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Chrysakis, N.
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Chrysakis, N.
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Find support for a specific problem in the support section of our website. Get Support FeedbackPlease let us know what you think of our products and services. Give Feedback InformationVisit our dedicated information section to learn more about MDPI. Get Information clear JSmol Viewer clear first_page settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing: Column Width: Background: Open AccessReview Myocardial Recovery byNikolaos Chrysakis 1 , Andrew Xanthopoulos 1, Dimitrios Magouliotis 2, Randall C. Starling 3, Stavros G. Drakos 4, Filippos Triposkiadis 1,5,* and John Skoularigis 1
1
Department of Cardiology, University Hospital of Larissa, 41110 Larissa, Greece
2
Unit of Quality Improvement, Department of Cardiothoracic Surgery, University of Thessaly, Biopolis, 41110 Larissa, Greece
3
Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA
4
Division of Cardiovascular Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health, Salt Lake City, UT 84132, USA
5
School of Medicine, European University Cyprus, Nicosia 2404, Cyprus
*
Author to whom correspondence should be addressed.
Diagnostics 2023, 13(8), 1504; https://doi.org/10.3390/diagnostics13081504
Received: 20 March 2023
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Revised: 11 April 2023
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Accepted: 17 April 2023
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Published: 21 April 2023
(This article belongs to the Section Pathology and Molecular Diagnostics)
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Abstract: In this paper, the feasibility of myocardial recovery is analyzed through a literature review. First, the phenomena of remodeling and reverse remodeling are analyzed, approached through the physics of elastic bodies, and the terms myocardial depression and myocardial recovery are defined. Continuing, potential biochemical, molecular, and imaging markers of myocardial recovery are reviewed. Then, the work focuses on therapeutic techniques that can facilitate the reverse remodeling of the myocardium. Left ventricular assist device (LVAD) systems are one of the main ways to promote cardiac recovery. The changes that take place in cardiac hypertrophy, extracellular matrix, cell populations and their structural elements, β-receptors, energetics, and several biological processes, are reviewed. The attempt to wean the patients who experienced cardiac recovery from cardiac assist device systems is also discussed. The characteristics of the patients who will benefit from LVAD are presented and the heterogeneity of the studies performed in terms of patient populations included, diagnostic tests performed, and their results are addressed. The experience with cardiac resynchronization therapy (CRT) as another way to promote reverse remodeling is also reviewed. Myocardial recovery is a phenomenon that presents with a continuous spectrum of phenotypes. There is a need for algorithms to screen suitable patients who may benefit and identify specific ways to enhance this phenomenon in order to help combat the heart failure epidemic. Keywords: remodeling; recovery; markers; cardiac resynchronization therapy; left ventricular assist devices 1. IntroductionThe heart shows changes in its structure and morphology. This occurs either as a physiological response of the organism when subjected to a physiological stimulus (physical growth, exercise, etc.) or as a pathological response to harmful factors that cause volume, pressure overload or direct cellular damage in combination with the subsequent excessive activation of the renin-angiotensin axis and the sympathetic system. In several cases, either after the remission of the aforementioned harmful factors or the application of an appropriate therapeutic approach, there is a reversal of both the macroscopic anatomical abnormalities and the restoration of cellular structures and functions with a tendency to return to the pattern of the normal heart. In this way, the heart manages to improve its cardiac performance to pre-damage levels despite the hemodynamic disturbances that may continue to exist. This phenomenon is called reverse remodeling. On the occasion of the above data collection, the researchers created a term they called myocardial recovery. According to this definition, myocardial recovery is defined as the morphological and functional recovery of the heart either automatically or after one or more interventions while meeting the following criteria: (1) absence of recurrence of heart failure events and (2) freedom from future heart failure events [1]. In the international bibliography, this specific phenomenon was intensively studied in the context of the question of whether reverse remodeling is identified