Preclinical Diastolic Dysfunction

Abstract

Preclinical Diastolic Dysfunction (PDD) has been broadly defined as subjects with left ventricular diastolic dysfunction, without the diagnosis of congestive heart failure (HF), and with normal systolic function. PDD is an entity which remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic heart failure including dyspnea, edema, and fatigue. In diabetic patients and patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared to patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients’ morbidity and mortality. This review will focus on what is known concerning preclinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed.

INTRODUCTION, DEFINITIONS, AND RELEVANCE

Heart failure (HF) is an epidemic affecting 5.1 million American adults based on 2013 estimates, and this epidemic will grow 25% by 2030 as the United States population continues to age.(1) Heart failure is a clinical diagnosis.(2) An ejection fraction (EF) of <50% in a patient with heart failure symptoms is termed heart failure with reduced ejection fraction (HFrEF), and an EF of ≥50% in a patient with heart failure symptoms is termed heart failure with preserved EF (HFpEF). Studies have demonstrated that HFpEF is as prevalent as HFrEF.(3) It is important to note that the above terms are not mutually exclusive as nearly all patients with systolic dysfunction have some degree of concomitant diastolic dysfunction.(4) Yet, the converse does not hold, which suggests the unclear relationship between systolic dysfunction (SD) and diastolic dysfunction (DD).

While the endpoint of heart failure and clinical symptoms may be similar in both categories, the pathophysiology of SD and DD are quite different. For example, studies have indicated that while SD seems largely a disease of calcium handling, DD seems to be a disease of increased myofilament sensitivity to calcium.(5,6) This highlights the importance of continued research at the molecular and clinical level for DD to allow for greater understanding and development of effective treatment options.

The American College of Cardiology and American Heart Association (ACC/AHA) has staged heart failure into four categories.(7) Stage A is defined as high risk for HF without structural heart disease or symptoms of heart failure. Stage B is defined as structural heart disease without signs or symptoms of heart failure. Stage C is defined as symptomatic heart failure and stage D, heart failure refractory to treatment.

Preclinical diastolic dysfunction (PDD), defined as diastolic dysfunction with normal systolic function and no symptoms of HF, therefore, resides in stage B according to the ACC/AHA scheme. The importance of PDD is evident in that even after controlling for comorbidities, preclinical diastolic dysfunction has been shown to be associated with development of heart failure and is predictive of all-cause mortality.(4,8) Also, advanced diastolic dysfunction is associated with reduced quality of life and structural abnormalities that reflect increased cardiovascular risk.(9)

Despite the seemingly simplistic definition of PDD, truly understanding diastolic dysfunction, heart failure symptoms, and their relationship is exceedingly complex. This complexity stems from the fact that in addition to diastolic dysfunction, comorbid conditions, including pulmonary, renal, and hematologic dysfunction, play an important role in development of symptomatic heart failure. (Figure) It has been recognized that while some patients with normal EF may have overt HF symptoms or HFpEF, others may have marked impairment in diastolic function which may be associated with no symptoms or PDD.(10)

Figure 1. Cardiovascular and noncardiac risk factors in the development and progression of preclinical diastolic dysfunction (PDD) and heart failure with preserved ejection fraction (HFpEF).

Cardiovascular risk factors contribute to the development of preclinical diastolic dysfunction (Stage B). Both cardiovascular and noncardiac risk factors contribute to the progression from preclinical diastolic dysfunction to symptomatic heart failure with preserved ejection fraction (Stage C/D). While survival decreases dramatically in symptomatic heart failure, the duration of Stage A and B heart failure with regards to survival remains to be fully elucidated

Additionally, it has been shown that left ventricular function measured at rest can differ significantly from exercise tolerance and severity of heart failure symptoms.(11) Therefore, exercise intolerance has significant diagnostic implications. Cardiopulmonary exercise testing (CPX), including determination of peak oxygen uptake, is an objective method used to determine the functional capacity of a patient with heart failure and for determination of disease severity.(12) Recent literature has suggested the importance of measuring diastolic and peripheral function variables during exercise, which may not correlate to rest measurements, to better characterize heart failure severity.(13–15) Future studies in PDD should include exercise testing, which would allow for greater diagnostic accuracy, as well as advance the understanding of PDD.

ASSESSMENT OF DIASTOLIC DYSFUNCTION

While systolic function is well characterized by determinations of ejection fraction, diastolic function characterization of the heart’s stiffness, relaxation, and pressure changes is more difficult. Invasive measures of rate of left ventricular pressure decline, left ventricular relaxation time constant, and stiffness modulus can characterize diastolic function. Echocardiography as a common noninvasive imaging technique is useful in determining the presence of systolic dysfunction or diastolic dysfunction. In diastole, the left ventricle filling pattern consists of two phases: early (E) and late or atrial contraction (A). The E/A ratio is used as an estimate of the relaxation pattern of the ventricle. Furthermore, tissue Doppler imaging can be used to measure myocardial motion, specifically the amount the mitral annulus recoils towards the base during early diastole (e’). The left ventricular filling pressures can be estimated by the E/e’ ratio.

