CVD Prevention in Asia- A Status Update and Future Directions

Lee HY, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans that discussed on cardiovascular disease prevention in Asia. According to Zhao D, et al., JACC Asia 2021 paper, cardiovascular disease is the leading cause of death in Asia in 2019 with 35% of total death while 39% of CVD deaths and premature death. From 1990 to 2019, CVD deaths increased 5.6 million to 10.8 million. Crude mortality rates increased both in men and women and age-standardized CVD mortality is decreasing. The proportion of premature CVD deaths was substantially lower in high-income Asian countries. In total CVD deaths among Asian regions, IHD and stroke deaths have high proportion.

Obesity, aging, and high salt intake are the triple threat to cardiovascular disease control in Asia. As per the East-West center 2002 study, there will be significant growth of the elderly population > 75 years old in Asia till 2050. From 2000-2020, obesity showed increased prevalence in Asian countries, and the obesity rate in elderly is increasing. In Wild S, et al., 2004 study, India will have the highest prevalence of diabetes by 2030 with 151% increase in patients. Lancet’s 2019 study showed that an age-standardized proportion of deaths are attributable to individual dietary risks with excessive intake of high sodium in the Asian population. SBP change with age is directly proportional according to their habitual daily salt intake. In the Korean HT population, the same distribution of renin activity status was observed as white westerners. In the Asian region, high sodium intake has a direct association with an increased risk of stroke. Also, Perkvoic V, et al. study showed the linear relationship between SBP and stroke risk is markedly more pronounced in Asian patients than in Caucasian patients. Elderly patients have a high risk of hypertension among chronic conditions. As per the 2021 study, hypertension and diabetes have a high prevalence as comorbidities in HF patients.

CVD mortality rate is continuously increasing in Asia. CVD mortality in Asia showed marked geographic differences due to the combined effects of age and other determinants including SES. Whereas IHD is the main dominant type for CVD deaths in Central, Western, and Southern Asia, stroke is much more common than IHD in Eastern and South-eastern Asia. Social aging, obesity, and high salt intake become triple threats of CVD control in Asia, forming a vicious cycle.


Implementation Strategies to Improve Global Heart Failure Care: HFrEF Polypills

Agarwal A, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans. The high-quality evidence stated that guideline-directed medical therapy (GDMT) substantially reduces morbidity and mortality of patients. 1 in 4 patients with HFrEF are discharged on GDMT. The lack of GDMT is associated with higher mortality at 5 years (p<0.001). A systemic review from 14 RCTs exhibited no consistent effect on GDMT at hospital discharge. From these trials, there is no trials from low- and middle-income countries.

Qualitative research is done in Kerala with 21 semi-structured in-depth interviews. Among 1400 patients hospitalized with HF, a locally contextualized quality improvement intervention increased GDMT at discharge from 28% in the control period to 41% in the intervention period. Additional implementation strategies are needed to improve care for HFrEF patients. HFrEF polypills work as a pragmatic implementation strategy. A pilot randomized trial investigated the HFrEF polypill implementation strategy in India. 40 patients were randomized in 1:1 proportion. Polypill intervention was done stepwise. In step 1 half dose, step 2 full dose, and step 3 double dose of drugs was given. In a multicentre, type I hybrid, randomized clinical trial, 900 patients were equally randomized. The primary outcome of the study was a composite rate of CVD mortality and HF hospitalizations at 12 months.

Future directions of HFrEF polypill formative research can be done through the 4 stages

  • Implementation – Implementation in other settings within and beyond India
  • Evaluation – Evaluating additional multi-level implementation strategies
  • Evolution – Incorporating new medications into future-generation HFrEF polypills
  • Extension – Extending the polypill-based implementation strategy to other under-treated conditions

Long-term goals as global cardiovascular physician should include generating new evidence as a global cardiovascular clinical trialist to improve cardiovascular care in low and middle-income countries and bring lessons back to the US, using implementation science methods to contextualize, scale, and increase the impact of interventions across global settings, developing expertise in regulatory science to lead large scale trials and translate findings to global health policy to impact clinical practice and public health and mentoring trainees and early career scientists to advance the field of global CV health research, including global CV trials.


