SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). OBJECTIVES: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. METHODS: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. RESULTS: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). CONCLUSIONS: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.

Prognostic Value of Standard Heart Failure Medication in Patients with Cardiac Transthyretin Amyloidosis.

Introduction: Cardiac transthyretin amyloidosis (ATTR) is a progressive, fatal disease leading to heart failure due to accumulation of amyloid fibrils in the interstitial space and may occur as a hereditary (ATTRv) or wild-type (ATTRwt) form. Guidelines recommend the use of ACE inhibitors (ACEis) and beta-blockers (BBs) as heart failure therapy (HFT) in all patients with symptomatic heart failure and reduced ejection fraction, independent of the underlying etiology. However, the prognostic benefit of ACEis and BBs in ATTR has not been elucidated in detail yet. We thus sought to retrospectively investigate the outcome of patients with ATTRwt or ATTRv under HFT. Methods: Medical records of 403 patients with cardiac ATTR (ATTRwt: n = 268, ATTRv: n = 135) were screened for long-term medication as well as clinical, laboratory, electrocardiographic and echocardiographic data. Patients were assessed between 2005 and 2020 at the University Hospital Heidelberg. Kaplan-Meier analysis was used to analyze potential differences in survival among different subgroups. Results: The mean follow-up was 28 months. In total, 43 patients (32%) with ATTRv and 140 patients (52%) with ATTRwt received HFT. Survival was significantly shorter in patients receiving HFT in ATTRv (46 vs. 83 months, p = 0.0007) vs. non-HFT. A significantly better survival was observed in patients with comorbidities (coronary artery disease, arterial hypertension) and HFT among ATTRwt patients (p = 0.004). No significant differences in survival were observed in the other subgroups. Conclusions: Survival analysis revealed a potential benefit of HFT in patients with ATTRwt and cardiac comorbidities such as coronary artery disease and/or arterial hypertension. In contrast, HFT should be used with caution in patients with ATTRv.

Treatment of Chronic Heart Failure in Advanced Chronic Kidney Disease: The HAKA Multicenter Retrospective Real-World Study.

INTRODUCTION: Chronic heart failure (HF) has high rates of mortality and hospitalization in patients with advanced chronic kidney disease (aCKD). However, randomized clinical trials have systematically excluded aCKD population. We have investigated current HF therapy in patients receiving clinical care in specialized aCKD units. METHODS: The Heart And Kidney Audit (HAKA) was a cross-sectional and retrospective real-world study including outpatients with aCKD and HF from 29 Spanish centers. The objective was to evaluate how the treatment of HF in patients with aCKD complied with the recommendations of the European Society of Cardiology Guidelines for the diagnosis and treatment of HF, especially regarding the foundational drugs: renin-angiotensin system inhibitors (RASi), angiotensin receptor blocker/neprilysin inhibitors (ARNI), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). RESULTS: Among 5,012 aCKD patients, 532 (13%) had a diagnosis of HF. Of them, 20% had reduced ejection fraction (HFrEF), 13% mildly reduced EF (HFmrEF), and 67% preserved EF (HFpEF). Only 9.3% of patients with HFrEF were receiving quadruple therapy with RASi/ARNI, BB, MRA, and SGLT2i, but the majority were not on the maximum recommended doses. None of the patients with HFrEF and CKD G5 received quadruple therapy. Among HFmrEF patients, approximately half and two-thirds were receiving RASi and/or BB, respectively, while less than 15% received ARNI, MRA, or SGLT2i. Less than 10% of patients with HFpEF were receiving SGLT2i. CONCLUSIONS: Under real-world conditions, HF in aCKD patients is sub-optimally treated. Increased awareness of current guidelines and pragmatic trials specifically enrolling these patients represent unmet medical needs.

Programmatic approach to patients with advanced ischemic cardiomyopathy: Integrating microaxial support into strategies for the modern era.

Patients with advanced ischemic cardiomyopathy manifesting as left ventricular dysfunction exist along a spectrum of severity and risk, and thus decision-making surrounding optimal management is challenging. Treatment pathways can include medical therapy as well as revascularization through percutaneous coronary intervention or coronary artery bypass grafting. Additionally, temporary and durable mechanical circulatory support, as well as heart transplantation, may be optimal for select patients. Given this spectrum of risk and the complexity of treatment pathways, patients may not receive appropriate therapy given their perceived risk, which can lead to sub-satisfactory outcomes. In this review, we discuss the identification of high-risk ischemic cardiomyopathy patients, along with our programmatic approach to patient evaluation and perioperative optimization. We also discuss our strategies for therapeutic decision-making designed to optimize both short- and long-term patient outcomes.