Diastolic dysfunction is categorized by Doppler echocardiographic findings into the following progression: mild (Grade I or Ia), defined as impaired relaxation without or with mild evidence of increased filling pressures respectively; moderate (Grade II), defined as impaired relaxation associated with moderate elevation of filling pressures or pseudonormal filling, and severe, defined as advanced reduction in compliance or reversible (Grade III) or fixed (Grade IV) restrictive filling.(16,17)

To better understand and characterize the pathophysiology of diastolic dysfunction, recent imaging research has focused on using echocardiographic strain rate imaging. As the apex of the heart stays relatively stationary during the cardiac contraction and relaxation cycle, the base move towards the apex during systole and retracts during diastole. Therefore, the velocity at the apex is zero while the velocity at the base during cardiac contraction and relaxation is maximum. By characterizing the rate of change of velocity throughout the heart, or the amount of deformity of cardiac muscle, strain rate can be calculated.(18) While strain rate imaging has not been officially incorporated into the diastolic classification algorithm, it has shown promise in differentiating between those with and without diastolic dysfunction.(19) However, recent evidence demonstrates that peak strain is not only dependent on ventricular relaxation, but also on restoring forces and early diastolic load as well.(20) Given the recent new evidence on limitations of using strain rate for characterizing ventricular relaxation, it remains to be seen how clinically useful strain rate imaging will be compared with traditional methods for diastolic dysfunction determination.

Cardiac magnetic resonance (CMR) imaging has long been used for assessment of systolic function, but recent efforts have been made to apply CMR techniques to evaluation of diastolic function. Tagged magnetic resonance imaging of the heart has the potential as a noninvasive technique to provide myocardial strain and deformation information. CMR offers tremendous spatial resolution advantages when compared with echocardiography, and can accurately assess left atrial size and trans-mitral flow.(21) However, the limited temporal resolution of MR imaging along with the high costs associated with its use compared to conventional echocardiography limits CMR’s widespread use.

EPIDEMIOLOGY OF PRECLINICAL DIASTOLIC DYSFUNCTION

Given the nuances in defining ventricular diastolic dysfunction and heart failure, and the lack of preclinical diastolic dysfunction as a common diagnostic code, exact measurements of PDD prevalence are difficult. Previously, Fischer et al. found an overall prevalence of diastolic abnormalities to be 11.1% in a randomly selected sample from the Monitoring Trends and Determinants on Cardiovascular Diseases (MONICA) project, and Kuznetsova et al. found an overall prevalence of 27.3% for diastolic dysfunction.(22,23) Despite the valuable diastolic dysfunction prevalence data provided by these studies, a limitation is that this data is for diastolic dysfunction as a whole without regard to symptoms, i.e. it does not distinguish between patients with PDD and those with HFpEF.

Currently, there are four original publications which have contributed most to our understanding of PDD epidemiology.(4,9,24,25)

Redfield et al. conducted a survey of 2042 randomly selected residents of Olmsted County, Minnesota aged 45 years and older from June 1997 through September 2000. Participants underwent Doppler echocardiographic assessment of systolic and diastolic function, and the presence of HF diagnosis was determined by review of the medical record.

Abhayaratna et al. conducted a cross-sectional survey of 1275 randomly selected residents of Canberra, Australia aged 60 to 86 years between February 2002 and June 2003. Participants underwent Doppler echocardiography and completed a self-administered questionnaire regarding their medical history which was cross-referenced with documentation in the medical records. Abhayaratna et al. found on echocardiography that 23.5% and 5.6% of the study population had mild and moderate-to-severe diastolic dysfunction, respectively.

In both studies, subjects with diastolic dysfunction but without a HF diagnosis by history or clinically were considered as having PDD.(4,9) Redfield et al. found, in the general adult population, a prevalence of 20.6% for mild PDD and a prevalence of 6.8% for moderate to severe PDD. High-risk groups, or patients ≥65 years old with diagnoses of hypertension or coronary artery disease, were found to have a higher prevalence of preclinical diastolic dysfunction: 47.6% for mild PDD and 16.5% for moderate to severe PDD (Table 1).(4)

Table 1.

