Background— Cardiotropic viral infections have been suspected as one possible cause of myocarditis and dilated cardiomyopathy. Although adverse outcomes in dilated cardiomyopathy patients have been documented, the natural course of heart diseases caused by cardiotropic viruses is unknown. Methods and Results— Consecutive patients (n=172) with biopsy-proven viral infection in endomyocardial biopsies (EMBs) were followed up by reanalysis of EMBs and hemodynamic measurements after a median period of 6.8 months (range, 5.4 to 11.9). Nested polymerase chain reaction (PCR) and reverse transcription–PCR were performed to analyze the genomic sequences. Myocardial inflammation was assessed by histology and immunohistology. At baseline, 32.6% of EMBs in the study group contained enteroviral (EV) RNA, 8.1% adenovirus (ADV) DNA, 36.6% parvovirus B19 (PVB19) DNA, and 10.5% human herpesvirus type 6 (HHV6) DNA. In 12.2% of the samples, dual infection with PVB19 and HHV6 was present. Follow-up analysis of EMBs by PCR documented spontaneous clearance of viral genomes in 36.2% (55/151) of all patients with single infections. Virus-specific clearance rates were 50% for EV, 35.7% for ADV, 22.2% for PVB19, and 44.4% for HHV6. In patients with dual infection with PVB19 ⁺ and HHV6 ⁺ -, HHV6 was cleared in 42.8% (9/21), whereas PVB19 persisted in all 21 patients. Clearance of viral genomes was associated with a significant improvement in left ventricular ejection fraction (LVEF), improving from 50.2±19.1% to 58.1±15.9% ( P <0.001). In contrast, LV function decreased in patients with persisting viral genomes (LVEF, 54.3±16.1% versus 51.4±16.1%, P <0.01). Conclusions— In this first biopsy-based analysis of the course of viral heart disease, we show that EV, ADV, PVB19, and HHV6 persistence detected in the myocardium of patients with LV dysfunction was associated with a progressive impairment of LVEF, whereas spontaneous viral elimination was associated with a significant improvement in LV function.

Background— Various conventional and tissue Doppler echocardiographic indexes were compared with pressure–volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF). Methods and Results— Diastolic dysfunction was confirmed by pressure–volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (τ, dP/dt _min ), LV end-diastolic pressure, and LV end-diastolic pressure–volume relationship (stiffness, b [dP/dV], and stiffness constant, β) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, τ (E/A: r =−0.36, P =0.013; isovolumic relaxation time: r =0.31, P =0.040) and b (deceleration time: r =0.39, P =0.012) but not with β, in contrast to the tissue Doppler imaging indexes E’/A’ _lateral ( r =−0.37, P =0.008) and E/E’ _lateral ( r =0.53, P <0.001). Diastolic dysfunction was detected in 70% of the HFNEF patients by mitral flow Doppler but in 81% and 86% by E’/A’ _lateral , and E/E’ _lateral , respectively. Conclusions— Of all echocardiographic parameters investigated, the LV filling index E/E’ _lateral was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.

Background— Viral infections are important causes of myocarditis and may induce cardiac dysfunction and finally lead to dilated cardiomyopathy. We investigated whether interferon (IFN)-β therapy is safe and may achieve virus clearance and prevent deterioration of left ventricular (LV) function in patients with myocardial virus persistence. Methods and Results— In this phase II study, 22 consecutive patients with persistence of LV dysfunction (history of symptoms, 44±27 months) and polymerase chain reaction–proven enteroviral or adenoviral genomes were treated with 18×10 ⁶ IU/week IFN-β (Beneferon) subcutaneously for 24 weeks. Histological and immunohistological analysis of endomyocardial biopsies was used to characterize myocardial inflammation. LV diameters and ejection fraction were assessed by echocardiography and angiography, respectively. During the treatment period, IFN-β was well tolerated by all patients. No patient deteriorated. Clearance of viral genomes was observed in 22 of 22 of patients after antiviral therapy. Virus clearance was paralleled by a significant decrease of LV end diastolic and end systolic diameters, decreasing from 59.7±11.1 to 56.5±10.0 mm ( P <0.001) and 43.2±13.6 to 39.4±12.1 mm ( P <0.001), respectively. LV ejection fraction increased from 44.6±15.5% to 53.1±16.8% ( P <0.001). Conclusions— A 6 months, IFN-β treatment was safe in patients with myocardial enteroviral or adenoviral persistence and LV dysfunction and resulted in elimination of viral genomes (22 of 22 patients) and improved LV function (15 of 22 patients).

Background— Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results— Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. Conclusions— Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.

Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.