Left ventricular assist devices for treatment of refractory advanced heart failure: the Western Australian experience.

BACKGROUND: Left ventricular (LV) assist devices (LVADs) can prolong survival and improve quality of life in end-stage heart failure. AIMS: Review outcomes of the Western Australian LVAD programme. METHODS: Retrospective database and medical record review. RESULTS: One hundred forty-seven LVADs have been implanted in 23 years, of which 95 were newer-generation devices (HeartWare HVAD [HW], HeartMate II and HeartMate 3). Presented data refer to these devices only. Most patients (94%) were classed as bridge-to-transplant or -candidacy/decision, with the remainder classed as 'destination therapy' (DT). Mean LV ejection fraction was 20%, and 36% had severe right ventricular dysfunction. Sixty-two percent of patients had a nonischaemic cardiomyopathy. Following LVAD implant, the median length of stay in intensive care was 2 days, and in the hospital overall was 23 days. Ninety-six percent of patients survived to hospital discharge, and, following discharge, 98% of days with LVAD were spent as an outpatient. The median number of hospital readmissions was 1.5 per patient per year. LVAD-associated infection requiring admission or intravenous antibiotics at any time after implant occurred in 36%, significant gastrointestinal bleeding in 19% and stroke in 11%. The percentage of patients alive with LVAD still in situ at 1, 2 and 5 years was 94%, 88% and 62% respectively, which exceeds current international registry outcomes. All DT patients survived at least 4 years, spending 97% of days with LVAD as an outpatient. The two longest-surviving HW DT patients worldwide (11.3 and 10.5 years) are among this cohort. CONCLUSIONS: Excellent outcomes can be achieved with LVADs in appropriately selected patients.

The Role of Palliative Care in Heart Failure, Part 1: Referring Provider Perspectives About Opportunities in Advanced Cardiac Therapies.

Background: There are many ways that palliative care can support patients with heart failure, but the role of palliative care in supporting patients who are considering or are already using advanced cardiac therapies is less clear. Objective: To understand referring providers' perspectives about the role of palliative care in the treatment of patients with heart failure considering or using advanced cardiac therapies. Design: Qualitative study using a semistructured interview guide. Setting/Subjects: This study was conducted at an academic medical center in the United States with an integrated cardiac palliative care program. Interviews were conducted with cardiology providers, including cardiologists, cardiac surgeons, and nurse practitioners who care for patients with heart failure and who are considering or receiving advanced cardiac therapies. Measurements: Interview transcripts were analyzed deductively and inductively to reveal themes in providers' perspectives. Results: Five themes were identified about the role of palliative care when advanced therapies were considered or being used: (1) educating patients; (2) supporting goal-concordant care; (3) managing symptoms; (4) addressing psychosocial needs; and (5) managing end-of-life care. Providers suggested palliative care could be a facilitator of advanced therapies, rather than merely something to add to end-of-life care. Conclusions: Cardiology providers recognize the value of integrating palliative care across the heart failure disease trajectory to provide therapy options, support decision-making processes, and provide goal-concordant care for patients considering or receiving advanced therapies. Increasing awareness of opportunities to integrate palliative care throughout the treatment of these patients may help cardiology providers better coordinate with palliative care specialists to improve patient care.

Clinical benefits of angiotensin receptor-Neprilysin inhibitor in adults with congenital heart disease.

