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Cardiovascular AND Dilated cardiomyopathy, primary [keywords]
- Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy. [JOURNAL ARTICLE]
- Eur J Heart Fail 2013 Jun; 15(6):660-670.
AIMS:Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non-ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long-term prognostic significance of LAV assessed by CMR in DCM.
METHODS AND RESULTS:We measured LAV indexed to body surface area (LAVi) in 483 consecutive DCM patients referred for CMR. Patients were prospectively followed up for a primary endpoint of all-cause mortality or cardiac transplantation. During a median follow-up of 5.3 years, 75 patients died and 9 underwent cardiac transplantation. After adjustment for established risk factors, LAVi was an independent predictor of the primary endpoint [hazard ratio (HR) per 10 mL/m(2) 1.08; 95% confidence interval (CI) 1.01-1.15; P = 0.022]. LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.19; P = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.18; P = 0.001). The optimal LAVi cut-off value for predicting the primary endpoint was 72 mL/m(2). Patients with LAVi >72 mL/m(2) had a three-fold elevated risk of death or transplantation (HR 3.00; 95% CI 1.92-4.70; P < 0.001). LAVi provided incremental prognostic value for the prediction of transplant-free survival (net reclassification improvement 0.17; 95% CI 0.05-0.29; P = 0.002).
CONCLUSIONS:LAVi is a powerful independent predictor of transplant-free survival and HF outcomes in DCM. Assessment of LAV improves risk stratification in DCM and should be incorporated into routine CMR examination.
- Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2013 Mar 6; 309(9):896-908.
Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions.To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy.Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011.Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation.Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively).Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.
- United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. [JOURNAL ARTICLE]
- Europace 2013 Feb 28.
AIMS:The aim of this study was to describe the early phase United Kingdom (UK) clinical experience with a novel entirely subcutaneous implantable cardioverter-defibrillator (S-ICD).
METHODS AND RESULTS:A questionnaire was sent to all UK hospitals implanting S-ICDs. Nineteen of 25 (76%) hospitals responded with the details of 111 implanted patients [median 5/hospital (range 1-18)]. Mean duration of follow-up was 12.7 ± 7.1 months. Median patient age was 33 years (range 10-87 years). Underlying pathology was primary electrical disease in 43%, congenital heart disease 12%, hypertrophic cardiomyopathy 20%, ischaemic cardiomyopathy 14%, idiopathic dilated cardiomyopathy 5%, and other cardiomyopathies 7% patients. Nineteen (17%) patients required 20 re-operations, including permanent device explantation in 10 (9%). Twenty-four appropriate shocks were delivered in 13 (12%) patients, including 10 for ventricular fibrillation. One patient suffered arrhythmic death, but there were no failures to detect or terminate ventricular arrhythmias above the programmed detection rate. Fifty-one inappropriate shocks were delivered in 17 (15%) patients. Forty-one (80%) were for T-wave over-sensing and 1 (2%) for atrial flutter-wave over-sensing. The 11 patients who received inappropriate shocks due to T-wave over-sensing were significantly younger than patients who did not (24 ± 10 vs. 37 ± 19 years; P = 0.02).
CONCLUSION:The S-ICD is an important innovation in ICD technology. However, these data indicate that adverse event rates are significant during early clinical adoption. Important lessons in patient selection, implant technique, and device programming can be learnt from this experience.
- TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human end-stage dilated cardiomyopathy. [JOURNAL ARTICLE]
- Int J Cardiol 2013 Jan 27.
BACKGROUND:The transcription factor TWIST1 has been described to regulate the microRNA (miR)-199/214 cluster. Genetic disruption of TWIST1 resulted in a cachectic phenotype and early death of the knock-out mice. This might be connected to the activity of the ubiquitin-proteasome-system (UPS), as miR-199a has been suggested to regulate the ubiquitin E2 ligases Ube2i and Ube2g1.