with the concept of myocardial recovery. In the first criterium, the cardiac tissue recovers morphologically and functionally, but without ensuring that the second criterium above is satisfied. Thus, it follows that the two concepts are not identical as reverse remodeling is a necessary condition for achieving myocardial recovery, but it is not sufficient without the fulfillment of the two aforementioned criteria. Therefore, myocardial recovery of the heart requires macroscopic and microscopic morphological and functional restoration of the myocardium to the extent that it brings about present and future freedom of the patient from heart failure and its complications.In this paper, through a systematic review of the international literature, the feasibility of myocardial recovery is studied, the mechanisms that contribute to its achievement, possible molecular markers for its identification, interventions that are capable of bringing about the above result based on the modification of specific pathophysiological mechanisms and, finally, the recognition of specific characteristics of patients who may experience myocardial recovery and the criteria for their detection [1,2]. 2. PathophysiologyRemodeling of the heart causes changes both macroscopically, involving its mass and geometry, and microscopically, involving two factors. The first is the cardiomyocyte in which the following changes take place: (1) cellular hypertrophy with modification of the structure, constitution and histophysiology of myofibrils as well as changes in their alignment in space (in series, parallel), (2) remodeling of the protein coupling and communication structures among them, (3) changes in the physiology of cell groups at the level of metabolism, signaling, apoptosis as well as the effect of the neurohormonal axis on the above and (4) the modification of the genome at all levels of gene expression. The second is the extracellular basic substance with changes that take place in its structure, composition and quantity. Several possible mechanisms have been proposed to achieve reverse remodeling. The predominant approach to the physiology of this phenomenon is related to the deformability of myocardial fibers. We know from mechanics that, in a material, when an increasing tension is applied to it, it can increase its length up to a certain point where, if the applied tension is interrupted, it can return to its original state without affecting its structure (elastic deformation). From this point onwards, the material will partially return to its original state as permanent structural changes are created in its structure (plastic deformation). Myocardial tissue shows a similar behavior. When exerting tension on the myocardial wall either due to increased volume or pressure, the damage it will suffer can be either permanent or reversible in whole or in part. In the second case, after the removal of the damaging factor, the heart gradually tends to restore its geometry and its thickness to a certain extent, depending on the type and severity of the damage, the length of time it suffered and the effect of additional factors such as the degree of activation of the neurohormonal axis.Therefore, reverse remodeling is directly related to the extent of damage the myocardium undergoes at the microscopic level from the effect of the plastic deformation it has undergone. The three factors that will determine the evolution of the functionality of the myocardium are (1) the macroscopic geometry of the heart as the structure of its cavities directly affects its hemodynamic function, (2) the cardiomyocyte and (3) the extracellular matrix. Depending on the degree of damage and the dysfunctions that the above will show, the degree of reverse remodeling of the heart will be determined. In turn, the clinical impact that will be brought about by the degree of remodeling, and specifically the absence of recurrence of heart failure due to the improvement of the structure and function of the myocardial tissue and also the freedom from future heart failure events due to the residual damage that will remain in the tissues, will also determine the clinical outcome. The two possible outcomes are myocardial remission where we have reverse remodeling without meeting the above two criteria and myocardial recovery (Figure 1) where, in addition to the macroscopic recovery of the myocardium, the corresponding clinical benefit to the patient is presented as defined [1]. 3. BiomarkersThe scientific community has put a lot of effort into defining various indicators such as biomarkers, molecular, imaging techniques, etc. to identify reverse remodeling and by extension myocardial recovery with the aim of rapid and early stage response to potential therapies. In this particular paper, the possible indicators that have been mentioned in the international literature and the possibilities they provide in the clinical and research fields are reviewed. 