BACKGROUND: There are limited data about the clinical benefits of angiotensin receptor-neprilysin inhibitor (ARNI) in adults with congenital heart disease (CHD). The purpose of the study was to assess the clinical benefits (chamber function and heart failure indices) of ARNI in adults with CHD. METHOD: In this retrospective cohort study, we compared the temporal change in chamber function and heart failure indices between 35 patients that received ARNI for >6 months, and a propensity matched control group (n = 70) of patients that received angiotensin converting enzyme inhibitor or angiotensin-II receptor blocker (ACEI/ARB) within the same period. RESULTS: Of the 35 patients in the ARNI group, 21 (60%) had systemic left ventricle (LV) while 14 (40%) had systemic right ventricle (RV). Compared to the ACEI/ARB group, the ARNI group had greater relative improvement in LV global longitudinal strain (GLS) (28% versus 11% increase from baseline, p < 0.001) and RV-GLS (11% versus 4% increase from baseline, p < 0.001), and greater relative improvement in New York Heart Association functional class (-14 versus -2% change from baseline, p = 0.006) and N-terminal pro-brain natriuretic peptide levels (-29% versus -13% change from baseline, p < 0.001). These results were consistent across different systemic ventricular morphologies. CONCLUSIONS: ARNI was associated with improvement in biventricular systolic function, functional status, and neurohormonal activation, suggesting prognostic benefit. These results provide a foundation for a randomized clinical trial to empirically test the prognostic benefits of ARNI in adults with CHD, as the next step towards evidence-based recommendations for heart failure management in this population.

The role of imaging in the selection of patients for HFpEF therapy.

Heart failure with preserved ejection fraction (HFpEF) traditionally has been characterized as a form of heart failure without therapeutic options, in particular with a lack of response to the established therapies of heart failure with reduced ejection fraction (HFrEF). However, this is no longer true. Besides physical exercise, risk factor modification, aldosterone blocking agents, and sodium-glucose cotransporter 2 inhibitors, specific therapies are emerging for specific HFpEF etiologies, such as hypertrophic cardiomyopathy or cardiac amyloidosis. This development justifies increased efforts to arrive at specific diagnoses within the umbrella of HFpEF. Cardiac imaging plays by far the largest role in this effort and is discussed in the following review.

Clinical course and therapy optimization of patients after discharge from a specialized heart failure clinic.

Aim: We aimed to describe the clinical course of patients with heart failure with reduced ejection fraction (HFrEF) after discharge from the heart failure clinics (HFC). Patients & methods: We reviewed the hospital's records of 610 patients that were discharged between 2013 and 2018 from the HFC at a single centre. Patients with no recurrent contact to ambulatory cardiac care were invited to an echocardiographic assessment. Results: Of the survivors, 72% were re-referred after discharge. Nearly 30% of the patients with no recurrent contact with ambulatory cardiac care had persistent HFrEF and further therapeutical optimizations were indicated in half of them. Conclusion: This highlights the importance to identify high-risk patients that would benefit from extended management in the HFC.

What is this summary about? In Denmark, it is standard practice to discharge patients with heart failure from heart failure clinics to primary care after achieving optimized guideline-directed medical therapy. However, little is known about their subsequent clinical course and whether their treatment could be further optimized. To answer that question, we reviewed the hospital's records of heart failure patients that were discharged between 2013 and 2018. What were the results? Of the 610 heart failure patients that were discharged from our clinic, 30% had died; 72% of the survivors were re-referred to cardiac clinics in the interim period. Nearly 30% of the patients with no recurrent contact with cardiac clinics had persistent heart failure and further therapeutical optimizations were indicated in half of them. What do the results mean? Deaths and re-referral to cardiac clinics accounted for the majority of the heart failure patients that were initially discharged; while further intervention was indicated in half of the stable patients that had no recurrent contact with cardiac ambulatory care. This highlights the challenges in identifying high-risk patients that would benefit from an extended management programme in the heart failure clinic and the importance of following up heart failure patients despite initial optimized therapy.

Getting ahead of the game: in-hospital initiation of HFrEF therapies.

Hospitalizations for heart failure (HF) have become a global problem worldwide. Each episode of HF decompensation may lead to deleterious short- and long- term consequences, but on the other hand is an unique opportunity to adjust the heart failure pharmacotherapy. Thus, in-hospital and an early post-discharge period comprise an optimal timing for initiation and optimization of the comprehensive management of HF. This timeframe affords clinicians an opportunity to up titrate and adjust guideline-directed medical therapies (GDMT) to potentially mitigate poor outcomes associated post-discharge and longer-term. This review will cover this timely concept, present the data of utilization of GDMT in HF populations, discuss recent evidence for in-hospital initiation and up-titration of GDMT with a need for post-discharge follow-up and implementation this into clinical practice in patients with heart failure and reduced ejection fraction.

