The cardiac cell therapy using MPCs may have a significant benefit on the natural history of heart failure with reduced ejection fraction (HFrEF)

Physician-scientists at The Texas Heart Institute announced today the results of the largest cell therapy trial to date in patients with chronic heart failure due to low ejection fraction.

The therapy benefited patients by improving the heart’s pumping ability, as measured by ejection fraction, and reducing the risk of heart attack or stroke, especially in patients who have high levels of inflammation.

Also, a strong signal was found in the reduction of cardiovascular death in patients treated with cells. The findings are published in the Journal of the American College of Cardiology.

https://www.sciencedirect.com/science/article/pii/S0735109723000244?via%3Dihub

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Heart failure (HF) is a complex clinical syndrome that results from either functional or structural impairment of ventricles resulting in symptomatic left ventricle (LV) dysfunction. The symptoms come from an inadequate cardiac output, failing to keep up with the metabolic demands of the body.

It is a leading cause of cardiovascular morbidity and mortality worldwide despite the advances in therapies and prevention. It can result from disorders of the pericardium, myocardium, endocardium, heart valves, great vessels, or some metabolic abnormalities.

Definition

Three main phenotypes describe HF according to the measurement of the left ventricle ejection fraction (EF), and the differentiation between these types is important due to different demographics, co-morbidities, and response to therapies:

• Heart failure with reduced ejection fraction (HFrEF): EF less than or equal to 40%
• Heart failure with preserved EF (HFpEF): EF is greater than or equal to 50%
• Heart failure with mid-range EF (HFmrEF) (other names are: HFpEF-borderline and HFpEF-improved when EF in HFrEF improves to greater than 40%): EF is 41% to 49% per European guidelines and 40 to 49% per the US guidelines.[1][2] 
• A new class of HF that introduced by the 2016 European Society of Cardiology (ESC) guidelines for diagnosis and management of HF. This class was known as the grey area between the HFpEF and HFrEF and now has its distinct entity by giving it a name as HFmrEF.

All patients with HFrEF have concomitant diastolic dysfunction; in contrast, diastolic dysfunction may occur in the absence of systolic dysfunction.

Etiology

Multiple conditions can cause HF, including systemic diseases, a wide range of cardiac conditions, and some hereditary defects. Etiologies of HF vary between high-income and developing countries, and patients may have mixed etiologies.[3] Ischemic heart disease and chronic obstructive pulmonary disease (COPD) are the most common underlying causes of HF in high-income regions.

Conversely, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, and myocarditis are the primary conditions for HF in low-income regions, according to a systemic analysis for the Global Burden of Disease Study.[4] More than two-thirds of all cases of HF are attributable to ischemic heart disease, COPD, hypertensive heart disease, and rheumatic heart disease. 

