Perspectives on Secondary Mitral Regurgitation in Heart Failure.

PURPOSE OF THE REVIEW: This review focuses on broader perspectives of mitral regurgitation (MR) in patients with heart failure. RECENT FINDINGS: The ratio of regurgitant volume to end-diastolic volume appears to help identify patients who may benefit from valve interventions. Secondary MR is not only attributed to geometric changes of the LV but also related to the structural changes in the mitral valve that include fibrosis of the mitral leaflets and changes in the extracellular matrix. The transition from mild to severe secondary MR can occur at different rates, from a slow LV remodeling process to a more abrupt process precipitated by an inciting event such as atrial fibrillation. Septal flash and apical rocking, two new visual markers of LV mechanical dyssynchrony, appear to be predictive of MR reduction following cardiac resynchronization therapy. Optimal guideline-directed medical therapy has been shown to decrease the severity of secondary MR effectively. A theoretical framework to characterize secondary MR as it relates to the onset of MR is proposed. Type A: Early onset of MR contemporaneous with myocardial injury. The maladaptive LV remodeling occurs in parallel with MR. Type B: LV remodeling proceeds without significant MR until the LV is moderately dilated, which coincides with or without inciting factors such as atrial fibrillation. Type C: LV remodeling proceeds after myocardial injury without significant MR until the LV is severely dilated. MR is a late manifestation of LV remodeling.

Mitoxantrone-Induced Cardiotoxicity in Acute Myeloid Leukemia-A Velocity Vector Imaging Analysis.

BACKGROUND: The purpose of this investigation was to: (1) determine incidence and predictors of mitoxantrone-induced early cardiotoxicity and (2) study left ventricular mechanics before and after receiving mitoxantrone. METHOD AND RESULTS: We retrospectively analyzed 80 subjects diagnosed with acute myeloid leukemia (AML) who underwent chemotherapy with bolus high-dose mitoxantrone. Echocardiographic measurements were taken at baseline and at a median interval of 55 days after receiving mitoxantrone. Thirty-five (44%) of the patients developed clinically defined early cardiotoxicity, 29 (36%) of which developed heart failure. There was a significant decrease in the ejection fraction (EF) not only in the cardiotoxicity group (17.6 ± 14.8%, P < 0.001) but also in the noncardiotoxicity group (5.3 ± 8.4%, P < 0.001). Decrease in global longitudinal strain (GLS) (-3.7 ± 4.5, P < 0.001 vs. -2.4 ± 4.3, P = 0.01) and global circumferential strain (GCS) (-5.6 ± 9, P = 0.003 vs. -5.3 ± 8.7, P < 0.001) was significant in both the cardiotoxicity and noncardiotoxicity group, respectively. A multivariate model including baseline left ventricular end-systolic diameter, baseline pre-E/A ratio, and baseline pre-E/e' ratio was found to be the best-fitted model for prediction of mitoxantrone-induced early clinical cardiotoxicity. CONCLUSION: High-dose mitoxantrone therapy is associated with an excellent remission rate but with a significantly increased risk of clinical and subclinical early cardiotoxicity and heart failure. Mitoxantrone-induced systolic dysfunction is evident from reduction in EF, increase in Tei index, and significant reduction in GLS and GCS. Baseline impaired ventricular relaxation evident from higher E/e' ratio and lower E/A ratio independently predicts increased risk of mitoxantrone-induced early cardiotoxicity.

Decision-making under uncertainty in advanced heart failure.

The challenges managing advanced heart failure (AHF) are mounting, not least by the presence of multiple coexisting comorbidities, the lack of evidence of clinical benefit in many subsets of AHF, but also surrounding the uncertainty of the both short-term and long-term prognosis. Clinicians are highly variable in their interpretation of clinical data and are prone to considerable bias when it comes to treatment recommendations. This manuscript provides a critical appraisal of the uncertainties as it pertains to the natural history of AHF and management decisions. First, clinical examples are explored to illustrate common errors of judgment due to unrecognized biases. Secondly, a tool is provided that promulgates a structured approach to key data elements in an attempt to create a sound platform for decision-making.

Systolic pulmonary and hepatic vein flow reversal due to pacemaker-induced retrograde ventriculoatrial conduction.