Prevalence of preclinical diastolic dysfunction

	Preclinical Diastolic Dysfunction (PDD) %
Preclinical DD (Redfield)(4)
General Adult Population
All	27.4
Men	28.5
Women	26.4
High Risk Population*
All	64.1
Men	63.3
Women	64.7
Elderly Population in Central Italy (25)
Men
All	35.8
65–74 years	31.3
>74 years	44.2
Women
All	35.0
65–74 years	30.0
>74 years	44.0
Framingham Heart Study (24)
General Adult Population	36
Australian Population(9)
General Adult Population, PDD with moderate to severe DD	4.9

^*High risk population defined by Age ≥65 years and Hypertension or Coronary Artery Disease

Redfield et al. found that even among those subjects with moderate or severe diastolic dysfunction, less than half had recognized HF and the majority were therefore in the preclinical stage of disease. This result was consistent with the findings of Abhayaratna et al. who found that 86% of subjects with moderate to severe DD with normal EF were in the preclinical stage of disease as assessed by Framingham criteria. Abhayaratna et al. also found that 36% of these same patients were asymptomatic as judged by New York Heart Association classification.(4,9,26)

Similarly, Lam et al. found in the Framingham cohort of 1038 elderly patients that the prevalence of preclinical diastolic dysfunction was 36% using Doppler echocardiographic data and evaluating for heart failure symptoms of dyspnea, edema, and exertional fatigue.(24)

Both Redfield et al. and Abhayaratna et al. found that the prevalence of diastolic dysfunction increased with age; the presence of cardiovascular co-morbidities such as hypertension, obesity, coronary artery disease, history of myocardial infarction, and cardiomyopathies; diabetes; and systolic dysfunction. Abhayaratna et al. also found that clinical predictors of DD with normal EF included hypertension, angina, myocardial infarction, and obesity. They also reported that the rates of isolated DD, that is DD with normal EF, increased with age.(4,9) In the PREDICTOR investigation, an Italian population study of 1720 elderly subjects 65 to 84 years old, Mureddu et al. found that 35.4% of the population had PDD.(25) Doppler echocardiographic data was used to evaluate cardiac function, and heart failure was defined based on history and physical examination using the European Society of Cardiology (ESC) guidelines, with each subject evaluated by a panel of three cardiologists.

Another finding of Abhayaratna et al. was that moderate to severe DD with normal EF was independently associated with structural abnormalities (increased LV mass and left atrial volume) that reflect increased cardiovascular risk, with increased circulating amino-terminal proB-type natriuretic peptide concentrations, and with decreased quality of life.(9) Similarly, Redfield et al. determined that increasing severity of PDD was associated with higher mean LV mass index and mean left atrial volume index. Furthermore, multivariate analysis revealed that DD was predictive of all-cause mortality even when controlling for age, sex, and EF.(4)

Two additional comorbidities that have profound impact on diastolic dysfunction are chronic obstructive pulmonary disease (COPD) and anemia. COPD and heart failure are often comorbid conditions that make accurate diagnosis challenging, as the presenting symptoms for both these entities can be similar. However, lung pathology decreases cardiopulmonary reserve and may convey an overall poorer prognosis.(27,28) Anemia is also an important comorbid condition in cardiac dysfunction, stemming from hemodilution, decreased red blood cell production, and concurrent renal disease. Anemia has been shown to convey a worse prognosis to those with heart failure.(29)

Aging is one of the most profound factors that influences PDD and development of HFpEF. While the work of both Redfield et al. and Abhayaratna et al. show that diastolic dysfunction increases with age, this remains a topic requiring further exploration given the lack of age-adjusted reference standards for diastolic dysfunction measurements. A Better understanding of normal aging with regards to diastolic function would allow for greater understanding of PDD and subsequent development of HFpEF.

In summary, the prevalence of PDD in the general adult population is approximately 20 to 30%, with increasing age, coronary artery disease, cardiovascular comorbidities and diabetes as independent risk factors for development of PDD.

PATHOPHYSIOLOGY

Diastole encompasses the isovolumic relaxation and filling phases of the cardiac cycle and includes active and passive components. Diastolic filling of the left ventricle (LV) is generally biphasic, with rapid filling in early diastole and late filling is determined by atrial contraction, left atrial pressure, and LV operating chamber stiffness.(30) Diastolic dysfunction refers to abnormal mechanical properties of the myocardium and includes abnormal LV diastolic distensibility, impaired filling, and slow or delayed relaxation.(30) In DD, the ventricle cannot accept blood at low pressures and ventricular filling is slow or incomplete unless atrial pressure rises.(31) Therefore, there is an increased dependence on filling through atrial contraction and there are higher atrial pressures to maintain filling or cardiac output.(32–34) With regards to relaxation, any mechanism that interferes with actin-myosin cross-bridge detachment or with removing calcium from the cytosol can delay this process.(35)