METHODS:Cardiac tissue from explanted hearts of 42 patients with dilated cardiomyopathy and 20 healthy donor hearts were analysed for protein expression of TWIST1 and its inhibitors Id-1, MuRF-1 and MAFbx, the expression of miR-199a, -199b and -214, as well as the activity of the UPS by using specific fluorogenic substrates.
RESULTS:TWIST1 was repressed in patients with dilated cardiomyopathy by 43% (p=0.003), while Id1 expression was unchanged. This was paralleled by a reduced expression of miR-199a by 38±9% (p=0.053), miR-199b by 36±13% (p=0.019) and miR-214 by 41±11% (p=0.0158) compared to donor hearts. An increased peptidylglutamyl-peptide-hydrolysing activity (p<0.0001) was observed in the UPS, while the chymotrypsin-like and trypsin-like activities were unchanged. The protein levels of the rate limiting ubiquitin E3-ligases MuRF-1 and MAFbx were up-regulated (p=0.005 and p=0.0156, respectively). Mechanistically silencing of TWIST1 using siRNA in primary rat cardiomyocytes led to a down-regulation of the miR-199/214 cluster and to a subsequent up-regulation of Ube2i.
CONCLUSION:The TWIST1/miR-199/214 axis is down-regulated in dilated cardiomyopathy, which is likely to play a role in the increased activity of the UPS. This may contribute to the loss of cardiac mass during dilatation of the heart.
- Novel regulation of cardiac metabolism and homeostasis by the adrenomedullin-receptor activity-modifying protein 2 system. [Journal Article, Research Support, Non-U.S. Gov't]
- Hypertension 2013 Feb; 61(2):341-51.
Adrenomedullin (AM) was identified as a vasodilating and hypotensive peptide mainly produced by the cardiovascular system. The AM receptor calcitonin receptor-like receptor associates with receptor activity-modifying protein (RAMP), one of the subtypes of regulatory proteins. Among knockout mice ((-/-)) of RAMPs, only RAMP2(-/-) is embryonically lethal with cardiovascular abnormalities that are the same as AM(-/-). This suggests that the AM-RAMP2 system is particularly important for the cardiovascular system. Although AM and RAMP2 are highly expressed in the heart from embryo to adulthood, their analysis has been limited by the embryonic lethality of AM(-/-) and RAMP2(-/-). For this study, we generated inducible cardiac myocyte-specific RAMP2(-/-) (C-RAMP2(-/-)). C-RAMP2(-/-) exhibited dilated cardiomyopathy-like heart failure with cardiac dilatation and myofibril disruption. C-RAMP2(-/-) hearts also showed changes in mitochondrial structure and downregulation of mitochondria-related genes involved in oxidative phosphorylation, β-oxidation, and reactive oxygen species regulation. Furthermore, the heart failure was preceded by changes in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. Metabolome and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) imaging analyses revealed early downregulation of cardiolipin, a mitochondrial membrane-specific lipid. Furthermore, primary-cultured cardiac myocytes from C-RAMP2(-/-) showed reduced mitochondrial membrane potential and enhanced reactive oxygen species production in a RAMP2 deletion-dependent manner. C-RAMP2(-/-) showed downregulated activation of cAMP response element binding protein (CREB), one of the main regulators of mitochondria-related genes. These data demonstrate that the AM-RAMP2 system is essential for cardiac metabolism and homeostasis. The AM-RAMP2 system is a promising therapeutic target of heart failure.
- Factors predisposing to ventricular tachyarrhythmia leading to appropriate ICD intervention in patients with coronary artery disease or non-ischaemic dilated cardiomyopathy. [Journal Article]
- Kardiol Pol 2012; 70(12):1264-75.