Anticoagulation Strategies in Non-critically Ill Hospitalized Covid-19 Patients: Principal Outcomes of The Freedom Covid Anticoagulation Trial

Fuster V, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans. Mononuclear cell activation, endothelial cell inflammation, and vascular damage are the hallmarks of COVID-19, which cause diffuse in situ pulmonary micro thrombosis in addition to arterial and venous thrombosis. The standard of care in hospitalised COVID-19 patients is prophylactic dose anticoagulation. It is unknown if full-dose oral anticoagulation with a direct-acting anticoagulant or a heparin-based regimen can further enhance clinical results without causing more bleeding.

An international investigator-sponsored trial in which 3600 hospitalized patients with confirmed COVID-19 not requiring ICU-level treatment were randomized 1:1:1 to prophylactic-dose SQ Enoxaparin (40 mg qd; 30 mg qd for CrCI <30 ml/min); full-dose SQ Enoxaparin (1 mg/kg bid; 1 mg/kg qd for CrCI <30mL/min), or oral Apixaban (5 mg bid; 2.5 mg bid for high-bleeding risk). The primary endpoints assessed were; 30-day composite rate of all-cause mortality, requirement for ICU level of care, systemic thromboembolism, or ischemic stroke, and the primary safety endpoint assessed was the in-hospital rate of BARC types 3 or 5 bleeding.

Out of a total of 3434 non-critically ill hospitalized COVID-19 patients, 1149 patients were randomized to prophylactic-dose Enoxaparin, 1150 patients to full-dose Enoxaparin or 1135 patients to Apixaban. The mean age was 52.5 ± 15.9 years; 59.8% were male, 19.6% had diabetes, 16.6% were current or past smokers, and 8.4% had chronic lung disease. Corticosteroids and Remdesivir were both used pre-admission in 21.6% and 9.5%, respectively. 89.8% of CT scans and 81.5% of chest x-rays taken at admission were abnormal. Follow-up is complete through 30 days and is ongoing through 90 days.

This is the largest randomised trial to date evaluating outcomes with various anticoagulant regimes in patients hospitalised with COVID-19 who are non-critically ill.


The STELLAR Phase III Trial: A Study of Sotatercept in Combination with Background Therapy for The Treatment of Pulmonary Arterial Hypertension

Hoeper M, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans. A progressive condition known as pulmonary arterial hypertension (PAH) causes proliferative remodeling of the pulmonary arteries and elevations in pulmonary vascular resistance (PVR). Sotatercept binds to select TGF-β superfamily ligands and rebalances anti-proliferative (BMPR-II-mediated) and pro-proliferative (ActRIIA-mediated) signaling, potentially reversing pulmonary vascular remodeling.

In the PULSAR Phase II trial, Sotatercept dramatically and sustainably decreased PVR throughout the course of 18 months of treatment. STELLAR is the pivotal Phase III trial of Sotatercept in adult participants (pts) with PAH. In the multicenter, double-blind STELLAR trial, PAH patients were randomized1:1 to receive Sotatercept or a placebo subcutaneously every three weeks along with background PAH medication. The beginning dose of Sotatercept was 0.3 mg/kg, and the goal dose was 0.7 mg/kg. The primary endpoint assessed was the change from baseline at week 24 in 6MWD and a total of 9 secondary endpoints ((improvement of WHO FC or maintenance of WHO FC II; ≥30% decrease in NT-proBNP or <300 ng/L; and ≥30 m improvement in 6MWD); improvements in PVR, NT-proBNP, and WHO FC; time to clinical worsening or death; achievement of low French Risk score; and improvement in PAH-SYMPACT® domain scores (Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts).

