accidents. The incidence of TEs with respect to LAAO was evaluated using Kaplan-Meier and Cox proportional hazards analyses.
The analysis included 102 patients, 36 of whom received LAAO and 66 did not. LAAO patients were an average age of 60 years, and 69.4% were men. Non-LAAO patients were an average age of 59.3 years, and 71.2% were men. There were no significant differences in characteristics other than history of coronary artery bypass grafting (8.3% of LAAO vs 44% of non-LAAO, p = 0.0005). Preoperative atrial fibrillation was present in 19 LAAO patients (52.7%) and in 36 non-LAAO patients (54.5%; p = 1.0). Patients were monitored for a median of 306 days. TEs occurred in 3 LAAO patients (1 device thrombosis and 2 cerebrovascular accidents) compared with 15 non-LAAO patients (5 device thromboses and 11 cerebrovascular accidents, p = 0.049). In a Cox hazards analysis including age, sex, hypertension, and atrial fibrillation, LAAO demonstrated a decreased risk of TE (hazard ratio, 0.27; 95% confidence interval, 0.08 to 0.95; p = 0.04).
In patients undergoing LVAD implantation, LAAO is associated with reduced TEs, and this effect may be independent of atrial fibrillation. A prospective randomized study to examine the efficacy LAAO in prevention of TE is needed to confirm these findings.
This comprehensive review highlights the significant advancements in Left Ventricular Assist Device (LVAD) therapy, emphasizing its evolution from the early pulsatile flow systems to the cutting-edge ...continuous-flow devices, particularly the HeartMate 3 (HM3) LVAD. These advancements have notably improved survival rates, reduced complications, and enhanced the quality of life (QoL) for patients with advanced heart failure. The dual role of LVADs, as a bridge-to-transplantation and destination therapy is discussed, highlighting the changing trends and policies in their application. The marked reduction in hemocompatibility-related adverse events (HRAE) with the HM3 LVAD, compared to previous models signifies ongoing progress in the field. Challenges such as managing major infections are discussed, including innovative solutions like energy transfer systems aimed at eliminating external drivelines. It explores various LVAD-associated complications, including HRAE, infections, hemodynamic-related adverse events, and cardiac arrhythmias, and underscores emerging strategies for predicting post-implantation outcomes, fostering a more individualized patient care approach. Tools such as the HM3 risk score are introduced for predicting survival based on pre-implant factors, along with advanced imaging techniques for improved complication prediction. Additionally, the review highlights potential new technologies and therapies in LVAD management, such as hemodynamic ramp tests for optimal speed adjustment and advanced remote monitoring systems. The goal is to automate LVAD speed adjustments based on real-time hemodynamic measurements, indicating a shift towards more effective, patient-centered therapy. The review concludes optimistically that ongoing research and potential future innovations hold the promise of revolutionizing heart failure management, paving the way for more effective and personalized treatment modalities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The 2018 U.S. heart allocation system offers an accelerated pathway for heart transplantation to the most urgent patients.
This study sought to determine whether the new allocation system resulted in ...lower likelihood of candidate recovery.
Adult patients waitlisted for heart transplantation with temporary mechanical circulatory support at the time of initial listing between 2010 and 2020 in the United Network for Organ Sharing registry were included. Competing events of heart transplantation, waitlist death or delisting for deteriorating condition, and delisting for improved condition (candidate recovery) were analyzed in the new vs old heart allocation system.
A total of 688 patients were waitlisted with venoarterial extracorporeal membrane oxygenation or a surgical nondischargeable biventricular assist device (status 1 or old 1A). Overall, 2,237 patients were waitlisted with an intra-aortic balloon pump, a percutaneous left ventricular assist device (LVAD), or a surgical nondischargeable LVAD (status 2 or old 1A). Patients waitlisted with venoarterial extracorporeal membrane oxygenation or a nondischargeable biventricular assist device had significantly shorter median waitlist times (5 vs 31 days), higher incidence for cardiac transplantation (81.5% vs 43.0%), and lower incidence of candidate recovery (1.5% vs 7.9%) in the new vs old heart allocation system (all P < 0.05). Patients waitlisted with an intra-aortic balloon pump or percutaneous or a nondischargeable LVAD also had significantly shorter median waitlist times (8 vs 35 days), higher incidence of transplantation (88.9% vs 64.9%), and lower incidence of candidate recovery (0.2% vs 1.6%) in the new vs old heart allocation system (all P < 0.05).