In order to achieve optimal outcomes when treating ventricular tachyarrhythmias with implantable devices, it is extremely important to identify parameters predisposing to arrhythmia. In view of current restrictions in healthcare funding, there is a growing demand for additional predictors of arrhythmia that would allow better patient selection for implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death (SCD).To identify parameters predisposing to ventricular tachyarrhythmia/appropriate ICD intervention in ICD recipients.We analysed 376 patients (56 women, 320 men, mean age 66.1 ± 11.2 [range 22-89] years) who underwent ICD implantation between January 2008 and December 2010. Of these, 275 patients underwent ICD implantation for primary prevention of SCD and 101 for secondary prevention. Operative protocols and in-hospital and outpatient records were analysed retrospectively. Mean QRS width and heart rate (HR) were calculated in resting surface electrocardiograms (25 mm/s, 10 mm/1 mV). Intracardiac electrograms stored in ICD memory were used to evaluate appropriateness of anti-arrhythmic interventions and analyse the number of ventricular tachyarrhythmia events, ICD interventions and their type. We analysed the following clinical and procedural variables: age, gender, left ventricular ejection fraction (LVEF), type of SCD prevention (primary or secondary), ICD type (single chamber--VR, dual chamber--DR), performing defibrillation threshold testing to establish defibrillation safety margin at ICD implantation, ventricular lead location (right ventricular outflow tract region, right ventricular apex), mean HR, QRS width, New York Heart Association (NYHA) functional class, occurrence of ventricular tachyarrhythmia/appropriate ICD intervention after implantation, ICD interventions, history of cardiovascular disease and arrhythmia (myocardial infarction, ischaemic and non-ischaemic dilated cardiomyopathy, arterial hypertension, ventricular fibrillation, ventricular tachycardia, permanent atrial fibrillation, percutaneous coronary intervention, and/or coronary artery bypass grafting), and medications (amiodarone, sotalol, beta-blockers, angiotensin-converting enzyme inhibitors [ACEI]/angiotensin receptor blockers [ARB], statins, loop diuretics, aldosterone antagonists).During the mean follow-up period of 387 ± 300 (range 5-1400) days, appropriate ICD intervention due to ventricular tachyarrhythmia occurred in 68 of 376 ICD patients (61 men, 7 women, mean age 64.7 ± 12.3 [range 22-89] years). Mean time interval from ICD implantation to the occurrence of arrhythmia was 281 ± 229 (range 5-972) days (p 〈 0.001). To optimize sensitivity and specificity when analysing ventricular tachyarrhythmia/appropriate ICD intervention vs. no ventricular tachyarrhythmia/appropriate ICD intervention, cutoff values were established using ROC curves (cutoff for LVEF = 31%, HR = 79 bpm). Using these cutoff values, patients with ventricular tachyarrhythmia/appropriate ICD intervention were compared to those without ventricular tachyarrhythmia/appropriate ICD intervention. Significant differences were observed in LVEF (p< 0.001), HR (p< 0.022), ACEI/ARB use (p< 0.034), and NYHA class (p< 0.001). By Kaplan-Meier univariate analysis, patients with LVEF> 31% (log-rank test p< 0.001), HR ≤ 79 bpm (log-rank test p< 0.022), QRS width ≤ 114 ms (log-rank test p < 0.045), and NYHA class II (log-rank test p< 0.001) were more likely to be free from ventricular tachyarrhythmia/appropriate ICD intervention. Cox multivariate analysis showed that reduced LVEF (≤ 31%) was the only independent predictor of arrhythmia/intervention. LVEF values below 31% are associated with a significant 20-fold increase (p< 0.02) in the risk of arrhythmia during the first 3 years after ICD implantation. Among 68 patients with ventricular tachyarrhythmia/appropriate ICD intervention, mean 4.1 interventions per person occurred during the follow-up period. In the overall study population, the number of interventions was 0.28 per person per year. Overall, 92 inappropriate ICD interventions were observed, all resulting from atrial fibrillation with rapid ventricular rate. Interventions had no effect on total mortality. Higher numbers of appropriate interventions were observed in patients who died due to heart failure.Factors associated with a significantly increased risk of ventricular tachyarrhythmia/appropriate ICD intervention included reduced LVEF, increased resting HR, NYHA class II or higher heart failure, and wide QRS. Patients with low LVEF (< 31%) are at particular risk of SCD due to ventricular arrhythmia and this parameter alone can influence the decision regarding ICD implantation. No effect of ICD interventions on total mortality was observed, although more ICD interventions were observed in patients who died due to heart failure.