A total of 323 patients have enrolled in the study and the study met its primary endpoint (change from baseline at week 24 in 6MWD) and 8 of the 9 secondary endpoints and the overall safety profiles were consistent with other studies.

Sotatercept provided broad therapeutic benefit across a range of effectiveness endpoints and significantly increased exercise capacity as measured by the 6MWD. Our findings demonstrate the clinical efficacy of Sotatercept as a novel mechanistic PAH treatment when used in conjunction with current PAH medications.


A Novel Breakthrough in Wrist-Worn Transdermal Troponin-I-Sensor Assessment for Acute Myocardial Infarction

Evaluation of patients with possible acute myocardial infarction (AMI) is one of the most common presentations in the emergency room, yet the diagnostic steps are time-consuming and expensive.

Sengupta S, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans, that evaluated a wrist-worn transdermal infra-red spectrophotometric sensor (ISS) for the bloodless estimation of elevated Troponin I (Trop-I) in a multi-center prospective cohort study of AMI patients.

 239 AMI patients from five sites were enrolled. The final diagnosis was adjudicated using ECG, Trop-I, echocardiography (regional wall motion abnormality), or a coronary angiogram (detecting a culprit lesion). A transdermal ISS- the Sderived machine-learning model was trained using data from three sites and externally validated with biochemical and clinical data from two sites.

The ISS model predicted elevated Trop-I with the area under the receiver operator characteristics of 0.89 (95% confidence interval [CI], 0.71-0.99; sensitivity, 0.89; specificity, 0.97) and 0.92 (95% CI, 0.78-0.99; sensitivity, 0.91; specificity, 0.90), for internal and external validation cohorts, respectively. In addition, a prediction of elevated Trop-I was associated with regional wall motion abnormalities (Odds Ratio [OR], 8.3; CI, 2.6-26.2; P=0.0003) and significant coronary stenosis (OR, 5.8; CI:1.4-23.3; P=0.01).

The use of a transdermal-ISS for bloodless estimation of Trop-I may substantially improve early diagnosis and risk stratification of AMI patients.


“Just The Two of Us” HFrEF and HF Sans rEF

Lewsey S, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans. HFrEF is defined as LVEF < 35%, < 40%, and HFpEF is defined as LVEF >40 % or ≥ 40% in CHARM,EMPEROR, DELIVER, SPIRIT-HF trials. The existence of an ‘evidence gap’ for the patients with mid-range LVEF occurred due to the historical development of HF trials rather than due to a strong pathophysiological basis for a third entity in HF.  The ESC said a grey area exists between HFrEF and HFpEF. These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF. EF is a continuous variable, HFmrEF is not distinct, and any cutoff used to categorize is arbitrary. HFmrEF is a clinical overlap and not clinically distinct. A retrospective analysis from HF RCTs that have included LVEF between 40-45% suggests benefit from similar therapies to those with LVEF ≤ 40%.

Recommendations for patients with (Stage C) mildly reduced (41-49%) LVEF:

  • An ACE-I, ARB, beta-blocker, MRA, and Sacubitril/ Valsartan may be considered for patients with HFmrEFto reduce the risk of hospitalization and death.

HFmrEF originated to stimulate inquiry into a systematically understudied group of patients and not a strong pathophysiologic basis for the third entity of HF. HFmrEF physiologically behaves as HFrEF, eccentric LV remodeling, decreased contractility, and the rightward shift of the end-diastolic pressure relation. Intraobserver variability ~8-21% and interobserver variability 6-13% in LVEF measurement, measurement bias, and misclassifications for a category of LVEF of 8% (41-49%). LVEF is dynamic and as such the HFmrEF population is not comprised of the same trajectories of EF, which matter more than static EF.

HFmrEF  is not clinically or biomarker distinct, this population is difficult to capture. HFmrEF may be subject to undertreatment from already pervasive clinical inertia and barriers to GDMT implementation.