Systolic pulmonary and hepatic vein flow reversals can typically be seen with severe atrioventricular (AV) valve regurgitation and during atrial fibrillation (AF). We report the case of a 67-year-old woman who presented with recent-onset exertional dyspnea. Her pacemaker was near end-of-life and reverted to a VVI mode from the preset DDDR mode. Electrocardiography demonstrated retrograde 1:1 ventriculoatrial (VA) conduction and spectral Doppler analysis revealed prominent systolic pulmonary and hepatic vein flow reversals. Symptoms, electrocardiogram (ECG) findings, and the spectral Doppler abnormalities resolved completely following a generator replacement and resumption of DDDR pacing.

Alterations in early filling dynamics predict the progression of compensated pressure overload hypertrophy to heart failure better than abnormalities in midwall systolic shortening.

To evaluate whether the evolution of compensated pressure overload hypertrophy (POH) to overt heart failure (HF) is better predicted by systolic versus diastolic dysfunction, serial echocardiography was performed 1, 2, 4, 8, and 10 weeks after suprarenal aortic banding in 52 rats. One week after banding, at comparable extent of left ventricular hypertrophy and geometry, myocardial and chamber systolic performance, a restrictive filling pattern was well evident only in rats which eventually developed overt HF, according to postmortem lung weight. In experimental POH, early assessment of transmitral flow velocity allows to predict a faster progression toward HF.

High-Output Heart Failure in a Patient With Klippel-Trénaunay Syndrome: A Case Report.

Klippel-Trénaunay syndrome (KTS) is a rare and complex congenital syndrome defined as the triad of cutaneous capillary malformation, bone and soft tissue hypertrophy, and venous and lymphatic malformations. KTS is thought to be due to a somatic mutation in phosphatidyl-inositol 3 kinase. It belongs to a group of syndromes termed the PI3CA-Related Overgrowth Spectrum (PROS) disorders. Because of the rarity and clinical heterogeneity of these disorders, management is patient specific, and best evidence guidelines are lacking. The most common clinical complications are thromboembolism, thrombophlebitis, pain, bleeding, and high-output heart failure. Surgery is recommended for hemangiomas and chronic venous insufficiency. The early identification of children with PROS disorders has allowed treatment with mTOR inhibitors which have been shown to be effective. The recent development of a direct PI3K inhibitor (alpelisib) has shown promise in preventing abnormal growth and long-term complications of KTS. This report documents a case of high-output heart failure due to the vascular malformations associated with KTS in a 57-year-old male patient and discusses current literature regarding the management of KTS with inhibitors of mTOR and PI3KCA.

An Appraisal of the Association of Clinical Outcomes With the Severity of Regurgitant Volume Relative to End-Diastolic Volume in Patients With Secondary Mitral Regurgitation.

Importance: Two randomized clinical trials of transcatheter edge-to-edge mitral valve repair in patients with secondary mitral regurgitation (the Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation [MITRA-FR] and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]) report clinical outcome disparities that are largely unexplained. This appraisal sought to provide insight and an explanation for the differences in clinical outcomes (survival and hospitalization rates) in the 2 clinical trials. The mean echocardiogram Doppler results (and derived volume parameters) from each of the 2 clinical trials were compared and examined relative to the clinical outcomes. Special emphasis was placed on the assessment of mitral regurgitation proportionality coefficients that were determined as the ratio of effective regurgitant orifice area (EROA) to end-diastolic volume and the ratio of mitral regurgitant volume to end-diastolic volume. Observations: In this analysis of the differences in the clinical outcomes of the MITRA-FR and COAPT clinical trials, the ratio of the EROA to the end-diastolic volume in the COAPT study was found to be twice that of the MITRA-FR study (0.002 cm-1 vs 0.001 cm-1, respectively). The finding of a larger proportional EROA in the COAPT study suggests more severe mitral regurgitation compared with the MITRA-FR study, thereby providing a potential explanation for the different outcomes in the 2 clinical trials. In contrast, the ratio of the mitral regurgitant volume to the end-diastolic volume in the COAPT study was similar to (but slightly lower than) that of the MITRA-FR study (0.15 vs 0.18, respectively), indicating that the proportional mitral regurgitant volume was comparable in the 2 clinical trials. This finding contradicts the conclusions of the EROA analysis. Conclusions and Relevance: The results of proportionality analyses based on EROA differ from those based on a volume analysis. This disparity casts doubt on the notion that an EROA analysis alone can explain the different results of the 2 randomized clinical trials.