Current practice of the new allocation system may not offer select temporary mechanical circulatory support patients the opportunity and adequate time to recover to the point of waitlist removal. Further research will determine which patients would benefit from urgent transplantation vs recovery strategy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heart transplantation remains the gold standard treatment for end-stage heart failure patients without contraindications. However, limited donor availability and long wait times have created a need ...for left ventricular assist devices (LVAD) to be used as a bridge to transplantation in appropriately selected patients. Improvements in LVAD technology have resulted in improved short- and long-term outcomes, further supporting the use of these devices for a bridge-to-transplant (BTT) indication. LVAD utilization as BTT exhibits notable disparities worldwide, mainly due to variations in organ availability, allocation policies, and financial constraints. Although Europe has experienced a consistent increase in the use of LVAD for this purpose, the United Network for Organ Sharing 2018 policy amendment resulted in a significant reduction in the number of LVADs used for BTT in the US. To overcome this issue, modifications in the US allocation policy to consider factors such as days on device support, age, and type of complications may be necessary to potentially increase implantation rates.The authors provide an overview comparing the current state of heart transplantation in the US and Europe, with a particular focus on how distinct allocation policies and organ availability impact medical practices. Additionally, the review will examine critical aspects ranging from patient selection and pre-implantation optimization to post-transplant outcomes.
Following the MOMENTUM 3 trial and the discontinuation of the HeartWare HVAD, the HeartMate 3 LVAD (HM 3) has become the main durable device for bridging to transplantation; however, outcome of this ...strategy in the new heart allocation system is not well understood.
The United Network for Organ Sharing (UNOS) registry was queried to include adult patients (≥18 years old) listed for heart transplantation between 2010 and 2020. Trends in durable LVAD utilization and outcomes of patients with HM 3 LVAD were examined in the pre- vs post-heart allocation system.
From 2017 to 2020, there was a 28.3% decline in the number of patients waitlisted with an FDA-approved durable LVAD. Overall, 449 patients were waitlisted with HM 3 in the pre-allocation era compared to 1094 patients in the post-allocation. Cumulative incidence of heart transplantation (53.4% vs 50.7%, p = 0.76) and death or delisting for worsening status (5.0%, vs 4.2%, p = 0.43) at 1-year after listing with HM 3 LVAD was comparable in the pre- vs post-allocation era. Old age (>50), ischemic HF, poor functional status, elevated creatinine (>1.3 mg/dL), pulmonary hypertension (>3 WU), and obesity (body mass index > 33 kg/m
) were predictors of post-transplant graft mortality after bridging with HM 3.
While the utilization of durable devices as BTT have declined under the new heart allocation system, bridging with HM 3 LVAD remains a safe strategy in carefully selected patients. Bridging decision should be individualized based on patient risk factors.
The physiological response of the right ventricle (RV) following left ventricular assist device (LVAD) implantation is difficult to predict. We aimed to investigate RV geometric and functional ...changes after LVAD insertion and their effects on clinical outcomes.
We retrospectively reviewed 188 patients who underwent HeartMate 3 implantation at our center between November 2014 and September 2021. The RV end-diastolic diameter (RVEDD) and RV end-diastolic area (RVEDA) were measured on preoperative and predischarge transthoracic echocardiography. The nonadapted group included patients with increased RVEDD and RVEDA at discharge. The composite outcome was defined as death or readmission due to worsening right heart failure.
There were 82 patients (44%) who had a nonadapted and 106 patients (56%) who had an adapted RV. Preoperatively, the nonadapted group had smaller RVEDD (46 vs 49 mm, p < 0.001) and RVEDA (27 vs 31 cm
, p < 0.001). At discharge, the nonadapted group had larger RVEDD (51 vs 43 mm, p < 0.001) and RVEDA (33 vs 27 cm
, p < 0.001). Kaplan-Meier analysis demonstrated worse 3-year survival (77% vs 91%, p = 0.006) and freedom from composite outcome (58% vs 85%, p < 0.001) in the nonadapted group. A multivariable Cox proportional hazards model showed that nonadaption (hazard ratio HR 3.09, 95% confidence interval CI 1.29-7.40, p = 0.01) and age (HR 3.73, 95% CI 1.42-9.77, p = 0.007) were independent predictors of composite outcome.
Acute RV dimensional changes after LVAD insertion may represent intrinsic RV function and may be a useful prognostic marker.
Little is known regarding the profile of patients with multiorgan failure listed for simultaneous cardiac transplantation and secondary organ. In addition, few studies have reported how these ...patients are bridged with mechanical circulatory support (MCS). In this study, we examined national data of patients listed for multiorgan transplantation and their outcomes after bridging with or without MCS.
United Network for Organ Sharing data were reviewed for adult multiorgan transplantations from 1986 to 2019. Post-transplant patients and total waitlist listings were examined and stratified according to MCS status. Survival was assessed via Cox regression in the post-transplant cohort and Fine–Gray competing risk regression with transplantation as a competing risk in the waitlist cohort.