Usefulness Of H2FPEF Score for Predicting New Atrial Fibrillation

H2FPEF score consists of six factors: heavy, hypertension, atrial fibrillation (AF), pulmonary hypertension, elder, and high filling pressure. These factors are known to be associated with left ventricular diastolic dysfunction.

Suwa Y, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans that evaluated whether the H2FPEF score could predict new AF development in patients without clinically significant cardiac disease.

Among patients referred for clinically-indicated echocardiogram in 2007-2008, those with EF>=50% and no clinical HF or cardiac structural abnormalities were consecutively included and followed up to September 2022. Patients who had a history of AF were excluded. Cox proportional hazards modeling was used to assess predictors of new AF development.

Of a total number of 961 patients (61±15year-old, 48%men), 39 (4.1%) developed new AF during a mean follow-up of 80±66 months. In a Cox-proportional hazard modeling, H2FPEF score was an independent predictor of AF development (per1, HR=1.51, 95%CI=1.05-2.16). The Kaplan-Meier estimates of cumulative event-free survival by H2FPEF status (<2 vs. >2) are shown (Figure).

H2FPEF score can predict new AF development in patients without clinically significant cardiac disease.


Mitral and Tricuspid TEE: Guideline-Based Screening for SHD

Hahn R, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans which talks about the new field – interventional cardiography. These are based on new guidelines that are published last year. These new guidelines are approved by a group of experts. We have multiple probe manipulation (Advance/Withdraw, rotate (CW/CCW), Ante- and Retro-Flexion, Right and left Flexion, and Mechanical Rotation), and advanced 2D and 3D imaging techniques (Simultaneous Multiplane, Real Time 30, 30 MPR, Full Volume 30, Zoom 30, and Color 30) that can be used to adequately characterize the valves. However, a few imaging techniques such as deep esophageal or shallow transgastric imaging were added to the new guidelines.

The techniques allow one to see 2D and 3D images. Functional imaging is also needed for the quantification of disease severity. The commissural view is one of the major imaging views. This allows us to sweep from lateral to medial and vice versa, and helps to understand the severity and location of valve malformation and mitral valve regurgitation. In addition, it is necessary to perform quantification.

Utilizing a protocol as a starting point for imaging in all procedures and all patients enables standardization of image acquisition, reduction in variability in the quality of imaging and reporting, and ultimately better patient care.

The transgastric view becomes an essential view for procedures and therefore should be attempted in all pre-procedural proceedings. The transgastric use is essential because apparently, not all regurgitation takes place in A2 P2 scallops. This is a 2D view where one can see all the tricuspid valves. Papillary muscles and chordae can be identified. With the use of the Deep Transgastric Level view, one can mimic a 5-chamber view as well as 3 chamber view.

One of the other essentials for structural imaging is anatomy. The ACCC/AHA guidelines are very clear that one should consider Transcatheter aortic valve repair (TAVR) if the anatomy is suitable.

The Carpentier classification divides mitral valve regurgitation into three types based on leaflet motion: Type I: normal leaflet motion (Leaflet perforation), Type II: excessive leaflet motion (Mitral valve prolapse/Flail), and Type III: restricted leaflet motion (Mitral Annular Ca/RHD). Finding the intended gripping zone(s) by locating the TR on colour Doppler and imaging the leaflets during systole and diastole to determine length and gaps are the screening’s objectives.

Imaging protocols should be tailored to be comprehensive but focused on the abnormal structure identified and/or transcatheter intervention under consideration.

Training Guidelines for Interventional Echo: Competencies Defined

Sayan E, presented a session at the American College of Cardiology (ACC) on 6th March 2023, at New Orleans which talks about transcatheter therapies. Transcatheter therapies for heart disease have advanced significantly over a decade and interventional echocardiography (IE) has an integral role in a plethora of heart interventions such as in all four heart valves including transcatheter mitral valve replacement, transcatheter tricuspid valve-in-valve (ViV), electrophysiology assessment Heart valves and interventions, LAO ablation, TAVR, etc. Imaging techniques have also evolved in parallel, such as Live 30 MPR (used in every single intervention), 4D intra-cardiac echo (emerging technology), and Live T fusion (adjunct to complex interventions).