Diastolic dysfunction during the late filling phase of diastole can be a result of increased LV operating stiffness (diastolic stiffness) which is determined mainly by myocardial mass and myocardial composition. In fact, numerous factors can influence LV stiffness including age, increased LV wall thickness relative to cavity size (such as in hypertension or aortic stenosis), intracellular changes in titin or microtubules, extracellular changes in collagen, and infiltration (e.g. amyloidosis).(35–39) In addition, neurohormonal and cardiac endothelial activity also modulate ventricular stiffness and relaxation.(31)

While left ventricular diastolic dysfunction is known to be associated with the development of LV hypertrophy (LVH), investigations in both human and animal models of hypertension suggest that early LV diastolic dysfunction may precede the development of LVH. Dupont et al. evaluated LV diastolic dysfunction in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis.(40) The authors reported that LV myocardial diastolic dysfunction precedes LVH in 3-week-old SHR rats and was associated with high diastolic [Ca²⁺]_i, possibly due to decreased SERCA 2a and p16-PLB protein levels. Previously, LV hypertrophy regression was identified as a relevant marker of significant improvement in LV diastolic function. Nevertheless, to this extent, the literature lacks consistent data. For instance, a previous double-blind, randomized trial reported significant LV hypertrophy regression with antihypertensive treatment (enalapril or nifedipine), but also reported little change in traditional Doppler diastolic parameters.(41) In contrast, an experimental LVH model which demonstrated beneficial effects of phosphodiesterase-5 inhibition on LVH failed to properly predict the results of the phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure (RELAX) study.(42,43) Future therapeutic studies are needed to determine whether the regression of LVH or the improvement of diastolic function would prevent the progression from PDD to HFpEF.

Additionally, recent evidence suggests that contractile dysfunction and myocardial remodeling may play a significant role in the pathophysiology of HFpEF. While contractile dysfunction is traditionally associated with HFrEF, Dunlay et al. showed that patients with HFpEF demonstrated progressive decline in ejection fraction over time.(44) However, this hypothesis will require further confirmatory investigations.

Interesting recent work in animal and human models have implicated titin isoform shifts, oxidative stress, nitric oxide synthase dysfunction, and myosin binding protein C in diastolic dysfunction. Titin isoform shift, or the overexpression of the stiff isoform of titin, has been found in endomyocardial biopsy samples of those with HFpEF.(45) In those with type 1 diabetes, advanced glycation end products and oxidative stress has been found to be associated with left ventricular dysfunction.(46) Nitric oxide is a known mediator of cardiac relaxation, and cardiac oxidation leading to uncoupling of cardiac nitric oxide synthase results in diastolic dysfunction.(47) Lastly, myosin binding protein C, a protein located in crossbridge zones of muscle sarcomeres, is important in regulating muscle contraction. Phosphorylation of this important protein leads to deregulations of cardiac muscle contraction and subsequent dysfunction of the ventricles.(48) Indeed, Paulus describes a paradigm shift in thinking of HFpEF as a process of comorbid conditions leading to a systemic inflammatory state and microvascular inflammation, rather than focusing on myocardial structure and function.(49)

NATURAL HISTORY OF PRECLINICAL DIASTOLIC DYSFUNCTION

Currently, there are only a few original publications which have specifically addressed the natural history of PDD.(50) Additionally, the natural history of PDD is largely determined by the underlying comorbidities which provide unique prognostic determinations to those with diastolic dysfunction. Mohammed et al. demonstrated that comorbidities among those with HFpEF led to different ventricular and vascular properties, resulting in unique routes along a natural history continuum.(51) Therefore, the evolution of PDD should be viewed in light of the underlying disease contributing to diastolic dysfunction.

Hypertension and peripheral vascular disease result in the progression of diastolic dysfunction via ventricular remodeling secondary to increased afterload. Kane et al. recently reported that longitudinal evaluation of participants in the population-based Olmsted County Heart Function Study (OCHFS) cohort revealed that left ventricular diastolic dysfunction is highly prevalent, tends to worsen over time, and is associated with advancing age.(8) The data suggests that persistence or progression of diastolic dysfunction is a risk factor for heart failure in elderly persons. Correa de Sa et al. reported that in a cohort of PDD patients, the two-year cumulative probability for development of HF according to Framingham criteria was 1.9%; however, the two-year cumulative probability for development of any HF symptoms was 31.1%.(50) It was also found that peripheral vascular disease and hypertension were independently associated with the progression of PDD to development of symptoms. The authors, therefore, speculated that ventricular-arterial interaction may be important for this progression.

