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Background: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%. Methods: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. Results: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control ( P =0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group ( P =0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group ( P =1.0). Conclusions: In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT02600234.

Background: Cardiac amyloidosis is characterized by progressive ventricular thickening and diastolic heart failure. The left ventricular ejection fraction (EF) often remains normal even in advanced disease. The myocardial contraction fraction (MCF, the ratio of left ventricular stroke volume to myocardial volume) is a novel measure of myocardial shortening and may be superior to EF for predicting survival in cardiac amyloidosis. Methods: We measured MCF and EF from two-dimensional echocardiograms obtained in 86 subjects undergoing heart transplant evaluation for AL cardiac amyloidosis. Cox proportional hazards models and Kaplan-Meier survival analysis were used to compare MCF and EF as predictors of all-cause mortality. Subjects were censored at the time of heart transplant. Results: The mean age was 54.6 ± 7.9 years. The mean EF was 49.3 ± 12.7% and the mean MCF was 13.0 ± 5.5%. Over a median follow-up of 59 days (IQR 29-110 days), 38 subjects (44.2%) died and 48 (55.8%) underwent heart transplant. In unadjusted analyses, both MCF (HR 0.89, 95% CI 0.82-0.96, p = 0.002) and EF (HR 0.96, 95% CI 0.94-0.99, p = 0.015) predicted overall survival. In multivariate analyses adjusted for serum free light chain difference, the hazard ratio associated with each 5% absolute decrease in MCF was 2.11 (95% CI 1.32-3.38, p= 0.002). The hazard ratio associated with each 5% absolute decrease in EF was not statistically significant (HR 1.16, 95% CI 0.97-1.39, p=0.09). Conclusions: Myocardial contraction fraction is superior to EF for predicting survival in patients undergoing heart transplant evaluation for AL cardiac amyloidosis.

Background— The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results— Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (−42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (−54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, −71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, −15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, −13.0±1.9%; isovolumic relaxation time, −14.0±1.7%; septal mitral annulus velocity, −76.4±9.2%). Results were similar at 12 months. Conclusions— The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01156636.

Background— The pathophysiology of diastolic heart failure (DHF) is poorly understood. One potential explanation is an active fibrotic process that produces increased ventricular stiffness, which compromises filling. The present study investigates collagen metabolism in hypertensive patients in different phases of diastolic function with and without proven DHF. Methods and Results— We studied 86 hypertensive patients divided into groups according to the presence of DHF (32 with, 54 without) and phase of diastolic function (20 with normal function, 38 with impaired relaxation, 10 with pseudonormalization, and 16 with restrictive-like filling). Serum carboxy-terminal, amino-terminal, and carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, matrix metalloproteinases (MMPs; total MMP-1, active MMP-2, and MMP-9), and tissue inhibitor of MMPs levels were assayed by radioimmunoassay and ELISA. Doppler-echocardiographic assessment of diastolic filling was made with measurements of E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Serum carboxy-terminal telopeptide of procollagen type I, carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 levels ( P P P =0.008), and MMP-2 ( P =0.03) were greater in more severe phases of diastolic dysfunction. Within phases of diastolic dysfunction, serum carboxy-terminal telopeptide of procollagen type I, amino-terminal propeptide of procollagen type III, MMP-2, and MMP-9 were elevated in those with DHF compared with those without DHF (all P Conclusions— These data demonstrate serological evidence of an active fibrotic process in DHF, which is more marked in more severe diastolic dysfunction. This observation may help explain the pathophysiology of DHF and may suggest new avenues for diagnostic and therapeutic intervention.

In contrast to systolic heart failure (SHF), for which knowledge of pathophysiology and therapy has advanced rapidly over the past decade, little is known about diastolic heart failure (DHF). The article by van Heerebeek et al1 in this issue of Circulation that describes an abnormal distribution of titin isoforms in DHF may herald a new approach to understanding the pathophysiology of this syndrome. Article p 1966 Recognition of 2 forms of heart failure is not new; almost 70 years ago, Fishberg2 described “those forms of cardiac insufficiency which are due to inadequate diastolic filling of the heart (hypodiastolic failure) [and] the far more common ones in which the heart fills adequately but does not empty to the normal extent (hyposystolic failure)” (p 23). This distinction has stood the test of time, because there is a growing consensus that these 2 clinical syndromes differ in epidemiology, demographics, and origin. Because DHF and SHF represent subgroups of patients with heart failure, they share many clinical features, notably the hemodynamic findings, but it is now clear that they are caused by different pathophysiological mechanisms. Hearts in SHF are characterized by eccentric hypertrophy, progressive left ventricular (LV) dilation, and abnormal LV systolic properties, whereas in DHF, the hearts generally exhibit concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function.3,4 In addition, cardiomyocyte size, shape, and molecular composition differ in these 2 syndromes. Diastolic dysfunction refers to mechanical and functional abnormalities present during relaxation and filling, whereas DHF refers to clinical syndromes in which patients with heart failure have little or no ventricular dilatation and significant, often dominant diastolic dysfunction. Diastolic dysfunction can be quantified with indices of LV pressure decline and filling. Abnormal pressure decline is characterized by decreased peak −dP/dt, prolonged isovolumic time constant (τ), and …

