Functional mitral regurgitation (FMR) can be broadly categorized into 2 main groups: ventricular and atrial, which often coexist. The former is secondary to left ventricular remodeling usually in the setting of heart failure with reduced ejection fraction or less frequently due to ischemic papillary muscle remodeling. Atrial FMR develops due to atrial and annular dilatation related to atrial fibrillation/flutter or from increased atrial pressures in the setting of heart failure with preserved ejection fraction. Guideline-directed medical therapy is the first step and prevails as the mainstay in the treatment of FMR. In this review, we address the medical therapeutic options for FMR management and highlight a targeted approach for each FMR category. We further address important clinical and echocardiographic characteristics to aid in determining when medical therapy is expected to have a low yield and an appropriate window for effective interventional approaches exists.

HomeCirculation: Heart FailureVol. 15, No. 8Letter by Li and Nie Regarding Article, “Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Li and Nie Regarding Article, “Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility” Ruopu Li, MD, PhD and Yu Nie, PhD Ruopu LiRuopu Li https://orcid.org/0000-0002-7724-018X State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Search for more papers by this author and Yu NieYu Nie https://orcid.org/0000-0002-8744-0046 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Search for more papers by this author Originally published27 Jun 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.009531Circulation: Heart Failure. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 27, 2022: Ahead of Print To the Editor:We read with great interest the recent article by Prisco et al1 regarding the cardiac-protective role of gp130 blockade in monocrotaline induced pulmonary artery hypertension reflected by the antihypertrophy, antifibrotic effect, and the mitigated right ventricle function after gp130 antagonist SC-144 administration. The study expanded our consideration of gp130’s downstream signal to right heart function and its connecting role of inflammation, cytoskeleton organization and energy metabolism. However, here are some questions we would like to raise regarding the findings in the original article.Regenerative repair after myocardial injury requires gp130-induced STAT3 and Src-YAP pathways.2,3 And it has been reported that the loss of gp130 signaling in heart lead to adaption incapacity under biomechanical stress of pressure overload.4 We would like to respectfully ask what is the authors’ perspective on the opposite biological effect of gp130 concerning cardiac tissue response toward stress between left and right ventricle.Although major, there are different pathways downstream of gp130 other than Jak-STAT3. Did the author also detect other signaling pathways, including Erk-MAPK (extracellular regulated protein kinases-mitogen activated protein kinase pathway), PI3K-Akt (phosphoinositide-3 kinase-serine/threonine kinase Akt [also known as protein kinase B or PKB] pathway), and Src-YAP (pathway of proto-oncogene tyrosine-protein kinase Src and its downstream protein Yes associated protein [YAP]) pathways, in the pulmonary artery hypertension model before and after SC-144 administration? And did the author confirm the similar effect with SC-144 treatment under STAT3 antagonized model? SC-144 was adopted for the construction of gp130 depletion model. But the agent triggers different gp130 downstream signaling alteration including STAT3 inhibition and Erk activation.5The author treated immortalized H9c2 cell line with cytoskeleton stabilizer paclitaxel and detected an impaired mitochondrial metabolic activity. Here, we expected whether cytoskeleton interference would result in the same outcome in mitochondrial metabolism in primary neonatal rat ventricular myocytes (primary cardiomyocytes isolated form neonatal Rattus norvegicus). Paclitaxel has cytotoxicity on proliferative cells by inhibiting spindle formation, and cell mitosis is an energy-consuming process. So, the impair of cell cycle results in metabolic dysfunction. It is confusing whether it was due to the cell cycle toxicity or the cytoskeleton stabilizing that causes the alteration of mitochondrial metabolism.Article InformationSources of FundingThis work was supported by the National Natural Science Foundation of China (grant 81970243) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2021-I2M-1-008).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 823.

Male hypogonadism is defined as low circulating testosterone level associated with signs and symptoms of testosterone deficiency. Although the bidirectional link between hypogonadism and cardiovascular disease has been clarified, the association between testosterone and chronic heart failure (HF) is more controversial. Herein, we critically review published studies relating to testosterone, hypogonadism, and HF and provide practical clinical information on proper diagnosis and treatment of male hypogonadism in patients with HF. In general, published studies are extremely heterogeneous, frequently have not adhered to hypogonadism guidelines, and suffer from many intrinsic methodological inaccuracies; therefore, data provide only low-quality evidence. Nevertheless, by selecting the few methodologically robust studies, we show the prevalence of testosterone deficiency (30%-50%) and symptomatic hypogonadism (15%) in men with HF is significant. Low testosterone correlates with HF severity, New York Heart Association class, exercise functional capacity, and a worse clinical prognosis and mortality. Interventional studies on testosterone treatment in men with HF are inconclusive but do suggest beneficial effects on exercise capacity, New York Heart Association class, metabolic health, and cardiac prognosis. We suggest that clinicians should measure testosterone levels in men with HF who have symptoms of a testosterone deficiency and conditions that predispose to hypogonadism, such as obesity and diabetes. These patients-if diagnosed as hypogonadal-may benefit from the short- and long-term effects of testosterone replacement therapy, which include improvements in both cardiac prognosis and systemic outcomes. Further collaborative studies involving both cardiologists and endocrinologists are warranted.

Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure. In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals. Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18-110] versus 74 [27-168] ng/L; P<0.01) and NT-proBNP (median, 212 [72-581] versus 297 [102-902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95-0.98] and 0.95 [95% CI, 0.93-0.96] versus 0.94 [95% CI, 0.92-0.95] and 0.91 [95% CI, 0.90-0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01). BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters. URL: https://www. gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.