Those with underlying renal disease are at higher risk of developing HFpEF given a chronically fluid-elevated state. In a cohort study by Vogel et al., 388 subjects were followed for a mean of 4 years to determine the progression of PDD to symptomatic heart failure.(52) Among those with PDD, at 1, 2, and 3 years of follow-up, the cumulative probabilities for development of symptomatic HF were 2.2%, 5.7% and 11.6 % respectively. Through both univariable and multivariable analyses, they showed that age, right ventricular systolic pressure, and renal dysfunction with glomerular filtration rate (GFR) <60 ml/min were independently associated with development of HF. Furthermore, those with PDD were more likely to develop atrial fibrillation (AF) and cardiac hospitalization for coronary artery disease (CAD), myocardial infarction (MI), or peripheral vascular disease (PVD). In addition, the three year mortality rate for PDD was found to be 10.1%.

Diabetics, especially among those with poorly controlled blood sugars, may develop diabetic cardiomyopathy, pathological changes leading to fibrosis and remodeling of cardiac muscle leading to increased left ventricular mass. In a recent study by From et al, a more specific PDD population was analyzed.(53) In this study, all diabetes mellitus patients with tissue Doppler imaging of diastolic function in Olmsted County, Minnesota from 2001–2007 were identified and followed to determine the probability of HF development.(53) Patients were excluded if they had a prior HF diagnosis. Overall, 1760 patients were included and 411 of these had PDD. The five-year cumulative probability of HF development among the PDD patients with diabetes was 36.9% compared to 16.8% for those without PDD. The one-year cumulative probability of HF development among the PDD patients with diabetes was 13.1% compared to 5.2% for those without PDD. Furthermore, the five-year cumulative probability of death among the PDD patients was 30.8% compared to 12.1% for those without PDD.

It was also determined that PDD was associated with the subsequent development of HF even after adjustment for age, sex, body mass index, hypertension, coronary artery disease, left atrial size, and LV muscle mass. In addition, for every 1 unit increase above 15 in the ratio of passive transmitral LV inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e’), there was a 3% greater likelihood of HF development.

In his editorial comments regarding the above-mentioned study by From et al., Dr. Greenberg emphasized the importance of realizing that there is now evidence showing a linearly increased risk for development of heart failure among diabetic patients based on E/e’.(54) In addition, he notes that diabetic patients with PDD who developed HF and/or died did so at rates that were similar to those reported previously for patients with asymptomatic LV systolic dysfunction.(55) While there have been studies that suggest that poor glycemic control among those with diabetes may increase progression to HFpEF, it remains not entirely clear if treating hyperglycemia will improve or reverse the condition.(56) PDD pathology, therefore, may not be directly related to hyperglycemia, but rather to oxidative stress and structural remodeling that occurs.

Coronary artery disease leads to ischemic cardiomyopathy, and subsequent cardiac remodeling results in heart failure development. Ren et al. also provided information regarding the natural history of PDD in a more specific population.(57) They looked at 693 subjects with coronary heart disease (defined as history of myocardial infarction, angiographic evidence of ≥ 50% stenosis in ≥1 coronary vessel, previous evidence of exercise-induced ischemia using treadmill electrocardiogram or stress nuclear perfusion imaging, or history of coronary revascularization), normal systolic function, and no history of HF. They found that 455 (66%) had normal LV diastolic function, 166 (24%) had mild LVDD, and 72 (10%) had moderate to severe LVDD. They also found that the presence of moderate to severe LVDD was strongly predictive of incident hospitalization for HF and death from heart disease.

Lam et al. studied the risk of development of heart failure for non-cardiac risk factors, such as hemoglobin, creatinine, and pulmonary function parameters.(24) They reported that with adjustment for established heart failure risk factors and the presence of cardiac systolic and diastolic dysfunction, subclinical renal impairment, pulmonary airflow limitation or anemia was associated with 30% increased risk of incident heart failure. These findings reinforce the importance of heart failure as a systemic, and not purely cardiac, disease. Diastolic dysfunction is a manifestation of systemic disease as there is a high association of non-cardiac death with DD. Supporting this concept, the I-Preserve Trial demonstrated that diabetes, COPD, and renal dysfunction were independent predictors of mortality and that among those HFpEF patients who died, there was a large proportion of non-cardiac deaths.(58) The most common cause of death in HFpEF patients is cardiac at 60%, with 26% from sudden death, 14% from heart failure, 5% from myocardial infarction, and 9% from stroke. However, 30% died from non-cardiac causes which include renal, respiratory, and infectious causes.

