Rationale and Design of the SOTA-P-CARDIA Trial (ATRU-V): Sotagliflozin in HFpEF Patients Without Diabetes.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia. OBJECTIVES: The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients. METHODS: In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life. RESULTS: Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001). CONCLUSIONS: Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity?

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,…) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222).

Synopsis of an epidemiologic study of a Kentucky county in the Coronary Valley.

Kentucky is part of the Coronary Valley, which comprises ten states along the Ohio and Mississippi Rivers that rank among those with the highest incidence of heart disease in the United States. Kentucky consistently ranks near the highest in the nation, and within the state, the incidence is markedly higher in the eastern, Appalachian region. In a study of heart disease risk factors among residents of Clay County, which is located in this region, woe found, surprisingly, that the prevalence of elevated plasma cholesterol is slightly lower than in the United States overall. However, we noted a higher incidence of other traditional risk factors, including hypertension, cigarette smoking, obesity, and physical inactivity in this county, as well as a greater frequency of metabolic syndrome (MS) components. These findings may explain the high prevalence of cardiovascular (CV) disease in general and coronary heart disease (CHD) in particular, in parts of rural Appalachia even without the presence of significantly elevated cholesterol levels.

Large annuloplasty rings facilitate mitral valve repair in Barlow's disease.

BACKGROUND: Excess leaflet tissue in Barlow's disease predisposes patients to left ventricular outflow tract obstruction and residual mitral regurgitation after mitral valve repair as a result of systolic anterior motion of the anterior mitral leaflet. In addition to conventional repair techniques such as sliding plasty and leaflet shortening, our approach in Barlow's disease has included the use of large remodeling annuloplasty rings (up to size 40 mm). We report our experience with the use of large rings in Barlow's disease. METHODS: From January 2002 to December 2005, 67 patients with Barlow's disease (46 men and 21 women; median age, 55 years; range, 22 to 85 years), mean ejection fraction 0.55 +/- 0.08, and grade 3+ or greater mitral regurgitation underwent mitral valve repair. All had Carpentier type II leaflet dysfunction, with anterior (n = 2), posterior (n = 41), or bileaflet (n = 24) prolapse. Predominant reconstructive techniques were posterior leaflet sliding plasty/plication (n = 65), anterior leaflet triangular resection (n = 16), and chordal transfer (n = 25). Concomitant procedures included coronary artery bypass grafting surgery (n = 8), tricuspid valve repair (n = 20), aortic valve replacement (n = 3), and CryoMaze (n = 22). RESULTS: Mitral valve repair was successfully completed in all patients. Annuloplasty ring size was 36 mm (n = 17), 38 mm (n = 22), and 40 mm (n = 28). Predischarge transthoracic echocardiography showed absence of systolic anterior motion (n = 67), no or trace mitral regurgitation (n = 62), and mild mitral regurgitation (n = 5). There was no operative mortality. CONCLUSIONS: Mitral valve repair can be predictably performed in Barlow's disease with excellent early outcomes. Large annuloplasty rings help minimize the risk of systolic anterior motion and are an important adjunct to established repair techniques in this patient cohort with large annular size and excess leaflet tissue.

Surgical management of functional tricuspid regurgitation with a new remodeling annuloplasty ring.

BACKGROUND: Moderate-to-severe functional tricuspid regurgitation (TR) should be corrected in patients undergoing surgery for left-sided valvular diseases, to improve long-term outcomes. Several techniques of surgical repair (suture annuloplasty or prosthetic annuloplasty) to correct this condition have been described. Multiple clinical studies have shown the superiority of prosthetic remodeling annuloplasty over the other surgical approaches. Despite this, suture-based annuloplasty remains the most commonly used technique for tricuspid valve repair. A new 3-dimensional remodeling prosthesis has been developed to address the issue of residual TR. We report our early experience with this new 3-dimensional prosthetic remodeling ring, the Edwards MC 3 system. MATERIAL: From August 2002 to March 2004, 51 patients (24 male, 27 female, mean age 64 +/- 15, ejection fraction 49 +/- 15, median NYHA III [II-IV]) underwent tricuspid valve repair for functional TR due to annular dilatation, with the Edwards MC 3 system. Etiology of left-sided valvular disease was: rheumatic (n = 19), degenerative (n = 16), ischemic cardiomyopathy (n = 1), and endocarditis (n = 5). Twenty (50%) patients underwent redo operations. Concomitant procedures included: mitral valve surgery (repair n = 34, replacement n = 14), aortic valve replacement (n = 5), coronary artery bypass graft (n = 8) and left arterial maze (n = 16). Median EuroSCORE was 12% (1-74%) in this patient population. RESULTS: Operative and late mortality were 3.8% (n = 2) and 13.7% (n = 7), respectively. Echocardiography at discharge showed a mean TR decrease from 3.1 +/- 0.9 to 0.3 +/- 0.4 (p < 0.001) and mean mitral regurgitation (MR) decrease from 3.2 +/- 1 to 0.1 +/- 0.1 (p < 0.001), while ejection fraction increased to 53% (p = 0.047), and at 6-month follow-up, mean TR and MR remained unchanged. CONCLUSION: Concomitant tricuspid valve repair for functional TR with left-sided valve surgery carries a low operative mortality. The Edwards MC 3 annuloplasty system is relatively simple to implant and corrects TR effectively (without significant residual TR), while providing excellent short-term clinical results. The 3-dimensional saddle shape of this ring may further optimize the fixation of the annulus in systolic position, and improve long-term results. Larger clinical series with longer-term follow-up are necessary to confirm these early promising results.