Recurrent and Life-Threatening Peripartum Cardiomyopathy: Diagnosis, Delivery Considerations, and Management.

Peripartum cardiomyopathy is an idiopathic reduction in left ventricular systolic function (ejection fraction <45%) toward the end of pregnancy or in the months after delivery. A multidisciplinary approach to management with shock team support is key to identifying and adequately treating patients with refractory heart failure and peripartum cardiomyopathy. (Level of Difficulty: Intermediate.).

Long-term survival after heart failure: a contemporary population-based perspective.

BACKGROUND: Heart failure (HF) is a major public health problem that is associated with substantial morbidity, impaired quality of life, and diminished survival. Despite the considerable prevalence of HF in the United States, there are limited published data describing the contemporary long-term prognosis of patients hospitalized with decompensated HF. METHODS: A total of 2445 residents in the Worcester metropolitan area discharged from 11 greater Worcester hospitals after confirmed acute HF during 2000 comprised the study sample. Follow-up of discharged hospital survivors was carried out through 2005. RESULTS: The mean age of the study population was 76 years, 43.4% were men, and approximately three quarters had been previously diagnosed as having HF. Among discharged hospital patients, 37.3% died during the first year after hospital discharge, while 78.5% died during the 5-year follow-up period. Several subgroups of patients were at significantly increased risk for dying during the first year after hospital discharge. This included older persons (> or =85 years) (adjusted odds ratio [OR], 2.11; 95% confidence interval [CI], 1.35-3.29), patients with a history of chronic obstructive pulmonary disease (OR, 1.39; 95% CI, 1.15-1.69) or HF (OR, 1.26; 95% CI, 1.00-1.59), and patients with elevated serum urea nitrogen levels during hospitalization (OR, 1.02; 95% CI, 1.01-1.03). CONCLUSIONS: The results of our community-wide study demonstrate the poor long-term prognosis of patients surviving hospitalization for decompensated HF. Despite advances in the therapeutic management of these patients, their long-term survival remains guarded. Efforts are needed to improve the long-term survival of patients with this clinical syndrome.

Secondary mitral regurgitation (part 1): volumetric quantification and analysis.

Secondary mitral regurgitation (MR) develops as a consequence of left ventricular (LV) dilatation and dysfunction, which complicates its evaluation and management. The goal of this article is to review the assessment of secondary MR with special emphasis on quantification and analysis of LV volume data. At the present time, the optimal method for making these measurements appears to be cardiac MRI. In severe MR (both primary and secondary), the regurgitant fraction (RF) exceeds 50%, and as a result, the LV end diastolic volume (EDV) is increased. In secondary MR, the ejection fraction is depressed (generally <40%) and despite an RF >50%, the regurgitant volume (RegV) rarely meets the current published criteria for severe MR (>60 mL). The ratio of the RegV to EDV, which is very low in secondary MR, reflects the effect of the RegV on the ventricle and it may be predictive of the fractional change in LV size that can be expected after correction of MR. Accurate measurement of the volumetric parameters is essential to proper management of patients with secondary MR.

Secondary mitral regurgitation (part 2): deliberations on mitral surgery and transcatheter repair.

Secondary mitral regurgitation (MR) develops as a consequence of postinfarction remodelling of the ventricle or other causes of left ventricular (LV) dilatation and dysfunction. The presence of MR amplifies the poor prognosis of the failing ventricle, but it has not been established whether the adverse outcomes stem from the MR or whether the MR is simply a marker of progressive LV dysfunction. In this article, an attempt will be made to clarify the clinical impact of mitral surgery and transcatheter repair in patients with secondary MR. Observational studies indicate symptomatic improvement, but the results of randomised trials are mixed. Furthermore, neither mitral surgery nor transcatheter repair consistently leads to reversal of the adverse LV remodelling. There is, however, general agreement that these procedures do not have a salutary effect on survival. Certainly mitral surgery and transcatheter repair can substantially reduce the mitral regurgitant flow, but inconsistencies and uncertainties regarding clinical outcomes persist in the published literature. Some such problems could be resolved by utilisation of more accurate and reproducible imaging modalities in randomised studies of patients who are most likely to benefit from a reduction in the regurgitant volume-namely those with the most severe MR.

Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure.

OBJECTIVES: Myocardial adenosine is increased in pressure-overload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A1-receptor gene and protein expression in experimental POH. METHODS: Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A1-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats). RESULTS: Both mRNA and protein A1-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues. CONCLUSIONS: In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease.

Heart failure in the "oldest old": clinical and echocardiographic insights.

While the incidence and prevalence of heart failure (HF) increase markedly with age, few studies have included data on a large series of patients aged 85 years and older. Clinical and echocardiographic data from 533 patients admitted to a tertiary care hospital for acute HF were obtained. Data from the oldest old (>or=85 years; n=252; mean age, 91.9+/-3.6 years) were compared with data from those aged 65 to 74 years (n=123; mean age, 70.1+/-2.8 years) and 75 to 84 years (n=158; mean age, 79.4+/-2.9 years). Echocardiographic data were consistent with hypertensive remodeling. The proportion of patients with HF and a preserved left ventricular ejection fraction was greatest in the oldest patients (61%) in comparison to patients aged 65 to 74 years (48%) and 75 to 84 years (48%). Approximately three-fourths of the oldest patients were women, and two-thirds of women had a left ventricular ejection fraction >or=50%.

Impedance to retrograde and forward flow in chronic mitral regurgitation and the physiology of a double outlet ventricle.

OBJECTIVE: Mitral regurgitation (MR) is generally characterised as exhibiting a 'low impedance leak into the left atrium'. This notion is widely accepted without measured impedance data. The aim of this study was to define the impedance to retrograde and forward blood flow and to examine hydraulic (pressure-volume) and mechanical (stress-shortening) function in chronic severe MR. METHODS: A mathematical model of a double outlet ventricle was developed and the ratio of retrograde to forward impedance was plotted over a wide range of regurgitant fraction (RF). The model predicts that an impedance ratio >1 indicates that the impedance to retrograde flow exceeds that of forward flow. Left ventricular (LV) systolic pressure/flow rate was used as an index of impedance (mm Hg/mL/s). Data from 10 patients with severe MR were used to assess the clinical applicability of the model. All patients had degenerative valve disease with partial flail leaflet, an RF >50% and an ejection fraction (EF) >0.60. There were seven males and three females, aged 59±10. LV volumes as well as retrograde and forward flow rates were determined with echocardiographic and Doppler techniques. RESULTS: The model indicates that the impedance ratio is >1 when the RF ranges from zero to 57%. Clinical data: end-diastolic volume=184±47 mL; EF=0.63±3%; RF=53±4%. Values for retrograde and forward impedance were 0.77±0.17 and 0.63±0.12 (p=0.003); the impedance ratio was 1.22±0.19. Total impedance to LV emptying was low (0.35±0.06). The ratio of systolic wall stress to EF (580±81 g/cm2) was normal. Data are mean±SD. CONCLUSIONS: The model, supported by clinical data, indicates that the impedance to retrograde flow exceeds the impedance to forward flow in chronic severe MR. These findings refute the notion of a low impedance leak into the left atrium. The double outlet of an enlarged ventricle provides a mechanism for low total impedance to ejection in the presence of a normal stress-shortening relation.

Bioimpedance-Based Heart Failure Deterioration Prediction Using a Prototype Fluid Accumulation Vest-Mobile Phone Dyad: An Observational Study.