Chen et al. reported that uncontrolled hypertension, new onset atrial fibrillation, infection and myocardial ischemia were frequently present in patients presenting with incident HFpEF.(59) This would suggest that both cardiac and non-cardiac systemic insults may have a role in influencing the progression from PDD to HFpEF. Furthermore, McKie et al. reported that subjects with PDD have impaired renal endocrine response to acute volume load.(60)

In summary, the above studies do provide useful natural history data regarding PDD (Table 2). However, what remains unknown is the specific relationship between PDD and the progression to HFpEF. While many progress from PDD to HFpEF, it is unclear whether this relationship is linear, or how patients may revert to a preclinical state after developing HFpEF. There is a significant proportion of those with PDD who subsequently develop HFpEF. However, not all people with PDD progress, and those with the same degree of diastolic dysfunction can have vastly different clinical syndromes. This risk of progression to HFpEF appears to be higher among those with hypertension, peripheral vascular disease, renal dysfunction, CPOD, anaemia, diabetes or coronary heart disease. It is important to note that despite the important contributions by the data presented, disease progression in specific comorbid conditions remains poorly established. Based on the current data, we speculate that impairment in cardiovascular, pulmonary and renal reserve in response to systemic insult may be a central key in differentiating between those with PDD that progress to develop HFpEF and those that remain asymptomatic.

Table 2.

Natural history of preclinical diastolic dysfunction and subsequent progression to symptomatic heart failure

Study	Year	Population	Incidence of symptomatic HF development
Correa de	2010	PDD	2-year incidence HF development: 1.9% (2 year incidence of any HF symptom: 31.1%)
Vogel(52)	2012	PDD	1-year incidence HF development: 2.2% 2-year incidence HF development: 5.7% 3-year incidence HF development: 11.6%
From(53)	2010	PDD + DM	1-year incidence HF development: 13.1% 5-year incidence HF development: 36.9%
Ren(57)	2007	PDD + CAD	3-year incidence HF hospitalization: 8.4%
Lam(24)	2011	PDD + Noncardiac	4-year incidence HF development: 4%, 7%, 10% (0, 1, 2 noncardiac risk factors, respectively)
Kane(8)	2011	PDD (moderate to severe diastolic dysfunction)	1-year incidence HF development: 3% 3-year incidence HF development: 7% 5-year incidence HF development: 10%

Abbreviations: HF = heart failure; PDD = Preclinical Diastolic Dysfunction; DM = Diabetes Mellitus; CAD = coronary artery disease; Noncardiac includes Renal, Pulmonary, and Hematologic Factors.

From a physiological level, this suggests that cardiovascular, pulmonary and renal reserve as well as extra-cardiac oxygen delivery and utilization are important factors in development of symptoms. From a clinical standpoint, future investigations into frailty, processes that predispose one to greater stressor susceptibility, may serve as one of the keys to elucidating this relationship between PDD and HFpEF. Clearly, understanding diastolic dysfunction, including PDD, is essential to decreasing patients’ morbidity and mortality.

MANAGEMENT OF PDD

That which predisposes to the development of PDD is not necessarily identical to that which propagates the disease to symptomatic heart failure or HFpEF, although there may be significant overlap. In the epidemiology section, the development of PDD was found to be associated with established cardiovascular risk factors such as increasing age, coronary artery disease, hyperlipidemia, metabolic syndrome, peripheral vascular disease and diabetes. (Figure) Therefore, treatment of these risk factors may prevent development of PDD. However, once the diagnosis of PDD is established, the natural history section demonstrated that in addition to the cardiovascular comorbidities, non-cardiac risk factors such as renal impairment, pulmonary airflow limitation or anemia are involved in the progression of the disease to symptomatic HFpEF. (Figure) Hence, the management of PDD can be divided 2 main categories 1) Prevention of development of PDD; and 2) Prevention of progression of PDD to HFpEF.

Prevention of development of PDD

The current data suggests that patients with PDD are diverse, with very different cardiovascular comorbidities such as coronary artery disease, hyperlipidemia, metabolic syndrome, peripheral vascular disease and diabetes. Hence, the treatment or prevention of PDD needs to be tailored to the underlying cardiovascular comorbidities.

The work by Arnold et al. from the Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that an angiotensin-converting enzyme inhibitor for those at high cardiovascular risk reduced the risk of development of HF, especially among those with higher baseline blood pressures, with a relative risk of 0.67.(61) A sub-study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) assessed the relative effect of chlorthalidone, lisinopril, and amlodipine in preventing HF. It reported that diuretics are superior to calcium channel blockers in preventing HF in hypertensive individuals.(62) Indeed, these studies suggested that good hypertension control may lead to regression of PDD, although this requires further validation.(63) As discussed in the natural history section, diabetes contributes to progression of diastolic dysfunction. Iribarren et al. demonstrated that among those with diabetes, poor glycemic control may be associated with the development of heart failure, suggesting the importance of diabetes treatment for the prevention of diastolic dysfunction progression.(56)

There are several trials that studied the modulation of left ventricular diastolic dysfunction through pharmacological means. The Hong Kong diastolic heart failure study demonstrated that in an elderly group of heart failure patients with normal EF, diuretics in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker improved left ventricular diastolic function longitudinally and led to decreased NT-proBNP levels.(64) The Swedish Doppler-echocardiographic study (SWEDIC) showed that carvedilol resulted in echocardiographic improvements in those with HFpEF.(65) Studies are needed to determine the efficacy of these strategies in PDD to improve clinical outcomes.