3.1. Biochemists 3.1.1. Natriuretic Peptides (Brain Natriuretic Peptide (BNP), N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP))From the PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure) study, a positive correlation of natriuretic peptides with left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), right ventricular systolic pressure (RVSP) and inverse with left ventricular ejection fraction (LVEF), E/e’ and right ventricular function was observed [3]. Further, from a study of patients with cardiomyopathy of pregnancy it was observed that, when NT-proBNP ≥ 900 pg/mL, there is a lower probability of recovery of LVEF and LVEDV [4]. Finally, regarding ischemic disease, increased levels of this in non-ST elevation myocardial infarction (NSTEMI) patients were associated with improved left ventricular (LV) function over 8 months [5] and decreased levels of this with improved right ventricular (RV) function in patients with ST elevation myocardial infarction (STEMI) [6]. Consequently, natriuretic peptides do not directly predict myocardial recovery but are associated with morphological and functional changes in response to treatments, indirectly indicating the potential for reverse remodeling. 3.1.2. TroponinIn a secondary analysis of the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study, elevated troponin values were associated with an increased likelihood of LV remodeling in chronic heart failure (HF) [7]. At the same time, from the Prediction of ICD Treatment Study (PREDICTS) study, its increased values in HFrEF after an acute coronary event were found to be an independent predictor of systolic dysfunction [3], while its reduced levels in patients with STEMI were related to improved RV function [6]. From the above, it also follows that it is not a direct indicator of myocardial recovery but an indicator of remaining ischemic damage and, indirectly, of a reduced possibility of reverse remodeling. 3.1.3. Soluble ST2 (sST2)It is a transmembrane receptor in cardiomyocytes, fibroblasts and endothelial cells where it is produced in increased myocardial stress and binds IL-33, playing a serious role in fibrosis and in general in the course of heart failure. In studies, its increased levels were associated with increased left ventricular dimensions and volumes, reduced ejection fraction and worse right ventricular function. Conversely, levels < 35 ng/mL were associated with reverse remodeling. 3.1.4. Interleukin-8 (IL-8)Studies in patients with STEMI, angioplasty and those hospitalized with heart failure as a complication showed a reduced likelihood of improvement in left ventricular contractility when elevated serum IL-8 levels were observed [8]. 3.2. ElectrocardiogramFrom the electrocardiogram (ECG) we can draw indirect conclusions about the possibility of improving myocardial function. Persistent ST elevation after successful luminal opening in patients with STEMI is considered a sign of poor microvascular circulation and a negative predictor of increased ejection fraction at 3 months [9]. Further, repolarization disturbances can add additional information. In a study of patients with non-ischemic heart disease with an ejection fraction 45% without changes after reducing the speed of the device; in the second stage a cardiorespiratory test is performed where PVO2 > 18 mL/kg/min and VE/VCO2 < 34; in the third stage right catheterization is performed where CI > 2.12 L/min and pulmonary capillary wedge pressure (PCWP) < 15 mmHg and finally; in the fourth stage, LVAD removal surgery is performed should the measurements in stage three apply when blocking the outlet cannula of the device [48]. In addition, published studies indicate several measures that could potentially predict myocardial recovery, such as pre-LVAD maximum LV Torsion [49], AP ventricular dilation time constant (tau) and LV dp/dt when measured with left cardiac catheterization, with the former being reduced and the latter increased in myocardial recovery [50] while also the former is a predictor of survival from hospitalization for heart failure and for reverse remodeling [51]. Finally, markers such as increased end-diastolic relative wall thickness (RWT) before LVAD removal, increased mean arterial pressure (MAP) during the 6 min walking test (6MWT) and increased S’ wave > 8 cm/s show increased correlation with recovery after LVAD weaning [52].Data on the role of nuclear medicine techniques in the prediction of myocardial recovery after LVAD implant remain scarce. An interesting study, including 18 clinically stable patients supported with the second-generation axial flow LVAD (median duration of LVAD support 7 months), examined the effect of hemodynamic unloading on myocardial viability with the use of technetium-99m ((99m)Tc)-sestamibi single photon emission computed tomography (SPECT) imaging [53]. The researchers observed no significant change in viable myocardium, globally (median Δ 0.10%, IQR −1.7, 2.2, p = 0.80; 95%CI 0.95, 1.00) and regionally (median Δ 0.10%, IQR −1.5, 1.9, p = 0.88; 95%CI 0.93–1.00), between baseline and after an interval of 2 to 3 months, while patients were at reduced LVAD support. However, a recent study investigated whether long-term LVAD mechanical unloading results in metabolic activation of quiescent myocardial regions by examining myocardial 18F-fluorodeoxyglucose (FDG) uptake in 4 patients with end-stage HF after LVAD implantation [54]. It was concluded that all participants exhibited some degree of increase in FDG uptake in areas of previous metabolic inactivity at baseline, suggestive of possible myocardial regeneration. Therefore, further studies are needed to determine the effect of mechanical unloading on myocardial viability.Therefore, although the international literature shows low rates of myocardial recovery in patients where LVAD placement has been performed, a great heterogeneity is observed in this work regarding the study population and its characteristics (age, heart disease, etc.) as well as the treatment and evaluation protocols of myocardial recovery internationally [55]. Elucidation of certain patient characteristics, as well as specific imaging and molecular markers such as those analyzed in the paper, could contribute to the creation of algorithms that will safely predict which patients will be suitable candidates for myocardial recovery. There also seems to be a need to adopt common international criteria for pharmaceutical treatment and evaluation. With the implementation of the above measures, it is likely that, in the future, the recovery rates will increase to a large percentage along with the developments presented through the minimally invasive techniques of removal of the systems that present significant advantages over the current ones. 7. Treatment of Arrhythmias and Use of CRTIn addition to studies on the recovery of the myocardium from direct damage to it, there is now also great interest in myocardial recovery in patients who have experienced heart failure as a result of a chronic burden of arrhythmias. The most characteristic is the NEw-Onset LBBB-Associated Idiopathic Nonischemic CardiomyopaTHy (NEOLITH) II substudy which highlighted the improvement of myocardial function through the improvement of the ejection fraction and the reduction of events in patients with non-ischemic cardiomyopathy caused by left bundle branch block (LBBB NICM) after synchronization therapy with CRT. The characteristics found in responders to CRT therapy are (1) absence of hypertension and (2) lower blood urea nitrogen (BUN) levels and reduced heart rate [56]. The literature also mentions the reduction of the mass and volume of the left ventricle [57] and the reduction of the functional insufficiency of the mitral valve (2) after the use of the above systems. The molecular mechanisms assumed to be involved are related to the improvement of the functioning of the Na+, K+, Ca2+ channels and, by extension, an improvement of the calcium cycle in the cell which will lead to a reduction in the duration of the depolarization potential resulting in the reversal of the desynchronization of ventricles. At the same time, the involvement of CRTs in the mechanisms of mitochondrial genome regulation, modulation of molecular signaling and inhibition of apoptotic signals has been speculated [58]. In addition, a specific study highlighted the improvement of cardiac function after reversal of any type of arrhythmia and its duration, with the exception of patients with an increased number of spontaneous ventricular contractions. Finally, in another study on the improvement of cardiac function and the achievement of reverse remodeling in pediatric tachycardia-induced cardiomyopathy (TIC) after treatment with pharmaceutical and interventional methods, an increased ejection fraction, younger age and increased heart rate were statistically significant indicators while small left ventricular dimensions were associated with reverse remodeling [59].From the above data, we first observe that, with the above interventions in specific arrhythmological conditions, the phenomenon of myocardial depression is achieved. Further, especially for CRT, the data advocate for the increased possibility of myocardial recovery with the criteria discussed above. There is therefore a need to design and conduct new studies with patients with specific inclusion criteria to certify the achievement of myocardial recovery in specific populations with specific arrhythmic conditions. 