- [Noncompaction myocardium as a primary phenomenon or consequence of myocardial dysfunction: clinical masks of the syndrome]. [English Abstract, Journal Article]
- Kardiologiia 2012; 52(11):17-26.
Noncompaction myocardium (NCM) is a genetic heterogeneous primary cardiomyopathy which affects both children and adults and can be either isolated or combined with other congenital heart disorders. It has common pathogenesis of symptoms but is distinguished by pronounced clinical polymorphism. We have observed 25 adult patients (15 men, 10 women aged from 20 to 62 years, mean age 42.9+/-13.3 years) with NCM syndrome. Heart failure have been found in 96% of patients (functional class [FC] I in 7, II - in 6, III in 7, and IV - in 4 patients). Ninety two percent of patients have ventricular extrasystoles, 32% - atrial fibrillation, 28% - FC I-III angina. Mean end diastolic left ventricular dimension is 6.5+/-0.8cm, ejection fraction 29.7+/-13.0%, mean pulmonary artery pressure - 42.6+/-13.5 mm Hg. Intracardiac thrombosis have been found in 24% of patients. In 7 patients morphological study of myocardium has been performed. NCM syndrome was diagnosed at initial investigation just in 1 case. We distinguished the following clinical masks (variants of diagnosis) of NCM: 1) clinically not manifest, is revealed at accidental examination (4%); 2) exists under mask of "idiopathic" rhythm disturbances (8%); 3) has a mask of ischemic heart disease; 4) is revealed in patients with acute or subacute myocarditis (12%); 5) has a mask of dilated cardiomyopathy (52%); 6) NCM in patients with other primary cardiomyopathies (hypertrophic, restrictive, genetic myopathy, arrhythmogenic right ventricular dysplasia). Combination of NCM with congenital heart defects has been found in 20% of patients. In 56% of cases myocarditis was diagnosed (it was viral in no less than 44%). Only in 32% of patients it is possible to consider presence of isolated NCM syndrome. This paper contains discussion of problems of diagnostics (including morphological) and treatment in the presented group of patients, significance of myocarditis for development of decompensation, role of NCM in patients with other primary cardiomyopathies, possibility of compensatory (secondary) character of NCM in severe systolic dysfunction.
- Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. [Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Am J Cardiol 2013 Feb 15; 111(4):609-12.
In 2015, there will be an estimated 11.3 million cancer survivors. With an increasing population of cancer survivors, it is imperative to understand the treatment options available and outcomes for chemotherapy-related cardiomyopathy. Anthracycline-based chemotherapy causes heart failure in approximately 5% of patients. Orthotopic heart transplantation (OHT) is an option for cancer survivors in complete remission who develop end-stage heart failure. We examined retrospective OHT data collected from the United Network of Organ Sharing from 1987 to 2011. The primary aim was to characterize the survival in patients with either the primary diagnosis of "dilated cardiomyopathy: Adriamycin" (DCA) versus "all other" causes of cardiomyopathy. The secondary aim was to define the differences in the primary cause of death and to describe the temporal relationship of DCA OHT. The United Network of Organ Sharing database identified 453 OHTs for the diagnosis of DCA and 51,312 OHTs for all other causes of cardiomyopathy. The DCA group was significantly younger with a greater percentage of women. After adjusting for age, gender, and history of malignancy, the 10-year survival curves showed that patients with DCA have an improved survival compared to those with all other causes of cardiomyopathy (hazard ratio 1.28, p = 0.026). No difference was found in the primary cause of death between the 2 groups. A statistically significant increasing temporal trend was seen in the number of OHTs for the diagnosis DCA. In conclusion, patients who undergo OHT for DCA have favorable 10-year survival, making OHT a good therapeutic option for end-stage heart failure due to anthracyclines. Additionally, no increased risk of cancer-related deaths was found in the DCA group, demonstrating that recurrent malignancy does not affect long-term survival. The temporal trends demonstrated that DCA remains a significant problem for cancer survivors.