Mitral valve repair with Carpentier-McCarthy-Adams IMR ETlogix annuloplasty ring for ischemic mitral regurgitation: early echocardiographic results from a multi-center study.

BACKGROUND: Ischemic mitral regurgitation (IMR) is associated with asymmetric changes in annular and ventricular geometry. Surgical repair with standard symmetric annuloplasty rings results in a high incidence of residual or recurrent mitral regurgitation (MR). The Carpentier-McCarthy-Adams (CMA) IMR ETlogix annuloplasty ring is the first remodeling ring specifically designed to treat asymmetric leaflet tethering and annular dilatation. We used quantitative 2-dimensional echo to examine early results of mitral valve (MV) repair with the CMA IMR ETlogix annuloplasty ring in patients with IMR. METHODS AND RESULTS: Fifty-nine patients (aged 68+/-12 years) with grade > or = 2+ IMR (graded on a scale of 0 to 4+) underwent MV repair with the CMA IMR ETlogix annuloplasty ring. We assessed the mitral annular diameter (MAD), tethering area (TA), and tenting height (TH) of the MV in 4-chamber, 2-chamber, and long axis views at mid-systole before and 3 to 10 days after surgery. After surgery, 57 of 59 (97%) patients had grade 0 or 1+ MR, whereas 2 patients had 2+ MR. MV repair with the CMA IMR ETlogix ring significantly reduced MAD, TA, and TH (P<0.001, for all 3 echo views), particularly in the long axis and 4-chamber views. CONCLUSIONS: Surgical repair of IMR with the novel asymmetric CMA IMR ETlogix annuloplasty ring provided excellent early results with effective reduction of MR, MAD, and leaflet tethering. This novel etiology-specific strategy may result in improved outcomes in IMR patients.

Multimodal characterization of a large right atrial mass after surgical repair of an atrial septal defect.

A 43-year-old woman with exertional dyspnea and a history of surgically repaired atrial septal defect was referred for a transthoracic echocardiogram, which demonstrated a large, mobile mass in her right atrium. The mass was further characterized with contrast transesophageal echocardiography (TEE) and delayed enhancement MRI, which together suggested a thrombus, attached to the eustachian valve and prolapsing through the tricuspid valve. The mass was resected and the diagnosis confirmed on histopathologic examination. This case illustrates the utility of a multimodal approach in characterizing cardiac masses.

Echocardiography in Percutaneous Balloon Mitral Valvuloplasty.

Percutaneous balloon valvuloplasty (BV) has been used successfully in recent years for the relief of mitral stenosis, and in many instances, as an alternative to cardiac surgery. This procedure requires precise evaluation of both valve morphology and function for preprocedure decision making and follow-up of patients. Two-dimensional (2-D) echocardiography is a unique, noninvasive tool for evaluating morphologic characteristics of valve, subvalvular apparatus, and valve annular size. Doppler echocardiography provides functional information on transvalvular flow velocity, which can be used to derive pressure gradient across valve and regurgitant flow. Mitral valve area can be either obtained from 2-D echocardiography or derived from Doppler pressure half time. Echocardiography is currently the most widely used technique for assessing results of percutaneous BV. More recently, transesophageal echocardiography (TEE) has been used for the evaluation of patients undergoing percutaneous mitral BV in whom left atrial thrombus is suspected and for the intraoperative monitoring of the valvuloplasty procedure. In this article we discuss the advantages and limitations of both transthoracic echocardiography and TEE, its recent developments in monitoring the procedure, evaluation of immediate results and long term follow-up after the valvuloplasty procedure, and its clinical utility in the selection of patients for percutaneous BV.