8. Medical Treatment and Cardiac RehabilitationSeveral studies, both prospective and retrospective, have demonstrated the association between the use of neurohormonal inhibitors and reverse remodeling in patients with LVADs [42,43,60,61]. An interesting retrospective analysis of 12,144 LVAD patients from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) revealed that those receiving any neurohormonal inhibitor at 6 months had a better survival rate at 4 years compared with patients not receiving neurohormonal inhibitor (56.0% vs. 43.9%) [62]. Interestingly, patients who were on neurohormonal inhibitors exhibited better functional capacity (assessed by 6MWT) and quality of life (assessed by Kansas City Cardiomyopathy Questionnaire score). On top of optimal guideline medical treatment, existing evidence shows that cardiac rehabilitation may benefit LVAD patients and facilitate myocardial recovery (i.e., metabolic changes in the failing myocardium and anabolic effects) [63,64]. A recent position Statement from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) highlights the importance of the patient’s screening to avoid complications as exercise training prescription should be individualized to meet the patient’s needs [64]. 9. ConclusionsFrom this work, specific conclusions are drawn about the feasibility of myocardial recovery. Initially, it is evident that it can exist as a phenomenon given that it has repeatedly described in many studies but also a number of involved pathophysiological mechanisms have been identified (Figure 4) [65]. The criteria for its definition are also set to avoid misinterpretations and wrong generalizations. The fact of the low and varying success rate of the interventions analyzed above, as well as the partial reversal of the pathophysiological mechanisms leading to heart failure, highlights that myocardial recovery manifests in a continuous spectrum rather than an all-or-none phenomenon. It directly depends on the type of damage to which the heart is subjected, the therapeutic intervention and the clinical characteristics of patients. Thus, there is a need to design studies with disease- and intervention-specific patient inclusion criteria, consistent medication protocols and monitoring protocols to determine true myocardial dimensions for recovery. Myocardial recovery should be an intensive field of study in the coming years [61,65]. This is evident from the tendency of now official organizations to recategorize these patients, for example, the American Heart Association (AHA), which created the HFimpEF classification for patients, studied as a separate group those who, after therapeutic interventions, improved their cardiac function (Figure 5). With the development of technology and the expansion of the use of neural networks and artificial intelligence, it is hoped that individual algorithms will improve the prediction of the potential of patients for myocardial recovery. This will benefit them, by offering the most and highest quality years of survival, but also reduce the number of candidate patients on heart transplant waiting lists. Author ContributionsConceptualization, N.C., A.X., R.C.S., S.G.D., F.T. and J.S.; methodology, N.C. and D.M.; investigation, N.C., A.X., D.M. and S.G.D.; data curation, N.C.; writing—original draft preparation, N.C., A.X. and D.M.; writing—review and editing, R.C.S., S.G.D., F.T. and J.S.; visualization, S.G.D., R.C.S., F.T. and J.S.; supervision, R.C.S., S.G.D., F.T. and J.S. All authors have read and agreed to the published version of the manuscript.FundingThis research received no external funding.Institutional Review Board StatementNot applicable.Informed Consent StatementNot applicable.Data Availability StatementNot applicable.Conflicts of InterestThe authors declare no conflict of interest.ReferencesMann, D.L.; Barger, P.M.; Burkhoff, D. Myocardial recovery and the failing heart: Myth, magic, or molecular target? J. Am. Coll. Cardiol. 2012, 60, 2465–2472. [Google Scholar] [CrossRef]Marinescu, K.K.; Uriel, N.; Mann, D.L.; Burkhoff, D. 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Figure 1.
(A) A material, when an increasing stress is applied to it, can increase its length up to a certain point and, when the applied stress is stopped, it can return to its original state without affecting its structure (elastic deformation). From this point onwards, the material will partially return to its original state as permanent structural changes are created in its structure (plastic deformation). (B,C) Myocardial tissue shows a similar behavior. When tension is exerted on the myocardial wall, the damage it will suffer can be either permanent or reversible, in whole or in part, depending on the damage and its duration. (D) The three factors that will determine the evolution of myocardial functionality are (1) its macroscopic geometry, (2) the cardiomyocyte and (3) the extracellular matrix. The clinical impact that the degree of remodeling will have concerns two possible outcomes, myocardial remission and myocardial recovery. Abbreviations: C, cardiac myocyte; M, extracellular matrix; LV, left ventricle. Reprinted with permission from Mann DL, et al., (2012), Copyright © 2012, American College of Cardiology Foundation. Published by Elsevier Inc. Ref. [1].