Cost-Effectiveness of Sacubitril/Valsartan Compared with Enalapril in Patients with Heart Failure with Reduced Ejection Fraction: A Systematic Review.

Background: To assess the cost-effectiveness of sacubitril/valsartan compared with enalapril in patients with heart failure with reduced ejection (HFrEF). Methods: A systematic literature search was conducted searching in major electronic databases from inception to January 1, 2021. All relevant full economic evaluation studies of sacubitril/valsartan versus enalapril for the treatment of patients with HFrEF were identified using ad hoc search strategies. Mortality, hospital admissions, quality-adjusted life years (QALYs), life-years (LYQs), annual drug costs, total lifetime costs, and incremental cost-effectiveness ratio (ICER) were considered as the outcomes. The quality of the included studies was assessed using the CHEERS checklist. This study was conducted and reported in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guidelines. Results: The initial search yielded a pool of 1026 articles, of which 703 unique articles were screened, 65 full-text articles were assessed for eligibility and 15 studies finally included in the qualitative synthesis. Studies show that sacubitril/valsartan reduces mortality and hospitalization rate. The mean of death risk ratio and hospitalization were computed at 0.843 and 0.844, respectively. Sacubitril/valsartan produced higher annual and total lifetime costs. The lowest and highest lifetime costs for sacubitril/valsartan were found in Thailand ($4,756) and Germany ($118,815), respectively. The lowest ICER was reported in Thailand ($4857/QALY) and the highest in the USA ($143,891/QALY). Conclusion: Sacubitril/valsartan is associated with better outcomes and may be cost-effective compared to enalapril for the management of HFrEF. However, in developing countries such as Thailand, sacubitril-valsartan costs must be reduced to yield an ICER below the threshold.

Focal severe decrease in myocardial technetium-99 m sestamibi uptake indicates ventricular irreversibility in patients with dilated cardiomyopathy.

OBJECTIVE: Technetium-99 m sestamibi (99mTc-MIBI) scintigraphy can identify non-viable left ventricular (LV) myocardium. However, the optimal cut-off value and the details of decreased 99mTc-MIBI uptake of the non-viable LV myocardium in patients with dilated cardiomyopathy (DCM) have not been well established. This study aimed to evaluate the decrease in 99mTc-MIBI uptake in each segment and in the whole LV myocardium, and to determine cut-off values for identifying non-viable LV myocardium in DCM patients. METHODS: Overall, 53 DCM patients with reduced LV ejection fraction (LVEF ≤ 40%) who underwent 99mTc-MIBI scintigraphy and any optimization of heart failure treatments were evaluated. LV myocardium was classified as viable or non-viable based on the absolute increase in LVEF of ≥ 10% unit leading to an LVEF of > 40% at follow-up, respectively. The decrease in myocardial 99mTc-MIBI uptake in each of the 17 segments was evaluated using three indices determined by different thresholds or standard references: segmental %uptake, rest score, and defect extent. Changes in the whole LV myocardium were evaluated by the minimum %uptake, and the summed rest score (SRS) and extent of LV defect were obtained using summed data of 17 segments. RESULTS: Segmental evaluation indicated a mild decrease in 99mTc-MIBI uptake in 18 patients with viable LV myocardium, whereas focal severe decrease in uptake was observed in patients with non-viable LV myocardium. In the receiver-operating characteristic curve analysis, the cut-off values of minimum %uptake, SRS, and LV defect extent for predicting non-viable LV were 39% (p < 0.01, area under the curve [AUC]: 0.87), 10 (p < 0.01, AUC: 0.91), and 23% (p < 0.01, AUC: 0.92), respectively. CONCLUSIONS: In DCM patients, myocardial 99mTc-MIBI %uptake of < 40% indicated non-viable myocardium. The focal and severe decrease in uptake in approximately more than a quarter of the LV myocardium may indicate non-viable LV.

An update on dapagliflozin for the treatment of heart failure.