Background— To support the clinical distinction between systolic heart failure (SHF) and diastolic heart failure (DHF), left ventricular (LV) myocardial structure and function were compared in LV endomyocardial biopsy samples of patients with systolic and diastolic heart failure. Methods and Results— Patients hospitalized for worsening heart failure were classified as having SHF (n=22; LV ejection fraction (EF) 34±2%) or DHF (n=22; LVEF 62±2%). No patient had coronary artery disease or biopsy evidence of infiltrative or inflammatory myocardial disease. More DHF patients had a history of arterial hypertension and were obese. Biopsy samples were analyzed with histomorphometry and electron microscopy. Single cardiomyocytes were isolated from the samples, stretched to a sarcomere length of 2.2 μm to measure passive force (F passive ), and activated with calcium-containing solutions to measure total force. Cardiomyocyte diameter was higher in DHF (20.3±0.6 versus 15.1±0.4 μm, P P passive (7.1±0.6 versus 5.3±0.3 kN/m 2 ; P passive was larger ( P Conclusions— LV myocardial structure and function differ in SHF and DHF because of distinct cardiomyocyte abnormalities. These findings support the clinical separation of heart failure patients into SHF and DHF phenotypes.

Received March 31, 2005; revision received July 15, 2005; accepted July 21, 2005. In diastolic heart failure, the left ventricular (LV) ejection fraction (EF) is normal and there is increased passive stiffness with impaired relaxation of the ventricle, resulting in disturbances in the pattern of filling and elevated diastolic pressure.1–3 The mechanism underlying such failure has been thought to be principally diastolic because LV diastolic function is universally abnormal and systolic performance, function, and contractility are normal.4 However, several reports suggest that abnormalities in regional shortening are present in diastolic heart failure.5–9 The significance of these findings, especially their relation to the syndrome of heart failure, remains uncertain. Accordingly, we will review some of the structural and functional differences between systolic and diastolic heart failure, and, emphasizing the systolic or contractile behavior of the left ventricle, we will attempt to reconcile what appear to be disparate conclusions about LV systolic function in patients with diastolic heart failure. The hearts of patients with systolic heart failure differ dramatically from those of patients with diastolic heart failure in regard to both gross and microscopic anatomic features. As will be seen, these anatomic differences tend to parallel physiological and functional differences in systolic and diastolic heart failure10,11 (Table 1). View this table: TABLE 1. LV Structure and Function in Chronic Heart Failure ### LV Chamber Remodeling Patients with diastolic heart failure generally exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by a normal or near-normal end-diastolic volume, increased wall thickness, and a high ratio of mass to volume with a high ratio of wall thickness to chamber radius.12 By contrast, patients with systolic heart failure exhibit a pattern of eccentric remodeling with an increase in end-diastolic volume, little increase in wall thickness, and a substantial decrease in the ratio …

Background: Heart failure with preserved ejection fraction remains a leading cause of hospitalization, without development of new medications and operative procedures to treat these patients. We hypothesize that trabeculae carneae serve an important role in modulating LV diastolic compliance, and during hypertrophy of the myocardium, trabeculae contribute to abnormal compliance. Methods and Results: Eight ex vivo human hearts from patients with LV diastolic dysfunction were perfused at 37[[Unable to Display Character: ⁰]]C and had a balloon inserted into the LV through the mitral annulus. Diastolic LV pressure-volume compliance curves were measured at baseline and following trabecular cutting. LV compliance improved significantly (n=6, p Conclusions: We demonstrate for the first time that rather than being an embryologic remnant, trabeculae carneae serve an important role in the maintenance of passive LV diastolic compliance, and can contribute to LV diastolic dysfunction. A new procedure, cutting trabeculae, is proposed to improve LV diastolic compliance.

Background— Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct HFpEF categories. Methods and Results— We prospectively studied 397 patients with HFpEF and performed detailed clinical, laboratory, ECG, and echocardiographic phenotyping of the study participants. We used several statistical learning algorithms, including unbiased hierarchical cluster analysis of phenotypic data (67 continuous variables) and penalized model-based clustering, to define and characterize mutually exclusive groups making up a novel classification of HFpEF. All phenomapping analyses were performed by investigators blinded to clinical outcomes, and Cox regression was used to demonstrate the clinical validity of phenomapping. The mean age was 65±12 years; 62% were female; 39% were black; and comorbidities were common. Although all patients met published criteria for the diagnosis of HFpEF, phenomapping analysis classified study participants into 3 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, invasive hemodynamics, and outcomes (eg, phenogroup 3 had an increased risk of HF hospitalization [hazard ratio, 4.2; 95% confidence interval, 2.0–9.1] even after adjustment for traditional risk factors [ P Conclusions— Phenomapping results in a novel classification of HFpEF. Statistical learning algorithms applied to dense phenotypic data may allow improved classification of heterogeneous clinical syndromes, with the ultimate goal of defining therapeutically homogeneous patient subclasses.