Minimally invasive surgery for left ventricular assist device implantation may have advantages over conventional sternotomy (CS). Additionally, ultra-fast-track anesthesia has been linked to better outcomes after cardiac surgery. This study summarizes our early experience of combining minimally invasive surgery with ultra-fast-track anesthesia (MIFTA) in patients receiving HeartMate 3 devices and compares the outcomes between MIFTA and CS. From October 2015 to January 2019, 18 of 49 patients with Interagency Registry for Mechanically Assisted Circulatory Support profiles >1 underwent MIFTA for HeartMate 3 implantation. For bias reduction, propensity scores were calculated and used as a covariate in a regression model to analyze outcomes. Weighted parametric survival analysis was performed. In the MIFTA group, intensive care unit stays were shorter (mean difference, 8 days [95% CI, 4-13]; P<0.001), and the incidences of pneumonia and right heart failure were lower than those in the CS group (odds ratio, 1.36 [95% CI, 1.01-1.75]; P=0.016, respectively). At 6 and 12 hours postoperatively, MIFTA patients had a better hemodynamic performance with lower pulmonary wedge pressure (mean difference, 2.23 mm Hg [95% CI, 0.41-4.06]; P=0.028) and a higher right ventricular stroke work index (mean difference, -1.49 g·m/m2 per beat [95% CI, -2.95 to -0.02]; P=0.031). CS patients had a worse right heart failure-free survival rate (hazard ratio, 2.35 [95% CI, 0.96-5.72]; P<0.01). Compared with CS, MIFTA is a beneficial approach for non-Interagency Registry for Mechanically Assisted Circulatory Support 1 HeartMate 3 patients with lower adverse event incidences, better hemodynamic performance, and preserved right heart function. Future large multicentric investigations are required to verify MIFTA's effects on outcomes.

Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients hospitalized with acute heart failure. We investigated whether SBP-drops are associated with outcomes in patients treated with serelaxin. Patient-level retrospective analyses of 4 prospective trials investigating serelaxin in acute heart failure. Main inclusion criteria were SBP 125 to 180 mm Hg, pulmonary congestion, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide). SBP-drops were prospectively defined as SBP<100 mm Hg, or, if SBP remained >100 mm Hg, a drop from baseline of 40 mm Hg from baseline. Outcomes were a short-term composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality. Overall, 2559/11 226 (23%) patients had an SBP-drop. SBP-drop, versus no SBP-drop, was associated with a worse outcome: cumulative incidence of 180-day mortality (11% versus 9%, hazard ratio [HR]. 1.21 [95% CI, 1.05-1.39]; P=0.009) and the short-term outcome (11% versus 9%, HR, 1.29 [95% CI, 1.13-1.49]; P<0.001). Of the 2 SBP-drop components, an SBP<100 mm Hg was associated with the worst outcome compared with a 40 mm Hg drop: short-term outcome (11% versus 10%) and HRs of 1.32 (95% CI, 1.13-1.55; P=0.0005) and 1.22 (95% CI, 0.97-1.56; P=0.09), for each component respectively, with a P value for interaction of 0.05. SBP-drops were associated with a worse short-term outcome in the placebo group (HR, 1.46 [95% CI, 1.19-1.79]; P=0.0003), but not in the serelaxin-group (HR, 1.18 [95% CI, 0.97-1.42]; P=0.10); P interaction=0.003. SBP-drops in patients with acute heart failure and normal to high SBP at admission is associated with worse short- and long-term outcomes especially for SBP <100 mm Hg. However, in patients treated with the intravenous vasodilator serelaxin, SBP-drops seemed less harmful. URL: https://www. gov; Unique identifiers: NCT02064868, NCT02007720, NCT01870778, NCT00520806.

Epicardial adipose tissue (EAT) accumulation is thought to play a role in the pathophysiology of heart failure (HF) with mid-range and preserved ejection fraction, but its effect on outcome is unknown. We evaluated the prognostic value of EAT volume measured with cardiac magnetic resonance in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction. Patients enrolled in a prospective multicenter study that investigated the value of implantable loop-recorders in HF with mid-range ejection fraction and HF with preserved ejection fraction were analyzed. EAT volume was quantified with cardiac magnetic resonance. Main outcome was the composite of all-cause mortality and first HF hospitalizations. Hazard ratios (HR) and 95% CI are described per SD increase in EAT. We studied 105 patients (mean age 72±8 years, 50% women, and mean left ventricular ejection fraction 53±8%). During median follow-up of 24 (17-25) months, 31 patients (30%) died or were hospitalized for HF. In univariable analysis, EAT was significantly associated with a higher risk of the composite outcome (HR, 1.76 [95% CI, 1.24-2.50], P=0.001), and EAT remained associated with outcome after adjustment for age, sex, and body mass index (HR, 1.61 [95% CI, 1.13-2.31], P=0.009), and after adjustment for New York Heart Association functional class and N-terminal of pro-brain natriuretic peptide (HR, 1.53 [95% CI, 1.04-2.24], P=0.03). Furthermore, EAT was associated with all-cause mortality alone (HR, 2.06 [95% CI, 1.26-3.37], P=0.004) and HF hospitalizations alone (HR, 1.54 [95% CI, 1.04-2.30], P=0.03). EAT accumulation is associated with adverse prognosis in patients with HF with mid-range ejection fraction and HF with preserved ejection fraction. This finding supports the importance of EAT in these patients with HF. URL: https://www. gov; Unique identifier: NCT01989299.

In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes. Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%. Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF (P value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission. In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.