- Determinants of patient survival rate after implantation of a cardioverter-defibrillator without resynchronisation capability. [Journal Article]
- Kardiol Pol 2012; 70(11):1099-110.
Proper selection of patients at high risk for sudden cardiac death (SCD) and increasing use of implantable cardioverter-defibrillators (ICD) may contribute to improved survival among patients at the highest SCD risk.To assess patient survival rate after implantation of an ICD without resynchronisation capability in our own patient population. Using uni- and multivariate analysis, we attempted to identify factors associated with significant worsening of patient survival rate.From the population of patients who underwent ICD implantation for primary or secondary prevention of SCD in 2008-2010, we selected 376 patients with coronary artery disease or dilated cardiomyopathy (56 females, 320 males). Mean age was 66.1 ± 11.2 (range 22-89) years. ICD implantation protocols and in-hospital and outpatient records were reviewed retrospectively. We analysed the following clinical and procedural variables: age, gender, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, mean heart rate (HR), QRS width, number of antiarrhythmic ICD interventions, type of SCD prevention, ICD type, performing defibrillation threshold testing (DFT) to establish defibrillation safety margin at ICD implantation, ventricular lead location, history of cardiovascular disease and arrhythmia, medications used (amiodarone, sotalol, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, loop diuretics, aldosterone antagonists). Date and cause of death were established by contacting patient family and/or the hospital to which the patient was admitted shortly before death or the general practitioner caring for the patient (verification of death certificates).During the mean follow-up period of 447 ± 313 days, 46 patients died of known causes. Causes of death included sudden death in 16 patients, heart failure in 20 patients, and other causes in 10 patients (respiratory failure - 1, bleeding diathesis - 2, lung cancer - 3, colorectal cancer - 1, traffic accident - 1, and stroke - 2 patients). A comparison between primary and secondary prevention patients was performed. Mean QRS width <118 ms, resting HR < 78 bpm and LVEF >30% were significant cutoff values for improved survival as determined using the ROC curves. HR >78 bpm was observed in all SCD patients. In Kaplan-Meier univariate analysis including 27 parameters potentially influencing survival, 10 significant parameters were identified (type of prevention, presence of cardiomyopathy, ventricular tachycardia, HR, QRS width, LVEF, NYHA class, performing DFT, and statin and diuretic treatment). In Cox multivariate analysis, risk of death was increased with mean LVEV <30% (3-fold increase in risk), no DFT (2-fold increase in risk), NYHA class III or IV (3-fold increase in risk), and no statin use (2-fold increase in risk). Mean HR <78 bpm and QRS width <118 ms were independently related to an increased survival.Death rate was higher in patients with LVEF <30%, NYHA class III or IV, no DFT performed and no statin treatment. In these patients, indications for cardiac resynchronisation therapy should be considered. HR <78 bpm and QRS width <118 ms are independent protective factors. HR >78 bpm was observed in all SCD patients. Sicker ICD patients live for a shorter time. The presence of atrial fibrillation, number of antiarrhythmic ICD interventions, ICD type and revascularisation approach did not affect survival/mortality.
- Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (the PROTECT Study). [Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- J Vet Intern Med 2012 Nov-Dec; 26(6):1337-49.
The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported.That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival.Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America.The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint.The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441-1152 days) versus the placebo group (441 days, IQR 151-641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491-1531 days) versus the placebo group (466 days, IQR 236-710 days) (log-rank P = .034).The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.