Background— No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. Methods and Results— We evaluated 137 patients with HF and an EF ≥0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21±12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, β-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P =0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153±45 versus 98±33 mg/dL, P P =0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P =0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P =0.082). Conclusions— Statin therapy may be associated with improved survival in patients with HF and a normal EF.

Received August 25, 2004; revision received December 23, 2004; accepted January 19, 2005. Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the “cardiorenal model”1), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the “cardiocirculatory” or “hemodynamic” model for heart failure,1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless “disease progression” that occurs in this syndrome. Thus, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure.1,2⇓ In the present review we will summarize recent advances in the field of heart failure, with a focus on the new therapeutic strategies that have been developed for treating systolic heart failure. For a complete discussion on recent advances in the diagnosis and treatment of diastolic heart failure, the interested reader is referred to several …

Background— Patients with diastolic heart failure (DHF) have significant abnormalities in left ventricular (LV) diastolic function, including slow and delayed relaxation and increased chamber stiffness. Whether and to what extent these abnormalities in diastolic function occur in association with abnormalities in LV systolic performance, function, and contractility has not been investigated thoroughly. Methods and Results— The systolic properties of the LV were examined in 75 patients with heart failure and a normal ejection fraction (ie, DHF) and 75 normal control subjects with no evidence of cardiovascular disease. LV systolic properties were assessed with echocardiographic and cardiac catheterization data. Stroke work (an index of LV systolic performance), preload recruitable stroke work and ejection fraction (indices of LV systolic function), systolic stress-shortening relationship, end-systolic pressure-volume relationship, and peak (+)dP/dt (indices of LV contractility) were examined. The systolic properties of the LV were normal in patients with DHF. Stroke work was 8.4±2.3 in DHF versus 8.8±2.5 kg · cm in controls ( P =0.26). Preload recruitable stroke work was 99±22 in DHF versus 109±18 g/cm 2 in controls ( P =0.13). The relationship between stroke work and end-diastolic volume was similar in DHF and controls. Peak (+) dP/dt was 1596±362 in DHF versus 1664±305 mm Hg/s in controls ( P =0.54). The end-systolic pressure-volume relationship was increased in DHF. The systolic stress versus endocardial fractional shortening relationship was similar in DHF and controls. Conclusions— Patients with DHF had normal LV systolic performance, function, and contractility. The pathophysiology of DHF does not appear to be related to significant abnormalities in these systolic properties of the LV.

Background— Heart failure (HF) with normal ejection fraction (diastolic HF [DHF]) usually occurs in elderly patients with hypertension. The presence and significance of altered systolic and diastolic ventricular function in DHF is increasingly controversial. Our objective was to develop a clinically relevant large-animal model to better understand the pathophysiology of DHF. Methods and Results— Ventricular structure and function were characterized in young control (YC group; n=6), old control (OC group; n=7), and old dogs made hypertensive by renal wrapping (experimental DHF [ExDHF] group; n=8). The ExDHF group was associated with normal left ventricular (LV) volume, increased LV mass, and myocardial fibrosis. LV relaxation was impaired in ExDHF (τ=53±6 ms) compared with OC (τ=35±3 ms; P P P P Conclusions— Aged dogs with chronic hypertension exhibit LV hypertrophy and fibrosis with impaired LV relaxation but no increase in the coefficient of LV diastolic stiffness. LV systolic and arterial stiffness are increased, which may exacerbate load-dependent impairment of relaxation and contribute to increased filling pressures with hypertensive episodes. This model mimics many of the structural and functional characteristics described in the limited studies of human DHF and provides insight into the pathogenesis of DHF.

Background— Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. Methods and Results— DHF patients (n=12) had an LVEF of 71±11%, an LV end-diastolic pressure (LVEDP) of 28±4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5±4.0%, P 2+ ]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca 2+ ], but their resting tension ( F passive ) in the absence of Ca 2+ was almost twice as high (6.6±3.0 versus 3.5±1.7 kN/m 2 , P F passive and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered F passive to control values. Conclusions— DHF patients had stiffer cardiomyocytes, as evident from a higher F passive at the same sarcomere length. Together with CVF, F passive determined in vivo diastolic LV dysfunction. Correction of this high F passive by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.