• Coronary artery disease (CAD): chronic and acute ischemia causes direct damage to the myocardium and leads to remodeling and scar formation, resulting in inadequate relaxation in diastole and impaired contraction in systole, which decreases contractility and cardiac output (CO). This scar formation may also correlate with aneurysm formation, and that further impairs contractile performance and relaxation. Myocardial infarction (MI) also causes dyssynchronous contraction of the infarcted segment, subsequent remodeling of the ventricle, ventricular dilatation with annular dilation, and mitral regurgitation that predispose to HF and decrease the CO. Several tachyarrhythmias such as atrial fibrillation/atrial flutter or non sustained ventricular tachycardia is common in patients with CAD and can deteriorate the cardiac function more. More than 70% of cases with HF have CAD.[5] CAD is a strong predictor of mortality in patients with acute HF. However, the role of coronary revascularization in reducing HF-related morbidity and mortality is still controversial, and viability testing may be useful to select the population that may benefit from revascularization.[6]
• High blood pressure (HBP): HBP is an independent risk factor for CAD. The high prevalence of HBP makes it a possible cause of HF in around one-fourth to one-third of cases. HBP increases vascular resistance and activates the renin-angiotensin-aldosterone system (RAAS). The heart must pump up blood against a higher afterload caused by HBP, which increases the myocardial mass as a compensatory mechanism to maintain a normal CO and that causes left ventricular hypertrophy (LVH). If blood pressure (BP) remains uncontrolled, apoptosis and fibrosis may result. LVH increases the myocardial stiffness and can cause ischemia, which leads to HFpEF or HFrEF. Control of BP is of paramount importance in improving the prognosis of HF. The Systolic Blood Pressure Intervention Trial (SPRINT) has shown that lowering the systolic BP to a target goal of less than 120 mmHg in HBP patients without diabetes had lower rates of HF with 38% lower relative risk comparing to systolic BP goal of less than140 mmHg.[7]
• Chronic obstructive pulmonary disease (COPD): COPD increases the risk of CAD and other smoking-related illnesses, cardiac dysrhythmias and can cause pulmonary hypertension and right heart failure. 
• Valvular heart disease: degenerate valve disease in developed countries and rheumatic valve disease in low-income countries can cause HF. Aortic and pulmonary stenosis increases the ventricular afterload and may cause HF. In valve regurgitation, a persistent volume overload can cause ventricular enlargement and functional impairment that may lead to HF. 
• Cardiomyopathies (CMP): CMP is a disease in which there are functional and structurally heart muscle abnormalities in the absence of CAD, HBP, valvular, or congenital heart disease. CMP categorizes into five types, which can be genetic or acquired: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and other unclassified cardiomyopathies (isolated noncompaction of the left ventricle [INLV] and Takotsubo syndrome are also in this category). CMP can cause HFrEF, HFpEF, or HFmrEF.

Other possible causes of HF include congenital heart disease, myocarditis, infiltrative disease, peripartum cardiomyopathy, human immunodeficiency virus (HIV), connective tissue disease, amyloidosis, substance abuse, long-standing alcohol use, obesity, diabetes mellitus (DM), hyperthyroidism (can cause high-output HF), pulmonary hypertension (can cause right HF), constrictive pericarditis (can cause HFpEF), pulmonary embolism (can cause right HF), and chemotherapies (like doxorubicin). 

reference link: https://www.ncbi.nlm.nih.gov/books/NBK553115/

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DREAM-HF is the largest clinical trial of cell therapy in HFrEF to date. The primary endpoint of a reduction in recurrent nonfatal hospitalization or urgent care events because of decompensated heart failure or successfully resuscitated high-grade symptomatic ventricular arrhythmias and its associated key secondary endpoint (time-to-first TCE) were negative in our study.

However, our findings suggest novel hypothesis-generating insights into how cardiac cell therapy using MPCs may have a significant benefit on the natural history of HFrEF. MPC therapy resulted in significant reductions in TTFE for MI or stroke over a mean follow-up of 30 months with the most benefit seen in patients with evidence of systemic inflammation (baseline hsCRP ≥2 mg/L).

These findings raise the possibility that treating patients with HFrEF with MPCs may improve outcomes by targeting local cardiac and systemic inflammatory changes that cause macrovascular and microvascular abnormalities in patients with heart failure (Central Illustration).

Historically, drug treatment of HFrEF has had disease-modifying effects that have predominantly been based on inhibiting the maladaptive effects of neurohormonal activation. Less attention has been paid to inflammatory factors that can also initiate and lead to progression of HFrEF.

Although previous studies addressing inflammation in heart failure have failed to provide convincing evidence of benefit,1,2,5 a subset analysis from the CANTOS trial showed that anti-inflammatory therapy targeting immune pathways could reduce cardiovascular events.20

The primary endpoint in our study addressed events related to clinical heart failure symptoms and low cardiac output, which mostly involve noninflammatory aspects of the maladaptive compensatory pathways.7,23, 24, 25 Moving forward in the field, separating endpoints related to congestive signs and symptoms from those relating to inflammation may become appropriate as more data regarding specific treatment of inflammation become available.