Prevention of progression of PDD to HFpEF

Given the true paucity of PDD specific treatment trials and that PDD can progress to HFpEF, the following discussion will focus mainly on treatment of HFpEF. In a randomized, double-blind, placebo-controlled trial by the Digitalis Investigation Group, patients with heart failure and left ventricular ejection fraction (LVEF) >45% on digoxin had a risk ratio of 0.82 for the combined outcome of death or hospitalization due to worsening heart failure (95% confidence interval (CI) 0.63 to 1.07) compared to placebo.(66)

In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study, it was found that among patients with HF and LVEF >40%, candesartan compared to placebo had a moderate impact in preventing admissions for HF (p=0.014), yet no difference in rates of cardiovascular death.(67) In the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) study, patients with HF and EF ≥45% had no significant differences in outcomes between irbesartan and placebo, including a composite of all-cause mortality or hospitalization for a cardiovascular cause (p=0.35), the overall rate of death (p=0.98), and the rate of hospitalization for cardiovascular causes (p=0.44).(68)

In the randomized, double-blind, placebo-controlled Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study, it was found that in the perindopril group, there were improvements in functional class (p<0.030) and exercise capacity (p=0.011) as well as fewer hospitalizations for heart failure (p=0.033).(69)

The three ongoing, randomized, double-blind, placebo-controlled phase III trials regarding aldosterone antagonism in HFpEF are the ARCTIC-D, PIE-II, and TOPCAT trials. The Aldosterone-blockade Randomized Controlled Trial in CHF - Diastolic (ARCTIC-D) study examines the effects of spironolactone on collagen turnover and correlates that to measures of LV mass regression and diastolic function on MRI after 4 months of aldosterone blockade. The Pharmacological Intervention in the Elderly II (PIE-II) study examines the effects of spironolactone on exercise tolerance and quality of life in elderly patients with isolated HFpEF. The Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) study evaluates the effectiveness of spironolactone therapy in reducing all-cause mortality in patients who have heart failure with preserved systolic function.(70)

The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial results were recently published, and demonstrated that there was significant improvement of diastolic function based on echocardiographic measurements, but there were no significant improvements in exercise capacity, symptoms, or quality of life in patients treated with spironolactone.(71)

Finally, the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) study is a randomized, double-blind, placebo-controlled trial examining the effects of sildenafil on exercise capacity and clinical status in patients with HFpEF.(72) This study did not demonstrate a significant improvement in exercise capacity or clinical status with sildenafil administration among those with HFpEF.(43) However, even with therapeutic PDE5 levels, there were minimal increases in plasma cGMP. Further studies may focus on the upregulation of cGMP through increased production by the nitric oxide pathway or natriuretic peptide pathway.

Over the past several years, there have been investigations into the use of ranolazine, an inhibitor of the late sodium transmembrane current. This late sodium current diverts extracellular sodium away from the sodium calcium exchanger, therefore resulting in decreased intracellular calcium removal. It is thought that delayed removal of calcium leads to delayed relaxation and therefore, diastolic dysfunction. Recent evidence in rat models has also proposed an additional mechanism of action for ranolazine, by reducing atrial fibrillation in heart failure via increase in repolarization refractoriness and increase in conduction time.(73) Initial results are promising, and in mice models, ranolazine has been shown to reverse diastolic dysfunction.(74) The Ranolazine for the Treatment of Diastolic Heart Failure (RALI-DHF), a small proof of concept randomized double-blind trial, attempts to bridge the gap between basic science research and clinical application.(75) The recently published results from the RALI-DHF trial demonstrated that ranolazine infusion significantly reduced left ventricular end diastolic pressure from 21.3 to 19.1 mmHg, improved hemodynamic measurements such as in pulmonary capillary wedge pressure, without improvement in the relaxation parameter of rate of left ventricular pressure decline, E/e’ ratio, or NT-proBNP.(76) Further large human trials should better elucidate the efficacy of ranolazine for HFpEF and further studies are necessary before consideration of ranolazine use in the clinical setting.