There were 4534 waitlist patients for multiorgan transplant during the study period, of whom 2117 received multiorgan transplants. There was no significant difference in post-transplant survival between the MCS types and those without MCS in the whole cohort and heart-kidney subgroup. Fine–Gray competing risk regression showed that patients bridged with extracorporeal membrane oxygenation had significantly greater waitlist mortality compared with those without MCS when controlling for preoperative characteristics (subdistribution hazard ratio, 2.27; 95% confidence interval, 1.48-3.47; P < .001), whereas those bridged with a ventricular assist device had a decreased incidence of death compared with those without MCS (subdistribution hazard ratio, 0.78; 95% confidence interval, 0.63-0.96; P = .017).
MCS, as currently applied, does not appear to compromise the survival of multiorgan heart transplant patients. Waitlist data show that extracorporeal membrane oxygenation patients have profoundly worse survival irrespective of preoperative factors including organ type listed. Survival on the waitlist for multiorgan transplant has improved across device eras.
Cumulative incidence curves (upper panel) that depict an increased incidence of death in patients who received extracorporeal membrane oxygenation (ECMO) while waitlisted for multiorgan transplantation. Curves were produced using Fine–Gray competing risk regression with transplantation as a competing risk. Patients were censored at the time of waitlist removal. Differences in incidence of death between mechanical circulatory support (MCS) types were assessed using the Gray test. The lower panel depicts adjusted survival curves on the basis of a Cox proportional hazards analysis that shows that there was no survival difference between patients bridged to multiorgan transplant with each MCS type and no MCS. This study suggests that ECMO is associated with increased waitlist mortality and the use of MCS bridging should not preclude patients from receiving multiorgan transplants because survival after transplantation does not appear to be compromised by its use. IABP, Intra-aortic balloon pump; TAH, total artificial heart; VAD, ventricular assist device. Display omitted
The clinical implications of the discrepancy between cystatin C (cysC)– and serum creatinine (Scr)–estimated glomerular filtration rate (eGFR) in patients with heart failure (HF) and reduced ejection ...fraction (HFrEF) are unknown.
Post-hoc analysis of randomized trial data.
1,970 patients with HFrEF enrolled in PARADIGM-HF with available baseline cysC and Scr measurements.
Intraindividual differences between eGFR based on cysC (eGFRcysC) and Scr (eGFRScr; eGFRdiffcysC-Scr).
Clinical outcomes included the PARADIGM-HF primary end point (composite of cardiovascular CV mortality or HF hospitalization), CV mortality, all-cause mortality, and worsening kidney function. We also examined poor health-related quality of life (HRQoL), frailty, and worsening HF (WHF), defined as HF hospitalization, emergency department visit, or outpatient intensification of therapy between baseline and 8-month follow-up.
Fine-Gray subdistribution hazard models and Cox proportional hazards models were used to regress clinical outcomes on baseline eGFRdiffcysC-Scr. Logistic regression was used to investigate the association of baseline eGFRdiffcysC-Scr with poor HRQoL and frailty. Linear regression models were used to assess the association of WHF with eGFRcysC, eGFRScr, and eGFRdiffcysC-Scr at 8-month follow-up.
Baseline eGFRdiffcysC-Scr was higher than +10 and lower than−10mL/min/1.73m2 in 13.0% and 35.7% of patients, respectively. More negative values of eGFRdiffcysC-Scr were associated with worse outcomes (subhazard ratio per standard deviation: PARADIGM-HF primary end point, 1.18; P=0.008; CV mortality, 1.34; P=0.001; all-cause mortality, 1.39; P<0.001; worsening kidney function, 1.31; P=0.05). For a 1–standard-deviation decrease in eGFRdiffcysC-Scr, the prevalences of poor HRQoL and frailty increased by 29% and 17%, respectively (P≤0.008). WHF was associated with a more pronounced decrease in eGFRcysC than in eGFRScr, resulting in a change in 8-month eGFRdiffcysC-Scr of−4.67mL/min/1.73m2 (P<0.001).
Lack of gold-standard assessment of kidney function.
In patients with HFrEF, discrepancies between eGFRcysC and eGFRScr are common and are associated with clinical outcomes, HRQoL, and frailty. The decline in kidney function associated with WHF is more marked when assessed with eGFRcysC than with eGFRScr.
Kidney function assessment traditionally relies on serum creatinine (Scr) to establish an estimated glomerular filtration rate (eGFR). However, this has been challenged with the introduction of an alternative marker, cystatin C (cysC). Muscle mass and nutritional status have differential effects on eGFR based on cysC (eGFRcysC) and Scr (eGFRScr). Among ambulatory patients with heart failure enrolled in PARADIGM-HF, we investigated the clinical significance of the difference between eGFRcysC and eGFRScr. More negative values (ie, eGFRScr>eGFRcysC) were associated with worse clinical outcomes (including mortality), poor quality of life, and frailty. In patients with progressive heart failure, which is characterized by muscle loss and poor nutritional status, the decline in kidney function was more pronounced when eGFR was estimated using cysC rather than Scr.
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