Background— Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results— Thirty medically treated ambulatory hypertensive patients (19 women, age 62±6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31±5 kg/m 2 ) with reduced treadmill exercise capacity (6.7±2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133±17/80±7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: −1.57±0.46 s −1 versus 6-months: −1.91±0.36 s −1 , P P P =0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months ( P =0.05, P =0.02, and P =0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness ( P =0.04) and a trend to reduced left atrial area ( P =0.09). Conclusions— Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Background — The definition of diastolic heart failure (DHF) relies on the use of sensitive tools to exclude the presence of systolic dysfunction. The use of ejection fraction (EF) of 50% as the cutoff point may not be adequate to address such a task. We believe that systolic dysfunction is common in DHF. Methods and Results — Echocardiography with tissue Doppler imaging was performed in 339 subjects, of whom 92 had systolic heart failure (SHF) (EFM ) and early diastolic (E M ) velocities were significantly lower in patients with SHF, DHF, and DD than in control subjects in almost all the myocardial segments. Likewise, the mean S M (SHFP ≤0.001) and mean E M (SHF=DHFP M of 4.4cm/s (−2 SD of control subjects) predicted the presence of systolic dysfunction in 92% of patients with SHF, 52% with DHF, and 14% with DD. Conclusions — Through the use of tissue Doppler imaging, systolic abnormalities were evident in patients previously labeled as DHF and to a much lesser extent, isolated DD. This indicates the common coexistence of systolic and diastolic dysfunction in a spectrum of different severity in the pathophysiological process of heart failure.

Patients with heart failure with preserved ejection fraction (HFpEF) have an increased mortality and morbidity similar to patients with systolic heart failure and reduced ejection fraction.1 The incidence of HFpEF is increasing,2 and roughly 30% to 50% of all patients with heart failure have a normal ejection fraction.3 The underlying pathophysiology is increased left ventricular diastolic stiffness that leads to high filling pressures.4,5 Additionally, left ventricular hypertrophy,6 accumulation of cardiac collagen,7 endothelial dysfunction,8 a shift in titin isoform, and increased passive stiffness of cardiac myocytes9 all contribute to these changes. For reasons that are yet uncertain, a subset of patients with HFpEF will go on to develop pulmonary hypertension (PH). Patients with HFpEF and PH can be subdivided into those with a normal pulmonary vascular resistance (PVR) and those with an increased PVR and pulmonary arterial remodeling. In fact, patients with HFpEF account for a significant percentage of patients with PH and right-sided heart dysfunction.10 Article see p 164 Importantly, both PH and right ventricular dysfunction are associated with decreased survival compared with HFpEF patients without PH.11 Although the underlying pathophysiology is poor left ventricular diastolic compliance, treatment focused on improving stiffness has been lacking, and management of patients with HFpEF has focused on control of factors known to exert effects on left ventricular end-diastolic pressure. The main emphasis has been on aggressive treatment of systemic blood pressure and heart rate, limiting pressure and volume overload of …

Background The diagnosis of diastolic heart failure is generally made in patients who have the signs and symptoms of heart failure and a normal left ventricular (LV) ejection fraction. Whether the diagnosis also requires an objective measurement of parameters that reflect the diastolic properties of the ventricle has not been established. Methods and Results We hypothesized that the vast majority of patients with heart failure and a normal ejection fraction exhibit abnormal LV diastolic function. We tested this hypothesis by prospectively identifying 63 patients with a history of heart failure and an echocardiogram suggesting LV hypertrophy and a normal ejection fraction; we then assessed LV diastolic function during cardiac catheterization. All 63 patients had standard hemodynamic measurements; 47 underwent detailed micromanometer and echocardiographic-Doppler studies. The LV end-diastolic pressure was >16 mm Hg in 58 of the 63 patients; thus, 92% had elevated end-diastolic pressure (average, 24±8 mm Hg). The time constant of LV relaxation (average, 51±15 ms) was abnormal in 79% of the patients. The E/A ratio was abnormal in 48% of the patients. The E-wave deceleration time (average, 349±140 ms) was abnormal in 64% of the patients. One or more of the indexes of diastolic function were abnormal in every patient. Conclusions Objective measurement of LV diastolic function serves to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without the measurement of parameters that reflect LV diastolic function.

Congestive heart failure (CHF) is a major public health problem in developed countries.1 2 3 It is a significant burden to patients, healthcare providers, and society.2 3 4 Several hospital-based reports have documented that a high proportion of patients with CHF have normal left ventricular (LV) systolic function,5 and 4 different epidemiological investigations further confirmed that nearly half of CHF subjects in the community have normal LV systolic function.6 7 8 9 This condition is commonly referred to as diastolic heart failure (DHF). Hospital readmission rates for patients with DHF are similar to those for patients with systolic heart failure (SHF),10 and it is estimated that DHF accounts for ≥25% of the total cost of CHF, which is estimated at $15 to $40 billion annually.4 11 A distinction between DHF and SHF is important because DHF is associated with better long-term survival5 and because these 2 forms of heart failure require different therapeutic approaches. Although the societal burden of DHF is high and its economic impact substantial, it is intriguing that most national and international guidelines either do not consider the condition12 13 or underscore that a paucity of information about it precludes any definitive therapeutic recommendations.14 Numerous clinical trials have documented the benefits of treatment for SHF; however, the optimal treatment for DHF has not yet been defined. The first step toward evaluating any potential treatment for DHF is to develop uniform criteria for its diagnosis. This task, however, is complicated by the pathophysiological heterogeneity of DHF11 and by the limitations of currently available noninvasive modalities for diagnosing LV diastolic dysfunction.5 Heart failure is defined as “a pathophysiological state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a …