The term “interventional echocardiographer (IE)” was first coined in 2009 by Dr. Martin Lyons. IE is an integral part of the multidisciplinary cardiac team with specialized functions in the overall path of care. The imager must also have specific knowledge and technical skills in all aspects of structural heart disease. However, skills are mostly acquired on a hands-on basis through on-the-job training and proctoring.

The ability to give interventionalists with imaging advice for transcatheter procedures comprehend how echocardiography can assist avoid or diagnose procedural problems, be fluent with 3D imaging, and have frequent exposure to these procedures are all requirements for this profession. In a retrospective cohort study, it was seen that after mitral valve surgery or interventions, the adjusted RR of mortality was 61% lower for patients in the dedicated heart team compared to no heart team, and 29% lower compared to a general heart team (without an imaging cardiologist).

According to the CMS National Coverage Determination TEER (2021), the concept of the Heart Team embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team should include a cardiac surgeon, interventional cardiologist, echocardiographer, and HF cardiologist (for FMR).

Fellows who have completed an ACGME-accredited 3-year general cardiology or 1-year CT anesthesiology fellowship or are practicing cardiologists or cardiothoracic anesthesiologists with specialization in TEE and have significant work experience can access Level III-SHD training.

Interventional echocardiography is a novel imaging specialization that is rapidly growing. Formalizing training, meanwhile, presents both possibilities and drawbacks. To make sure that interventional echocardiographers have the skills essential to handle this challenging duty, training criteria are required.


Functional Evaluation After Structural Intervention: TTE Pearls

Betz J, presented a session at the American College of Cardiology on 6th March 2023 which talks about Transcatheter aortic valve replacement (TAVR). TAVR is a minimally invasive heart procedure to replace a thickened aortic valve that cannot fully open (aortic valve stenosis). TAVR can help restore blood flow and reduce the signs and symptoms of aortic valve stenosis. However, there are several complications associated with TAVR such as paravalvular regurgitation (4-6%), mitral regurgitation (rare), annular rupture (1%), coronary obstruction (<1%), valve embolization (rare), RV perforation (Pacemaker-related). The forming mechanism for paravalvular AR after TAVR is calcification or shallow, deep, or undersized implantation of the valve. Post-TAVR is one of the most common procedures performed in the cath lab.

By looking at short-axis aortic levels where the circumferential extent of aortic regurgitation can be broadly identified through the imaging planes, one can identify valvular and paravalvular regurgitation. This can help determine the severity of pulmonary vascular resistance (PVR) also. Further to being useful in the short-axis view, a circumferential extent, sweeping over the detected numerous jets is also crucial.

It is crucial to have a CW Doppler for the pressure half-time once doctors have determined there is no leak at the short-axis level (PHT). A low PHT may signal severe regurgitation. Another symptom that there could be severe regurgitation is color imaging of the descending thoracic aorta if professionals notice diastolic flow reversal. The LVOT must not close in order for the aortic valve to calcify.

The LVOT Diameter is measured immediately proximal to the inflow aspect of the stent (From the leading edge to the following edge). In order to stay clear of the pre-valve acceleration area, the PW sample volume is placed close to the valve.

One of the many topics we must address is spectral doppler, which is quite significant. Doppler’s alignment is one of the most important factors; when aligned correctly, it provides accurate value. Angle correction feature usage in aortic continuous wave doppler is not recommended (avoided). Instead, it is suggested to test every window that is offered and record all attempts in other windows. According to one study, up to 25% of individuals’ aortic stenosis severity is incorrectly calcified as a result of disregarding the non-apical window.

The zoom/open view of the LVOT is the secret to success in this case. It was suggested to ensure correct volume placement to optimize gain, to use all available windows for CW and non-imaging probes, and to sweep through the valve to seek for PVL.