As discussed in the pathophysiology section, nitric oxide synthase uncoupling can occur with depletion of its cofactor tetrahydrobiopterin and subsequently lead to diastolic dysfunction given impairment of cardiac relaxation. Recent promising work has shown that supplementation of tetrahydrobiopterin may prevent or reverse diastolic dysfunction in hypertensive mice.(47)

The use of antifibrotic agents has also been studied in rat models and recent work has been promising. Tranilast, a medication for asthma and other allergic disorders, has antifibrotic activity via inhibition of collagen synthesis in fibroblasts. It has previously been studied for prevention of restenosis after coronary revascularization with mixed results.(77) Among diabetic rats, tranilast prevented development of diastolic dysfunction.(78) Given the physiological action of this agent, it may also prevent progression of PDD.

Atrial dyssynchrony has been proposed as a potential mechanism causing HFpEF. In a series of cases, Eicher et al. demonstrated that interatrial mechanical delay was present among 59% of subjects with HF with preserved ejection fraction, but none in control subjects.(79) This led to the proposal of atrial resynchronization therapy for treatment of HFpEF as well as prevention of atrial fibrillation development.(80) Furthermore, Kim et al. demonstrated that left ventricular dyssynchrony may also play an important role in diastolic dysfunction, both among those with HF symptoms (HFpEF) and without (PDD).(81)

The use of B-type natriuretic peptide (BNP) in PDD has also been studied. Recent evidence has shown that impairment in renal endocrine and natriuretic response may contribute to the underlying physiology of PDD. Following volume expansion, subjects with PDD were less able to adapt given decreased urinary excretion of cyclic guanosine monophosphate (cGMP) and sodium. In the setting of left ventricular diastolic dysfunction, a state of low levels of cGMP and high oxidative stress exists. Given this pathophysiological mechanism, McKie et al. showed that administration of subcutaneous BNP may restore the normal physiological cGMP and sodium excretion post volume expansion.(60)

Neprilysin is an enzyme that degrades biologically active natriuretic peptides including B-type natriuretic peptide (BNP). NT-proBNP, which can serve as a marker of heart failure severity, is not affected by neprilysin. Therefore, neprilysin inhibitors enhance the concentration and effects of endogenous BNP and may lead to improved cardiac function. In a recent multicenter, randomized, double-blind trial of 266 subjects with HFpEF, those given an angiotensin receptor neprilysin inhibitor had significantly lower NT-proBNP levels after 12 weeks compared to those who received valsartan.(82)

GAPS IN KNOWLEDGE/AREAS FOR FUTURE RESEARCH

As noted above, there are very few original studies which have focused on PDD. As a result, PDD as an entity remains poorly understood. While the baseline characteristics of clinical DD have been established, the only natural history studies to date (Correa de Sa et al., Vogel et al., Kane et al.) that are focused broadly on PDD were limited by a small, enriched population.(4,8,9,50,53) These and the work by From et al., Ren et al., and Lam et al. are the only studies at present that have focused closely on the progression of PDD to heart failure and the associated risk factors for this progression.(24,53,57)

It remains unknown what the specific relationship is between PDD and the progression to HFpEF. Hence, future prospective natural history and physiological studies are needed to better define the mechanisms of progression of PDD to HFpEF.

The current data suggests that patients with PDD are diverse, with very different cardiovascular comorbidities such as coronary artery disease, hyperlipidemia, metabolic syndrome, peripheral vascular disease and diabetes. Hence, the treatment for PDD needs to be tailored to the underlying cardiovascular comorbidities.

In addition to the cardiovascular comorbidities, non-cardiac risk factors such as renal impairment, pulmonary airflow limitation and anemia are suggested to be involved in the progression of PDD to symptomatic HFpEF. Hence, we hypothesize that while therapeutic strategies focusing on cardiovascular comorbidities have not been shown to be effective in improving outcomes in HFpEF, therapeutic strategies aimed at both systemic and cardiovascular comorbidities may play a crucial role in delaying the progression from PDD to HFpEF, as well as improve outcomes in patients with HFpEF. This hypothesis needs to be tested in clinical trials comparing PDD patients with patients with HFpEF.

CONCLUSIONS

Although preclinical diastolic dysfunction remains poorly understood, it has clear clinical significance. PDD is prevalent and has been shown to progress to overt heart failure (HFpEF). In the setting of a worsening heart failure epidemic, further PDD research will be essential to better characterize this entity, to identify risk factors for progression to overt heart failure, and to identify therapeutic interventions to delay the progression to HFpEF.

ABBREVIATIONS

PDD

preclinical diastolic dysfunction

HF

heart failure

EF

ejection fraction

HFrEF

heart failure with reduced ejection fraction

HFpEF

heart failure with preserved ejection fraction

SD

systolic dysfunction

DD

disastolic dysfunction

LV

left ventricle

GFR

glomerular filtration rate