Diastolic dysfunction contributes significantly to the clinical syndrome of congestive heart failure in the settings of both preserved and impaired left ventricular (LV) systolic function.1,2 Over the past 20 years, the clinical diagnosis of diastolic dysfunction has been based largely on echocardiographic Doppler parameters of LV filling.3 The most important limitation of these parameters is their dependence on loading conditions. New practical and comprehensive methods of evaluating diastolic function are critically needed not only for diagnosis but also for testing emerging new therapies. Article p 2524 Recent work has elucidated both intracellular and extracellular mechanisms that contribute to diastolic dysfunction, and some progress has been made in finding new treatments for diastolic heart failure. Additional research has evaluated the contribution of LV architecture and its role in maintaining the normal contraction sequence that optimizes mechanical efficiency. The importance of systolic twist and the subsequent recoil that leads to diastolic untwisting was examined in the article by Notomi et al4 using tissue Doppler techniques in both normal subjects and patients with hypertrophic cardiomyopathy, at rest and during exercise. Leonardo DaVinci5 in the 16th century and Rushmore6 in the 1950s described the rotational motion of the left ventricle.7 In 1970, McDonald7 reported a study in which he placed radiopaque markers on the epicardium of patients undergoing closed mitral valvuloplasty. He demonstrated that the pre-ejection phase was characterized by descent of the base and a counterclockwise rotation of the epicardial surface of the left ventricle with a thrust of the apex toward the chest wall. In late systole, there was a slight clockwise rotation and apical retraction. Using blunt dissection, Torrent-Guasp et al8 demonstrated that the ventricles consist of a single myofiber band starting at the right ventricle just below the pulmonary valve and forming …

Background Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure. Methods and Results Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23±2 mm Hg; BNP, 16±2 mm Hg; P P P Conclusions BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.

A large proportion of patients who present with symptoms of heart failure have a left ventricular ejection fraction within the normal range.1 Although some have postulated that ventricular systolic function is impaired,2 most investigators have concluded that the fundamental abnormality in these patients is a disorder of diastolic (rather than systolic) function,3–5 and in fact, these patients are frequently referred to as having diastolic heart failure. The use of such a term is troublesome, however, because it presumes that we understand the mechanisms leading to this disorder and therefore can justify the substitution of a mechanistic term for a descriptive phrase. A less presumptuous approach is to refer to these patients as having heart failure with a normal ejection fraction (HFNEF), a descriptive approach that makes no assumptions about our knowledge about the pathophysiology of this disorder. See p 714 Do most patients with heart failure and a normal ejection fraction have diastolic dysfunction? Patients with HFNEF are generally elderly women who have associated hypertension, diabetes, and/or coronary artery disease.6 These comorbid conditions have been linked to myocardial hypertrophy, ischemia, and/or interstitial fibrosis, each of which can prolong relaxation and increase passive myocardial stiffness.7 However, the coexistence of disorders known to affect these aspects of diastole is not sufficient to establish that diastolic dysfunction is the cause of heart failure when it occurs in patients with a normal ejection fraction. To determine that an abnormality of diastolic function is the cause of the patient’s symptoms, we need to demonstrate the existence of such a derangement and determine that it is sufficient to limit exercise tolerance. What kind of diastolic abnormalities can cause symptoms of heart failure? The sequestration of calcium and cross-bridge uncoupling after the end of systole are responsible for the active process of …

Heart failure is the final common pathway for many chronic heart diseases. With the aging of the population and advances in the treatment of cardiac disease, the number of patients with heart failure continues to increase. Although the majority of patients will remain stable for several years with standard medicines and surgery, a growing number will develop symptoms of advanced heart failure and may be referred for evaluation for heart transplant. For selected patients who are too ill to wait for a heart donor or who are not eligible for a heart transplant because of age or other medical problems, ventricular assist devices (VADs) offer life-saving therapy. Initially designed as temporary support to bridge patients to heart transplant, these devices are now available and increasingly being used as lifetime support or destination therapy. Improvements in device design, along with advances in surgical and medical management, have allowed VAD patients to return home, to work, and to their communities, with excellent quality of life. At the same time, however, unique challenges have been encountered. This Cardiology Patient Page will discuss the fundamentals of VADs, including patient selection, pump design, surgical and medical treatment, expected benefits and long-term risks, and the team approach to care. Heart failure is a common cardiac condition in which the heart is unable to pump blood at a sufficient rate to meet the demands of the body. There are 2 major types of heart failure: one is associated with abnormal heart filling (sometimes called diastolic heart failure or heart failure with preserved ejection fraction), and the other is associated with abnormal heart emptying (also called systolic heart failure or heart failure with reduced ejection fraction). Most patients who develop heart failure have had a prior injury or stress on the heart that caused the heart to weaken. …