Figure 1.
(A) A material, when an increasing stress is applied to it, can increase its length up to a certain point and, when the applied stress is stopped, it can return to its original state without affecting its structure (elastic deformation). From this point onwards, the material will partially return to its original state as permanent structural changes are created in its structure (plastic deformation). (B,C) Myocardial tissue shows a similar behavior. When tension is exerted on the myocardial wall, the damage it will suffer can be either permanent or reversible, in whole or in part, depending on the damage and its duration. (D) The three factors that will determine the evolution of myocardial functionality are (1) its macroscopic geometry, (2) the cardiomyocyte and (3) the extracellular matrix. The clinical impact that the degree of remodeling will have concerns two possible outcomes, myocardial remission and myocardial recovery. Abbreviations: C, cardiac myocyte; M, extracellular matrix; LV, left ventricle. Reprinted with permission from Mann DL, et al., (2012), Copyright © 2012, American College of Cardiology Foundation. Published by Elsevier Inc. Ref. [1].
Figure 2.
(A,B): The changes in the mRNAs of COLIAN1, TGF1β, in which no statistical difference is observed before and after the removal of the LVAD. (C,D): The changes in the mRNAs of THY1 and TIMP4, where there is a statistically significant difference between the patients who recovered and those who did not. (E–H): mRNA expression of COL1A1, COL3A1, FN and THY1 after LVAD removal was negatively correlated with ejection fraction. Reprinted with permission from Felkin LE, et al., (2009), Copyright © 2009 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. Ref. [19].
Figure 2.
(A,B): The changes in the mRNAs of COLIAN1, TGF1β, in which no statistical difference is observed before and after the removal of the LVAD. (C,D): The changes in the mRNAs of THY1 and TIMP4, where there is a statistically significant difference between the patients who recovered and those who did not. (E–H): mRNA expression of COL1A1, COL3A1, FN and THY1 after LVAD removal was negatively correlated with ejection fraction. Reprinted with permission from Felkin LE, et al., (2009), Copyright © 2009 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. Ref. [19].
Figure 3.
After LVAD placement (A): cell size and (B): capacitance (an index of cell surface area), tend to return to normal donor values, indicating reversal of hypertrophy. (C): No increase in the contraction-frequency-dependent relationship was observed in patient cells with or after LVAD use in contrast to donor cells. As a result, the researchers hypothesized the involvement of calcium transport mechanisms as responsible for the improvement in contraction. (D): LVAD-implanted HF patients show reduced calcium current amplitude compared to LVAD-removal patients and no-difference compared to donors. After LVAD removal there is an increase in the amount of calcium observed compared to heart failure patients and donors. The LVAD increases the amplitude of the calcium current and its quantity, improving the excitation-contraction relationship of the cardiomyocyte, being a mechanism for promoting cardiac recovery. * p < 0.05; ** p < 0.01; LVAD core: left ventricular tissue taken at LVAD implant; post LVAD: left ventricular tissue taken at LVAD removal. Reprinted with permission from Terracciano CMN, et al., (2003), Copyright © 2003, Oxford University Press [27].
Figure 3.