In the DREAM-HF trial, our results suggest that MPC treatment may have benefits in addition to those offered by concomitant GDMT. The mechanisms of action of MPC therapy appear to be directed predominantly toward altering the inflammatory environment within the heart and the vasculature once the cells are activated by local tissue cytokines.6, 7, 8, 9, 10, 11, 12,26,27

We found that a single transendocardial administration procedure of MPCs resulted in a long-term 58% reduction in the prespecified MACE of MI or stroke. In the post hoc analysis of the composite 3-point MACE, MPC treatment showed a 27% risk reduction (cause-specific HR: 0.725; 95% CI: 0.509-1.034) in the analysis population.

Our findings of a further risk reduction in patients with a greater degree of systemic inflammation suggest MPC therapy may provide clinical benefits via mechanisms that are different from but complementary to those of existing GDMT.

MPCs are a well-characterized STRO-1/STRO-3+ stem cell population with greater immunomodulatory activity than STRO-1-negative mesenchymal stromal cells.28 Moreover, MPCs can bind the proinflammatory cytokines produced at high levels in the myocardium of patients with HFrEF, resulting in the release of factors that are anti-inflammatory and induce microvascular network formation (ie, neovascularization).

In preclinical studies, MPCs reversed endothelial dysfunction within coronary arteries and peripheral arteries in the setting of systemic inflammation as well as induced angiogenesis and arteriogenesis within cardiac muscle in animal models of HFrEF.6, 7, 8, 9, 10, 11, 12,28

Atherosclerosis and heart failure have shared pathophysiological changes relating to inflammation. MI and stroke are common in patients with HFrEF, and when they occur, they adversely affect the clinical outcome.29 Our results suggest that the anti-inflammatory effects of MPCs target these events and thus may contribute additionally to the benefits of GDMT.

In a recent editorial, Braunwald4 urged investigators to continue to move cardiac cell therapy forward into clinical practice, reminding us that current therapies, although improved, do not cure heart failure. He cites the safety of cell therapy and recent advances made in understanding cell selection and mechanisms, including the DREAM-HF trial,14 as an urgent call for action in the field.4

Elevated plasma levels of hsCRP portend worse outcomes in patients with HFrEF.16, 17, 18, 19, 20, 21 Our reduction in MI or stroke after a single intramyocardial administration of MPCs suggests that the immunomodulatory effects of the cells extend to the systemic vasculature.

MPCs have been shown to polarize M1 proinflammatory macrophages to M2 anti-inflammatory macrophages in arteries with underlying atherosclerosis, thus potentially stabilizing atherosclerotic vulnerable plaque and preventing plaque rupture and thrombus formation.9, 10, 11, 12,26,27

In addition, microvascular neovascularization induced by mesenchymal lineage cells can form a functional vascular network that protects ischemic heart muscle against apoptosis and scar tissue replacement while improving myocardial energetics and function.9, 10, 11, 12 These beneficial effects may reduce cardiac mortality in patients with greater amounts of salvageable cardiac tissue at an earlier stage in the disease process.30

Endothelium-controlled signaling pathways in the heart are crucial for homeostasis in local tissue and regulate cardiac function and vasomotor tone, adjust vascular permeability, and preserve blood fluidity. Thus, generalized endothelial dysfunction plays a significant role in the pathophysiology of heart failure. Dysregulation of the communication between cardiac endothelial cells and cardiomyocytes has been implicated in the development of cardiac structural and functional abnormalities.31

Consistency was observed between echocardiographic demonstration of the positive treatment effect of MPCs on LVEF at 12 months and the decrease in TTFE composite MACE over a mean follow-up of 30 months. The improvement in LVEF seems to be driven predominantly by reductions in LVESV (a measurement of LV contractile state).

Improvement in early left ventricular systolic function appears to strongly support MPCs’ proposed mechanisms of action, which include improvement in the cardiac microvasculature with subsequent translation to left ventricular systolic functional recovery and long-term reduction in MACE.