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Michael A. Fifer), who responds to the information, sharing his reasoning with the reader (regular type). A Discussion by the authors follows. A 76-year-old man with a history of hypertrophic obstructive cardiomyopathy (HOCM), hypertension, dyslipidemia, and obstructive sleep apnea presents with dyspnea on exertion. This symptom has progressed slowly over the past year, to the point that he now has dyspnea on climbing 1 flight of stairs. The patient denies orthopnea, paroxysmal nocturnal dyspnea, edema, chest discomfort, palpitations, lightheadedness, and syncope. His medications are metoprolol, verapamil, disopyramide, rosuvastatin, and omeprazole. He is a retired electrician, is married with 3 adult children, and lives in Florida and Massachusetts, each for half the year. He has a history of heavy tobacco use but quit smoking more than 30 years ago. His family history is notable only for diabetes mellitus and stroke in his father; there are no family members with heart failure, hypertrophic cardiomyopathy (HCM), or sudden cardiac death (SCD). Dr Michael A. Fifer: This patient's presenting complaint is progressive dyspnea on exertion, for which he has possibly contributory comorbidities, namely, obstructive sleep apnea and hypertension. The history of HCM is particularly relevant because dyspnea is a common initial manifestation of the disease.1 Dyspnea may occur in HCM as a result of a variety of mechanisms, including diastolic heart failure due to myocardial hypertrophy and fibrosis, left ventricular outflow tract (LVOT) obstruction, and associated mitral regurgitation (MR). Although the correlation between symptoms and the magnitude of the LVOT gradient is weak,2 dyspnea is usually relieved by septal reduction therapy. In this patient, any or all of these factors might contribute to progressive dyspnea on exertion. More information regarding how the diagnosis of HOCM was …

Despite recent advances in the diagnosis and management of heart failure, the rate of hospitalizations for this condition is increasing. At least 50% of patients present with heart failure despite a normal ejection fraction (EF) and are referred to as having heart failure with normal EF or diastolic heart failure (DHF). Recently, a group of investigators met to address the issue of nomenclature and agreed that the term DHF is preferred but that it does not refute the presence of other abnormalities in this condition.1 We therefore use this term throughout the present review. There are several opinions about the pathophysiology of this condition that have been expressed passionately by many groups. They include issues pertaining to left ventricular (LV) systolic properties, ventricular arterial coupling, and last but not least, LV diastolic function. Recent studies that used novel imaging modalities and others that used conductance catheters in DHF patients have provided additional data that are pertinent to the ongoing debate and have potential therapeutic implications. However, before discussing the recent studies, it is important to comment on certain morphological characteristics in DHF patients that are distinct from those in patients with systolic heart failure. In particular, LV dimensions and volumes are normal in DHF patients,2 whereas wall thickness and LV mass are increased, although the latter finding is not universal. In an exception to the above findings, a recent study3 reported that LV end-diastolic volumes were increased in DHF patients. However, a single M-mode measurement was used to convert LV dimensions to volumes, only 51% of the original sample size was included, and 90% of DHF patients had normal LV volumes, with only 10% showing LV dilatation.4 In light of the above, it is reasonable to conclude that LV volumes are normal in most DHF patients. …

We appreciate the interest of Dwivedi et al in our study.1 They raise 3 points with respect to our results. The first deals with their belief that the untwisting rate (UR) should be abnormal in patients with diastolic heart failure (DHF), the second deals with cardiac function in these patients at rest and with exercise, and the third has to do with the underlying mechanisms. Dwivedi et al base their impression that DHF patients should have a reduced UR on reduced Ea, on other studies showing abnormal UR, and on a report in patients with hypertrophic cardiomyopathy that Dwivedi and colleagues believe showed that peak UR is an …

One of the hallmarks of aging is an increase in ventricular passive stiffness leading to diastolic heart failure, however, the molecular basis for this is unclear. The giant elastic protein titin, working as an entropic spring, is the major determinant of passive cardiomyocyte stiffness. We hypothesized that accumulation of oxidized titin in the aging heart results in increased cardiomyocyte passive stiffness and thereby contributes to diastolic dysfunction. We further hypothesized that an age-assocated disturbance in the ubiquitin/proteasome pathway plays a role in the accumulation of oxidized titin. Methods: Cardiomyocytes from adult (4 month) and aging (34 month) mouse hearts were isolated and chemically skinned and the passive force-sarcomere length relationship in single cells were obtained. Post-translational modification of titin was assessed in whole heart homogenates by determining the content of 1) titin carbonyls, a marker of irreversible protein oxidation, and 2) titin ubiquitinylation, a marker for proteasomal degradation. Results: Cardiomyocyte passive tension was significantly higher in the aging group (at SL=2.45 μm, 1008.4 ± 45.5 vs. 871.6 ± 48.3 μg; p Conclusion: Our data suggests that an age-associated impairment in titin turnover contributes to accumulation of oxidatively modified titins with consequent impairment of cardiomyocyte stiffness. We speculate that the oxidation of titin will change the elastic properties of titin, directly accounting for the change in passive tension and contributing to diastolic dysfunction associated with aging.

