Clinical management of dilated cardiomyopathy: current knowledge and future perspectives

ABSTRACT

Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by a progressive dilation and dysfunction of either the left or both ventricles. The management of DCM is currently challenging for clinicians. The persistent lack of knowledge about the etiology and pathophysiology of this disease continues to determine important fields of uncertainty in managing this condition. Molecular cardiology and genetics currently represent the most crucial horizon of increasing knowledge. Understanding the mechanisms underlying the disease allows clinicians to treat this disease more effectively and to further improve outcomes of DCM patients through advancements in etiologic characterization, prognostic stratification and individualized therapy. Left ventricular reverse remodeling predicts a lower rate of major cardiac adverse events independently from other factors. Optimized medical treatment and device implantation are pivotal in inducing left ventricular reverse remodeling. Newly identified targets, such as angiotensin–neprilysin inhibition, phosphodiesterase inhibition and calcium sensitizing are important in improving prognosis in patients affected by DCM.

KEYWORDS:

• Dilated cardiomyopathy
• left ventricular reverse remodeling
• phosphodiesterase inhibitors
• LCZ-696

Dilated cardiomyopathy: the etiologic characterization problem

Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by the progressive dilation and dysfunction of the left ventricle (or both ventricles), in the absence of abnormal pressure or volume overload or coronary artery disease, which can explain the dysfunction themselves.[1] Once symptoms develop, DCM usually leads to decompensated heart failure (HF) and it represents one of the most common causes of heart transplantation (HTx) in the Western world.[2] On the other hand often life-threatening arrhythmias and sudden cardiac death (SCD) can importantly characterize the course of DCM or represent the abrupt onset of the disease.[3]

Management of DCM is currently particularly difficult for the clinicians. DCM is fairly common (as reported by Hershberger et al., its prevalence is approximately 1 in 250 people [4]) and it affects relatively young patients with theoretically long life expectancy. Moreover, the persistent lack of knowledge about the etiology and pathophysiology of the disease continues to determine important fields of uncertainty (e.g. early arrhythmic risk stratification, the consequences of genetic mutations found in healthy relatives and the duration of treatment in apparently normalized patients) and the absence of unique classification.[5,6] An important effort toward the early and multiparametric etiological characterization and prognostic stratification appear to be of paramount importance in the clinical management of DCM patients. Etiologically speaking, DCM is the final common pathway of several heart diseases leading to HF. According to the current European Society of Cardiology Classification,[1] DCM is defined as familial and nonfamilial forms. Among the nonfamilial forms, numerous different agents (i.e. uncontrolled hypertension, alcohol or drug abuse, supraventricular sustained tachyarrhythmia, anti-neoplastic chemotherapy and acute myocarditis) might be responsible for the disease. Noteworthy, they should be identified early, since, once removed by an etiology-specific therapy (including antiviral or immunosuppressive agents when indicated), a regression of the disease can be observed. Accordingly, an etiological characterization of the condition underlining the disease appears to be the most important tool for improving the management and long-term prognostic stratification of these patients. Hereof, an integrated approach, including cardiac magnetic resonance and endomyocardial biopsy when indicated, should be performed systematically. On the other hand among the familial forms of DCM, approximately 30–50% of patients are carriers of genetic mutations. To date, more than 30 genes causative of DCM have been identified and some of them are in common with other conditions, such as the hypertrophic and the restrictive cardiomyopathy.[3] Unfortunately the increasing knowledge in the genetics of DCM has currently few clinical repercussions due to the lack of genotype–phenotype correlation studies. Apart from LMNA A/C no other genes have been clearly associated with a specific phenotype in DCM. Finally, in a relevant number of DCM patients, a causative condition continues to be hardly ever identified. These patients are affected by the so-called idiopathic DCM mostly due to de novo unknown mutations or post-inflammatory chronic processes. Idiopathic DCM patients reflect our inability in defining the real cause underlining the disease and up to date, even those presenting peculiar features, continue to be treated as if they are affected by the generic syndrome named nonischemic cardiomyopathy.

Left ventricular reverse remodeling: the concept of dynamic disease

In the last years, the concept of DCM as a dynamic (and not exclusively progressive) disease emerged, with important repercussions on the global clinical management of those patients.

Indeed, in the previous century, the prognosis of DCM was highly adverse. Mortality was about 50% at 2 years following the diagnosis.

However, during the last 30 years, a dramatic decrease in mortality has been observed. This reflects: (1) the efficacy of the progressively prompter diagnosis, in a less advanced stage of the disease, achieved by systematic familial screening [7] and, mostly, by (2) the improved efficacy of pharmacological and device treatment. In a large cohort of an Italian DCM population from the Heart Muscle Diseases Registry of Trieste, it has been shown that nowadays the incidence of major adverse cardiac events in patients affected by DCM is less than 2% per year, the survival free of transplantation at 8 years from diagnosis is more than 85% and the incidence of SCD is less than 0.5% per year.[2]

Pharmacological treatment is the cornerstone for preventing the progression of the disease. According to the most recent guidelines, ACE-I, β-blockers and mineralocorticoid antagonists are the pillar therapeutic agents demonstrated to improve survival in patients affected by HF. On the other hand, device treatment (i.e. implantable cardioverter defibrillator and cardiac resynchronization therapy (CRT)) significantly contribute to decrease the rates of SCD and global mortality.[3] Treating comorbidities such as anemia, rare but possible, also appears to be significant in patients affected by DCM.[8]