After LVAD placement (A): cell size and (B): capacitance (an index of cell surface area), tend to return to normal donor values, indicating reversal of hypertrophy. (C): No increase in the contraction-frequency-dependent relationship was observed in patient cells with or after LVAD use in contrast to donor cells. As a result, the researchers hypothesized the involvement of calcium transport mechanisms as responsible for the improvement in contraction. (D): LVAD-implanted HF patients show reduced calcium current amplitude compared to LVAD-removal patients and no-difference compared to donors. After LVAD removal there is an increase in the amount of calcium observed compared to heart failure patients and donors. The LVAD increases the amplitude of the calcium current and its quantity, improving the excitation-contraction relationship of the cardiomyocyte, being a mechanism for promoting cardiac recovery. * p < 0.05; ** p < 0.01; LVAD core: left ventricular tissue taken at LVAD implant; post LVAD: left ventricular tissue taken at LVAD removal. Reprinted with permission from Terracciano CMN, et al., (2003), Copyright © 2003, Oxford University Press [27].
Figure 4.
Extrapolating the lessons learned from patients with ventricular assist devices to the broader heart failure population. Reprinted with permission from Taleb I, et al., (2022), Copyright © 2022, Wolters Kluwer Health [65].
Figure 4.
Extrapolating the lessons learned from patients with ventricular assist devices to the broader heart failure population. Reprinted with permission from Taleb I, et al., (2022), Copyright © 2022, Wolters Kluwer Health [65].
Figure 5.
Heart failure (HF) is a spectrum of phenotypes. Each HF phenotype is the result of a patient-specific trajectory wherein the heart remodels towards concentric hypertrophy, eccentric hypertrophy or a combination of both. The way of entry and the subsequent path of the trajectory depend on the patient’s risk factors, comorbidities and disease modifiers (genome, proteome, metabolome). Both pharmaceutical treatment (i.e., β-blocker, ARNI/ACE-i/ARB, MRA, SGLT-2 inhibitor, diuretic) and device therapy (i.e., cardiac resynchronization therapy, left ventricular assist devices) may lead to reverse remodeling. Abbreviations: ARNI, angiotensin receptor-neprilysin inhibitor; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; MRA, mineralocorticoid receptor antagonists; SGLT2-inhibitor, sodium-glucose Cotransporter 2-nhibitor; CRT, cardiac resynchronization therapy; GDMT, guideline medical therapy.
Figure 5.
Heart failure (HF) is a spectrum of phenotypes. Each HF phenotype is the result of a patient-specific trajectory wherein the heart remodels towards concentric hypertrophy, eccentric hypertrophy or a combination of both. The way of entry and the subsequent path of the trajectory depend on the patient’s risk factors, comorbidities and disease modifiers (genome, proteome, metabolome). Both pharmaceutical treatment (i.e., β-blocker, ARNI/ACE-i/ARB, MRA, SGLT-2 inhibitor, diuretic) and device therapy (i.e., cardiac resynchronization therapy, left ventricular assist devices) may lead to reverse remodeling. Abbreviations: ARNI, angiotensin receptor-neprilysin inhibitor; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; MRA, mineralocorticoid receptor antagonists; SGLT2-inhibitor, sodium-glucose Cotransporter 2-nhibitor; CRT, cardiac resynchronization therapy; GDMT, guideline medical therapy.
Table 1.
Myocardial recovery studies in patients with LVADs.
Table 1.
Myocardial recovery studies in patients with LVADs.