Background— About half of the 5 million heart failure patients in the United States have diastolic heart failure (clinical heart failure with normal or near-normal ejection fraction). Except for candesartan, no drugs have been tested in randomized clinical trials in these patients. Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial, detailed findings from this important study have not previously been published. Methods and Results— Ambulatory chronic heart failure patients (n=988) with normal sinus rhythm and ejection fraction >45% (median, 53%) from the United States and Canada (1991 to 1993) were randomly assigned to digoxin (n=492) or placebo (n=496). During follow-up with a mean length of 37 months, 102 patients (21%) in the digoxin group and 119 patients (24%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.63 to 1.07; P =0.136) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Use of digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR, 0.79; 95% CI, 0.59 to 1.04; P =0.094) but also a trend toward an increase in hospitalizations for unstable angina (HR, 1.37; 95% CI, 0.99 to 1.91; P =0.061). Conclusions— In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics, digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations.

We appreciate Dr Sanderson’s interest and support of our efforts to better understand cardiac function in patients with diastolic heart failure (DHF) and welcome the opportunity to respond. We have previously reported normal left ventricular systolic performance, function, and contractility in patients with DHF and have concluded that the pumping ability of the whole ventricle is normal in the basal state.1 To our knowledge, there are no published data that refute this …

To the Editor: Aurigemma et al1 have attempted to reconcile the recent findings that ventricular long-axis function in systole is reduced in diastolic heart failure (DHF) with the standard concept that systolic function is entirely normal in this condition. They question the relevance of long-axis function mainly because annular velocities are within normal limits in some patients. However, DHF is episodic and often requires a triggering factor, such as an ischemic episode, arrhythmia, etc. No study to date has measured regional ventricular function …

To the Editor: This timely article by Baicu et al addresses the controversial topic of patients with diastolic heart failure (DHF), a term currently defined as heart failure in the presence of a normal ejection fraction >50%.1 Forty-seven DHF patients underwent catheterization in association with echocardiography.2 Ten patients who were catheterized had no evidence of cardiovascular disease and served as controls. From their analyses, the authors concluded that a majority of DHF patients displayed left ventricular normal systolic performance, function, and contractility. The article’s Figures 2 and 4 appear to indicate that both endocardial and midwall fractional shortening are load independent. A reevaluation was therefore conducted and yielded the following regression equations: (1) YU=33.4–.0214 XU (n=28, NS (0.11)), (2) YL =32.7–.0600 XL (n=15, NS (0.6)), (3) Ymid=14.9−0.00314 Xmid (n=26, NS (0.76)), and (4) Ymidout=12.8–0.0092 Xmidout (n=15, NS (0.72)). Here, YU versus XU and YL versus XL refer …

Case presentation : A 73-year-old female smoker with a history of hypertension presents to the emergency room with dyspnea on exertion for 2 weeks, now progressing to shortness of breath at rest for 1 day. She has no angina, but has 2-pillow orthopnea and possible paroxysmal nocturnal dyspnea. On examination, blood pressure is 180/96 mm Hg, heart rate is 95 beats per minute and regular, and she is afebrile. Jugular venous pressure is 11 cm, and there are rales in the lower third of both lung fields. On cardiac auscultation there is an S4, but no S3 or murmur. On chest radiography, emphysematous changes are present, and there are patchy bilateral infiltrates consistent with pulmonary edema or pneumonia. Heart size is mildly increased. Is she suffering from congestive heart failure, and if so, why? What are the best management options acutely and after hospital discharge? Congestive heart failure (CHF) is one of the most common reasons for hospital admission in the United States. The syndrome usually evokes images of an enlarged heart with reduced systolic function. However, perhaps 50% of patients with CHF have normal or only minimally impaired systolic dysfunction and are diagnosed with diastolic heart failure (D-CHF) by exclusion.1–4 Rather than define D-CHF by what it is not (that is, CHF without systolic dysfunction), we regard D-CHF as CHF due to increased resistance to diastolic filling of part or all of the heart. Causes of D-CHF so defined are listed in Table 1; this review will focus on the myocardial causes.5,6 View this table: TABLE 1. Causes of Diastolic Congestive Heart Failure Depending on the cohort studied and the exact definition, the prevalence of D-CHF increases with age and is higher in women than men. Hypertension and left ventricular hypertrophy (LVH) are common. Compared with classic systolic CHF …