Currently, however, the best management strategy appears to be characterized by a combination of early diagnosis and the identification of high-risk patients, together with the long-term, continuous, individualized surveillance of DCM patients. In fact several parameters have been identified to predict outcomes in patients affected by DCM, such as systolic dysfunction and New York Heart Association (NYHA) functional class at diagnosis.[9,10] Other variables, including functional mitral regurgitation (FMR), diastolic dysfunction and left bundle branch block (LBBB) or right ventricular (RV) dysfunction, are important indicators of worse outcomes in patients affected by DCM.[11] However their progression or regression during follow-up appears to be more useful prognostic tools than their presence at baseline.[12]

The key determinant of the treatments’ efficacy is the prevention and reversal of the cardiac remodeling. The concept of cardiac remodeling encases many changes occurring during the natural history of HF. Changes in genome and molecular expression lead to phenotypic and clinical manifestation. Pressure and volume overload and neurohormonal hyperactivation are involved in the process of cardiac remodeling.

Likewise, the myocardial extracellular matrix (ECM) results stiffer by the increased deposition of ECM components, principally collagen, with increased fibrils diameter and collagen cross-linking, an increased ratio of type I to type III collagen, and a decreased elastin content.

Cardiomyocyte apoptosis and necrosis, coupled with a low rate of myocardial renewal, appear to be important motely contributors of this process.[13]

In addition, microvascular damage, intrinsic abnormalities in myocardial blood flow, LBBB and RV pacing responsible for mechanical dyssynchrony and deterioration of coronary flow dynamics contribute to adverse remodeling.[14]

Although for years this process appeared to be unfavorable and irreversible, in the last decade, several studies have identified how this process can be stopped and potentially reversed. In patients affected by iDCM, early treatment can be incredibly beneficial in order to reverse this vicious process of cardiac remodeling.

Studies of both adults and children have reported a recovery of cardiac function in 21–37% of patients, as indicated by serial echocardiograms.[15]

Left ventricular reverse remodeling (LVRR) appears to predict a lower rate of major cardiac adverse events independently from other factors, such as NYHA class or FMR.[12] It is mostly induced within the first 6 months of optimal medical treatment,[16] but can be completed at 24 months.[12]

CRT can also induce LVRR by reducing in microvascular resistance and improving coronary blood flow.[17] Recently, Stolfo et al. demonstrated that CRT in DCM patients could induce acute hemodynamic improvement with subsequent stable FMR degree decrease and improved transplant-free survival.[18] CRT seems to promote LVRR at the molecular and cellular levels. Experimental studies have demonstrated that LVRR is dictated by decreases in extracellular matrix gene expression and the decreased activities of caspase −3, −8 and −9, and the inhibition of myocardial apoptosis coupled with a significant increase in calcium handling proteins and adenylate cyclase gene expression.[19]

Another important therapeutic option might be the correction of FMR. Hence, the introduction of novel device therapy, such as Mitraclip, could contribute to improve the outcomes of DCM patients. However further studies are necessary in order to identify the adequate selection of patients and timing for Mitraclip procedure in this subset of patients.

Moreover, cardiosphere transplantation enhances angiogenesis and reduces fibrosis, leading to partial reversal of cardiac dysfunction through the inhibition of Tgf-β1/smad signaling by CSp-secreted soluble endoglin and through paracrine effects.[20]

It is however fundamental to remember that long-term studies demonstrates that DCM patients with initial LVRR or even persistent long-term normalization of LVEF induced by medical or resynchronization therapy have a trend toward worsening of LV function or arrhythmic events in the very long term,[21] highlighting the importance of uninterrupted medical therapy and follow-up in those patients.

Future therapeutic perspectives

A recent and revolutionary trial marshaled within the clinical arena LCZ-696, a new combination drug of valsartan and sacubitril, demonstrating favorable effects in the reduction death or hospitalization for HF by over 20% on top of optimized medical treatment in patients affected by HF with reduced ejection fraction.[22]

Moreover, a recent study underlined the role of milrinone, a phosphodiesterase-3 inhibitor (PDE3i) in children, but not in adults, affected by iDCM. Actually, elevated level of cAMP and phosphorylated-phospholamban (pPLB) in children may contribute to the hemodynamic benefit seen in those patients.[23]

Despite the controversial role of cell therapy and the apparent lack of a consensus regarding the mechanism underlining the potential effects of this treatment, its efficacy needs to be further investigated in the setting of DCM.[24]

Likewise, in animal studies, gene therapy showed potential beneficial effects in the settings of nonischemic heart failure.[25] Hence further spotlights might be directed toward this field of research.

In addition, in experimental studies the Ca2+ sensitizer/PDE3i Pimobendan prevents the progression of cardiac dysfunction introducing new targets for medical therapy.

Molecular cardiology and genetics currently represent the most important fields of increasing knowledge in order to further improve the outcomes of DCM patients through advancements in etiologic characterization, prognostic stratification and individualized therapy.

In conclusion, given the current knowledge of DCM, the main goal of actual research is to better understand the mechanism underlying the disease, to improve survival and to guide our Beating Wayfarer on the road to better prognosis averting from HF.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

ORCID

Antonio Cannatà http://orcid.org/0000-0001-7609-6297

Gianfranco Sinagra http://orcid.org/0000-0003-2700-8478