StudyConductedCharacteristicsOutcomeThoratec registry [36]1990–1999Characteristics: 22 patients with non-ischemic heart failure (12 myocarditis, 4 sarcoid cardiomyopathy, 1 viral, 2 idiopathic), 12 female, mean age 32 years, duration of support 57 days, use of Thoratec device (pneumatic LVAD)Benefit of LVAD in acute myocarditisBerlin Group [37,38]1995–2004 and then until 200832 patients from a total of 131 with dilated cardiomyopathy. Eligible: 30 men, 4.5 months average LVAD supportFollow-up study 2008. Of 188 patients with idiopathic dilated cardiomyopathy in 30 LVAD removal. Characteris-tics: LVEF 30–44% and LVEDD 56–60 mm at device removal, use of LVAD, BiVAD, RVAD systems. Results: probability of survival 5 and 10 years after LVAD weaning when at 1 year there was no recurrence of heart failure 84% and 61%, respectivelyOf the 32, 4 died 2 for cardiac reasons, 2 for non-cardiac reasons, remaining survival >3 years. Overall study conclusion: LVEDD > 55, LVEF < 45% before LVAD removal and HF duration ≥ 5 years are poor prognostic factors. Patients having 2 of the 3 factors have a reduced chance of recoveryPatients with a shorter history of heart failure, were younger and required less time on LVAD support have an increased likelihood of recovery University of Pittsburgh study [39]1996–2003Of 154 subjects with LVAD, removal was considered possible in 10. Characteristics: 2 ischemic and 8 non-ischemic etiology (4 peripartum cardiomyopathy, 3 myocarditis, 1 idiopathic), 120 days mean support time, mean age 30 years, 88% womenLVAD support offers better outcomes in patients with gestational cardiomyopathy and myocarditis IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) cohort [40]2002–200814 patients with acute myocarditis had LVAD inserted, 8 were candidates for recovery. Characteristics: mean age 30 years, 38% male, 10 with pulsatile LVAD 4 with continuous flow, implantation 1 month after symptoms, in recoveries increased inflammation, little fibrosis and reduced LVEDD while in non-recoveries vice versaIncreased likelihood of recovery in recent-onset cardiomyopathy, biopsy and LVEDD guide potential recoveryMCS UNOS (United Network Organ Sharing) registry [41]2005–2013Out of 686 patients, LVAD removal was performed due to recovery in 34. Characteristics of persons with recovery: average age 40 years, women 41%, 33 HeartMate II and 1 Heartware device and average duration of support 382 days while in 66% of them recovery maintained after 1 yearPatients who experienced recovery were younger, female, had non-ischemic cardiomyopathy, had a lower BMI, had not had a prior ICD implanted and had a lower serum creatinine Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York [42]200621 patients (8 with coronary artery disease, 13 with idiopathic dilated cardiomyopathy) of 34 initially placed with an LVAD were given neurohormonal blockade and attempted weaning. Characteristics of selected patients: mean age 48 years, disease duration before LVAD up to 821 days, 20 HeartMate II and 1 VentrAssist device. Results: 16 subjects developed reverse remodeling and after device 3 downshift control weanedThe use of neurohormonal blockade aids in reverse remodeling while reduced pre-LVAD disease duration, less fibrosis, less hypertrophy and increased LVAD turns increase the likelihood of weaningHarefield Study [38,43]2006–200915 patients received a pulsatile flow LVAD and pharmacologic protocol for heart failure + clebuterol with 11 having the device removed. Characteristics of patients who recovered: LVEF at withdrawal 65 % mean, LVEDD 56 mm, 321 days of support. Final results: freedom from heart failure deregulation at 1 and 4 years 100% and 89%, respectively20 patients with nonischemic cardiomyopathy were implanted with a HeartMate II continuous flow LVAD device in combination with neurohormonal blockade and clebuterol. Patient characteristics before LVAD placement: age 16–58, LVEDD 57–91 mm, LVEF 7–34%, PCWP 31 mmHg, supported by inotropes, 16 were male, mean age results: 10 patients experienced 1–3 years of recovery with 66% having experienced heart failure prior to LVAD implantation up to 6 months prior. Further, before device removal at low flow they had a mean LVEF of 70%, LVEDD of 48 mm, PCWP of 6 mmHgMedication and pulsatile flow LVADs promote recovery. The use of continuous flow LVAD in combination with medication can promote myocardial recoveryINTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) Registry [44]2006–2015Of 13,454 LVAD patients 163 had recovery capable of weaning from the device and 8805 had partial recovery. Characteristics of patients with LVAD removal: Mean age 45 years, 38.7% female, 85.9% non-ischemic cardiomyopathy, 95.7% axial flow LVAD, mean duration of support 16 monthsYounger patients (
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