Heart failure (HF) is a substantial source of morbidity and mortality. Several clinical trials have reported a significant HF benefit of sodium/glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. In 2019, the Food and Drug Administration (FDA) approved dapagliflozin to reduce hospitalization risk for HF in adults with type 2 diabetes and established cardiovascular disease or risk factors. Regardless of the presence of diabetes, the recent DAPA-HF study reported a significant relative risk (RR) reduction with dapagliflozin in the composite primary outcome of worsening HF or death from cardiovascular causes in patients with New York Heart Association (NYHA) class II, III or IV HF and an ejection fraction of 40%. There was a 30% RR reduction in hospitalizations for HF, 57% RR reduction in urgent HF visits, and 18% RR reduction in cardiovascular death. These results led the FDA to approve dapagliflozin in 2020 for the treatment of HF with reduced ejection fraction (NYHA class II-IV) in adults with and without type 2 diabetes. This article summarizes HF outcomes from large clinical trials of SGLT2 inhibitors and focuses on dapagliflozin's HF benefits. The review also covers potential mechanisms of HF benefit and the safety profile of dapagliflozin in patients with HF.

Avoiding implantation of a cardioverter-defibrillator by bridging with wearable defibrillator vest.

BACKGROUND: Patients with a left ventricular ejection fraction (LVEF) ≤35% should be protected from sudden cardiac death with an implantable cardioverter-defibrillator (ICD). The onset of the effect of optimal medical therapy (OMT) is unclear, and a wearable cardioverter-defibrillator (WCD) can bridge this period. PATIENTS AND METHODS: Our study analyzed 104 patients (age, 68.9 ± 11.7 years; 81% [84/104] male) whose first diagnosis included an LVEF <35%. After exclusion of reversible causes for LVEF reduction and initiation/adjustment of the OMT, the WCD was employed. The LVEF and indication for ICD were re-evaluated after 62 ± 36 days. The LVEF development and implantation rate were correlated with underlying disease (ischemic [ICM] or nonischemic cardiomyopathy [NICM]), comorbidities, and age/gender. RESULTS: The wearing time of the WCD was 22.8 ± 1.9 h/day. An LVEF improvement from 28.5 ± 6.4% to 40 ± 11.7% was achieved through OMT (p < 0.0001). An improvement in LVEF of up to more than 35% was achieved in 66 of 104 patients (63%), and only 37% of patients were subsequently given an ICD. This affected 41% of patients with ICM and 30% of patients with NICM (p = 0.205). Notably, no ICD interventions were observed over 362 ± 89.5 days after implantation in the ICD-receiver group. CONCLUSION: The indication for ICD can be re-evaluated after 2 months. Patients with NICM respond better to OMT compared with ICM patients. The LVEF recovered to >35% in >60% of cases.

Can Stem Cells Improve Left Ventricular Ejection Fraction in Heart Failure? A Literature Review of Skeletal Myoblasts and Bone Marrow-Derived Cells.

Heart failure is a life-threatening condition that affects millions worldwide and is only expected to get worse with an ageing population. Current treatment regimens rely on medical therapy and heart transplantation as a last resort. Stem cells have been undergoing clinical trials worldwide as a hope for a new and safe clinical treatment. Skeletal myoblasts and bone marrow-derived stem cells are two types of stem cells being tested. The objective is to evaluate the efficacy of these two types of stem cells for heart failure therapy. Data were searched in PubMed using both regular and Medical Subject Heading (MeSH) keywords (stem cells, therapy, heart failure) and then filtered using inclusion/exclusion criteria (language, species, publication date, and age). In total, 31 research articles were reviewed (14 clinical trials, four randomized control trials, nine review articles, one case report, one comparative study, one systematic review, and one categorized as a systematic review and meta-analysis). Both skeletal myoblasts and bone marrow-derived stem cells showed mixed results in improving left ventricular ejection fraction in heart failure patients in the majority of studies. Larger studies need to be done to further investigate the efficacy of stem cells as a therapy for heart failure.

Emerging therapies for right ventricular dysfunction and failure.

Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.

Management of hyperkalaemia in acute kidney injury in a heart failure patient with patiromer.

AIMS: One prevalent comorbidity of chronic heart failure (CHF) is chronic kidney disease(CKD). Hyperkalemia is associated with both CHF and CKD, which often leads to withdrawal of heart failure medications in clinical praxis. METHODS AND RESULTS: A patient is presented who suffered from acute kidney injury with pre-existing CKD as heart failure comorbidity and a history of hyperkalemia. CONCLUSIONS: This case shows that potassium levels remained stable in acute kidney injury under ongoing heart failure medications, including an MRA, with the use of the potassium binder patiromer.