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.

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.).

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.

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.

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.

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.

Creating and Maintaining a Successful Service Line in an Academic Medical Center at the Dawn of Value-Based Care: Lessons Learned From the Heart and Vascular Service Line at UMass Memorial Health Care.

The service line (SL) model has been proven to help shift health care toward value-based services, which is characterized by coordinated, multidisciplinary, high-quality, and cost-effective care. However, academic medical centers struggle with how to effectively set up SL structures that overcome the organizational and cultural challenges associated with simultaneously delivering the highest-value care for the patient and advancing the academic mission. In this article, the authors examine the evolution of UMass Memorial Health Care's heart and vascular service line (HVSL) from 2006 to 2011 and describe the impact on its success of multiple strategic decisions. These include key academic physician leadership recruitments and engagement via a matrixed governance and management model; development of multidisciplinary teams; empowerment of SL leadership through direct accountability and authority over programs and budgets; joint educational and training programs; incentives for academic achievement; and co-localization of faculty, personnel, and facilities. The authors also explore the barriers to success, including the need to overcome historical departmental-based silos, cultural and training differences among disciplines, confusion engendered by a matrixed reporting structure, and faculty's unfamiliarity with the financial and organizational skills required to operate a successful SL. Also described here is the impact that successful implementation of the SL has on creating high-quality services, increased profitability, and contribution to the financial stability and academic achievement of the academic medical center.

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.

Usefulness of pancreatitis-associated protein, a novel biomarker, to predict severity of disease in ambulatory patients with heart failure.

Pancreatitis-associated protein (PAP) is a novel cytokine with putative anti-inflammatory effects. PAP gene expression has been found to be increased in the myocardium of rats with decompensated pressure-overload hypertrophy. A prospective pilot study was performed to test the hypotheses that PAP is elevated in ambulatory patients with heart failure (HF) and that concentrations correlate with the severity of disease. Blood samples were obtained from patients with HF (n = 70) and normal controls (n = 17). Patients with New York Heart Association class III and IV symptoms had a greater mean PAP than patients with class I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 µg/L, p <0.001) and normal controls (35.5 ± 4.0 vs 6.2 ± 0.5 µg/L, p <0.001). Receiver-operating characteristic curves revealed that PAP had similar sensitivity and specificity for HF admission at 6 months as B-type natriuretic peptide and equivalent predictive value for 12-month and 24-month all-cause mortality. On the basis of the receiver-operating characteristic curve analysis, patients were then grouped into those with a serum PAP <24 or ≥24 µg/L. Patients with PAP ≥24 µg/L had significantly worse renal function, greater B-type natriuretic peptide and C-reactive protein levels, higher pulmonary artery systolic pressure, and greater 6- and 24-month all-cause mortality (p <0.05). In conclusion, PAP levels correlate with disease severity in patients with HF and are a marker of cardiorenal syndrome, neurohormonal activation, and elevated filling pressures. PAP is a sensitive and specific marker for increased 6-month HF morbidity and 12- and 24-month all-cause mortality. These results justify the prospective evaluation of PAP as a novel prognostic marker for disease severity in patients with HF.

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.

Risk factors and comorbidities in a community-wide sample of patients hospitalized with acute systolic or diastolic heart failure: the Worcester Heart Failure Study.

OBJECTIVES: Few epidemiological studies have examined differences in the prevalence of risk factors and comorbidities in patients with systolic heart failure (HF), as compared with those with diastolic HF. METHODS: We analyzed data from 1426 residents of the Worcester (MA) metropolitan area hospitalized at all 11 greater Worcester medical centers for acute HF during 1995 and 2000 who had data available on ejection fraction (EF) findings during hospitalization. The analysis was conducted based on the presence of either normal (diastolic HF) as compared with reduced (systolic HF) EF, using an EF cutpoint of at least 50%. RESULTS: The average age of study patients was 71 years, 56% were women, and 43% had diastolic HF. Patients with diastolic HF were more likely to be older, female, obese, and to have higher systolic blood pressures and lower heart rates at the time of hospital presentation than patients with systolic HF. In contrast, patients with systolic HF had a greater prevalence of diabetes, previous myocardial infarction, and a history of alcohol abuse as compared with patients with diastolic HF. In multivariate analyses, the strongest metabolic correlates of diastolic HF were obesity, hypertension, and clustered metabolic risk factors; diabetes was associated with the occurrence of systolic HF. CONCLUSION: The results of our population-based investigation show that multiple risk factors and comorbidities are present in patients with systolic and diastolic HF. Consideration of these comorbidities and risk factors should be taken into account in distinguishing patients with diastolic HF from those with systolic HF and in their optimal management.