There is growing recognition that congestive heart failure (CHF) caused by a predominant abnormality in diastolic function (ie, diastolic heart failure) is both common and causes significant morbidity and mortality. However, there is continued controversy surrounding the definition of diastolic dysfunction and the diagnostic criteria for diastolic heart failure. As a result, clinical therapeutic trials have been slow to develop and difficult to design. Fortunately, these controversies are yielding to an emerging consensus. Recent clinical studies have provided sufficient data to develop standardized diagnostic criteria to define diastolic heart failure.1–4⇓⇓⇓ Experimental studies have provided increased insight into the mechanisms that cause diastolic heart failure.5–22⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ Together, these clinical and experimental studies are being used to design targeted clinical trials to test effective treatments for diastolic heart failure. The purpose of this 2-part article is to provide a perspective on these issues, highlight new research, and introduce emerging ideas. Part 1 will focus on the criteria used to diagnose diastolic heart failure, the effects of diastolic heart failure on prognosis, and measurements used to assess diastolic function. Part 2 will describe the mechanisms that cause diastolic heart failure and discuss approaches to treatment. ### Differentiating Diastolic Dysfunction From Diastolic Heart Failure Heart failure is a clinical syndrome characterized by symptoms and signs of increased tissue/organ water and decreased tissue/organ perfusion. Standardized criteria to diagnose heart failure have been developed, perhaps the best validated of which come from the Framingham Study.23 Definition of the mechanisms that cause this clinical syndrome requires measurement of both systolic and diastolic function. When heart failure is accompanied by a predominant or isolated abnormality in diastolic function, this clinical syndrome is called diastolic heart failure. Diastolic dysfunction refers to a condition in which …

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

The diagnosis of diastolic heart failure suggested by Vasan and Levy1 and Grossman,2 as definite, probable, or possible, presently hinges on the demonstration of diastolic left ventricular (LV) dysfunction at cardiac catheterization or echocardiography. It is likely that a far simpler …

Background —The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats. Methods and Results —DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy. Conclusions —The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Background —Left ventricular diastolic dysfunction is a major cause of cardiac allograft failure. Multimeric L-type calcium channels (α 1 -, α 2 /δ-, and β-subunits) are essential for excitation/contraction coupling in the heart. Their gene expression was studied in allografts that developed diastolic heart failure. Methods and Results —mRNA levels of calcium channel subunits were measured by competitive reverse transcriptase–polymerase chain reaction in microbiopsy samples from the interventricular septum. Size and tissue variabilities between biopsy samples were assessed by determination of cardiac calsequestrin mRNA levels. In the cardiac allografts studied, mRNA levels in microbiopsy samples were considered to represent left ventricular gene expression, because septal and left ventricular gene expression in Northern blots was equivalent, and left ventricles contracted homogeneously. Biopsy samples (n=72) were taken from allografts with normal left ventricular end-diastolic pressure (LVEDP; 8 to 13 mm Hg; n=30), moderately elevated LVEDP (14 to 18 mm Hg; n=26), and elevated LVEDP (19 to 28 mm Hg; n=16). Increased LVEDP was related to slowed diastolic relaxation determined by the time constant τ ( r 2 =0.86), whereas systolic performance (dP/dt; ejection fraction) was preserved. With increasing LVEDP, mRNA levels of the pore-forming α 1c -subunit (n=15) and of the regulatory α 2 /δ-subunit (n=17) remained unchanged but decreased exponentially ( r 2 =−0.83) for the regulatory β-subunit (n=40). Compared with cardiac allografts with normal LVEDP (n=15), β-subunit mRNA level was reduced by 75% at elevated LVEDP (n=9; P =0.012). In an explanted, diastolically failing cardiac allograft, β-subunit expression was reduced correspondingly by 72% and 76% on the mRNA level in septal and left ventricular myocardium and by 80% on the protein level. Conclusions —The downregulated expression of the calcium channel β-subunit might contribute to altered calcium handling in diastolically failing cardiac allografts.

The human intellect has an almost irresistible urge to categorize and simplify. Thus, over the years, heart failure has been classified as forward or backward, right or left, compensated or decompensated. These distinctions, which were made primarily on the basis of data obtained from the history and physical examination, provided a conceptual framework for thinking about heart failure and for rationalizing therapeutic decisions (eg, digitalis to increase cardiac output in “forward” failure). As information routinely available to the clinician has been extended from the history and physical examination to now include precise, noninvasive characterization of ventricular volumes and aortic flow, it has been increasingly recognized that the pathophysiology of heart failure cannot be assessed adequately by the older classifications. For example, it is now appreciated that “backward” heart failure with elevated ventricular filling pressures and consequent pulmonary or peripheral edema can result from either systolic or diastolic ventricular dysfunction. In fact, epidemiological and case-control studies of individuals presenting with clinical heart failure have estimated that 40% to 50% of such patients have normal systolic function and presumed diastolic heart failure.1 2 3 4 For example, Senni et al,1 from the Mayo Clinic, reported that 43% of patients with clinical congestive heart failure and adequate echocardiographic assessment of ejection fraction show normal/preserved left ventricular function. Although the prognosis of patients with heart failure and preserved systolic function has generally been regarded as intermediate between normal subjects and patients whose heart failure is associated with depressed systolic function, the recent Mayo study1 calls this into question, showing both systolic and diastolic heart failure to have a similar prognosis, at least over the first 3 to …