BACKGROUND: Recurrent heart failure (HF) events are common in patients discharged after acute decompensated heart failure (ADHF). New patient-centered technologies are needed to aid in detecting HF decompensation. Transthoracic bioimpedance noninvasively measures pulmonary fluid retention. OBJECTIVE: The objectives of our study were to (1) determine whether transthoracic bioimpedance can be measured daily with a novel, noninvasive, wearable fluid accumulation vest (FAV) and transmitted using a mobile phone and (2) establish whether an automated algorithm analyzing daily thoracic bioimpedance values would predict recurrent HF events. METHODS: We prospectively enrolled patients admitted for ADHF. Participants were trained to use a FAV-mobile phone dyad and asked to transmit bioimpedance measurements for 45 consecutive days. We examined the performance of an algorithm analyzing changes in transthoracic bioimpedance as a predictor of HF events (HF readmission, diuretic uptitration) over a 75-day follow-up. RESULTS: We observed 64 HF events (18 HF readmissions and 46 diuretic uptitrations) in the 106 participants (67 years; 63.2%, 67/106, male; 48.1%, 51/106, with prior HF) who completed follow-up. History of HF was the only clinical or laboratory factor related to recurrent HF events (P=.04). Among study participants with sufficient FAV data (n=57), an algorithm analyzing thoracic bioimpedance showed 87% sensitivity (95% CI 82-92), 70% specificity (95% CI 68-72), and 72% accuracy (95% CI 70-74) for identifying recurrent HF events. CONCLUSIONS: Patients discharged after ADHF can measure and transmit daily transthoracic bioimpedance using a FAV-mobile phone dyad. Algorithms analyzing thoracic bioimpedance may help identify patients at risk for recurrent HF events after hospital discharge.

Use of nonpharmacologic treatment approaches in patients with heart failure.

BACKGROUND: Patient education has been shown to beneficially impact the utilization of medical resources and certain outcomes in patients hospitalized with heart failure (HF). Little data are, however, available about the implementation of patient education and counseling of patients with HF in the community setting. The purpose of the present investigation was to examine the extent of health care provider recommendations for the monitoring or modification of lifestyle approaches or dietary factors in patients with new onset HF discharged from all greater Worcester (MA) hospitals in 2000. METHODS: The study sample consisted of 2411 metropolitan Worcester residents hospitalized at all 11 area medical centers with acute HF. Based on the review of medical records, we examined provider recommendations for the monitoring or modification of 5 lifestyle factors including salt restriction, dietary changes, increased physical activity, limitation of fluids, and daily monitoring of weight in hospital survivors of HF. RESULTS: Among all patients, approximately 22% were recommended to change either no or 1 lifestyle related factor, 2 in every 5 patients received recommendations to alter any 2 lifestyle characteristics, while 1 in 6 were counseled about the importance of monitoring or modifying 4 or more lifestyle or dietary factors. Physician counseling was associated with several demographic and clinical factors. Documentation of none or few patient education recommendations was also associated with the failure to receive multiple effective medical therapies for HF. CONCLUSIONS: The results of our community-wide investigation suggest that considerable opportunity remains for the more effective hospital counseling of patients with acute HF.

Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure: the National Registry of Myocardial Infarction.

BACKGROUND: Heart failure (HF) is an important predictor of poor outcome after acute myocardial infarction (AMI). However, limited data exist about the clinical significance of HF in the coronary reperfusion era and the impact of its timing on hospital outcomes. The objective of this study was to determine the clinical impact of HF complicating AMI in the National Registry of Myocardial Infarction (NRMI). A secondary objective was to determine differences in demographic and clinical characteristics, treatment, and hospital death rates in patients presenting with HF compared with those developing HF after presentation. METHODS AND RESULTS: The study sample consisted of patients with AMI and without a history of HF included in the NRMI. Of 606 500 cases included from July 1, 1994 to June 30, 2000, 123 938 (20.4%) patients had HF at the time of hospital presentation and 52 220 (8.6%) developed HF thereafter. Patients with HF were older, more likely female, had more comorbidities, and were less likely to receive effective cardiac medications compared with patients without HF. The multivariable adjusted odds for in-hospital death were higher for patients with HF at presentation and thereafter (3.1 and 5.5, respectively) than those without HF. CONCLUSIONS: Results from this nationwide registry suggest that the incidence and hospital death rates associated with HF complicating AMI remain high. Patients developing HF after hospital admission are at even greater risk than those presenting with HF. Effective cardiac therapies remain underutilized in these patients, and the reasons for this underutilization need to be explored.

Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction.

OBJECTIVES: We sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BACKGROUND: The mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. METHODS: Twenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. RESULTS: The LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure-diameter relationship and ex vivo from the pressure-volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress-midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress-strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. CONCLUSIONS: The two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.