Back to the basics: The need for an etiological classification of chronic heart failure.

The left ventricular (LV) ejection fraction (LVEF), despite its severe limitations, has had an epicentral role in heart failure (HF) classification, management, and risk stratification for decades. The major argument favoring the LVEF based HF classification has been that it defines groups of patients in which treatment is effective. However, this reasoning has recently collapsed, since medical treatment with neurohormonal inhibitors, has proved beneficial in most HF patients regardless of the LVEF. In addition, there has been compelling evidence, that the LVEF provides poor guidance for device treatment of chronic HF (implantation of cardioverter defibrillator, cardiac resynchronization therapy) since sudden cardiac death may occur and cardiac dyssynchronization may be disastrous in all HF patients. The same holds true for LV assist device implantation, in which the LVEF has been used as a surrogate for LV size. In this review article we update the evidence questioning the use of LVEF-based HF classification and argue that guidance of chronic HF treatment should transition to more contemporary concepts. Specifically, we propose an etiologic chronic HF classification predominantly based on epidemiological data, which will be foundational for further higher resolution phenotyping in the emerging era of precision medicine.

Acute mitral regurgitation with and without acute heart failure.

Acute severe mitral regurgitation (MR) is rare, but often leads to cardiogenic shock, pulmonary edema, or both. Most common causes of acute severe MR are chordae tendineae (CT) rupture, papillary muscle (PM) rupture, and infective endocarditis (IE). Mild to moderate MR is often seen in patients with acute myocardial infarction (AMI). CT rupture in patients with floppy mitral valve/mitral valve prolapse is the most common etiology of acute severe MR today. In IE, native or prosthetic valve damage can occur (leaflet perforation, ring detachment, other), as well as CT or PM rupture. Since the introduction of percutaneous revascularization in AMI, the incidence of PM rupture has substantially declined. In acute severe MR, the hemodynamic effects of the large regurgitant volume into the left atrium (LA) during left ventricular (LV) systole, and in turn back into the LV during diastole, are profound as the LV and LA have not had time to adapt to this additional volume. A rapid, but comprehensive evaluation of the patient with acute severe MR is essential in order to define the underline cause and apply appropriate management. Echocardiography with Doppler provides vital information related to the underlying pathology. Coronary arteriography should be performed in patients with an AMI to define coronary anatomy and need for revascularization. In acute severe MR, medical therapy should be used to stabilize the patient before intervention (surgery, transcatheter); mechanical support is often required. Diagnostic and therapeutic steps should be individualized, and a multi-disciplinary team approach should be utilized.

Aortic Stiffness: A Major Risk Factor for Multimorbidity in the Elderly.

Multimorbidity, the coexistence of multiple health conditions in an individual, has emerged as one of the greatest challenges facing health services, and this crisis is partly driven by the aging population. Aging is associated with increased aortic stiffness (AoStiff), which in turn is linked with several morbidities frequently affecting and having disastrous consequences for the elderly. These include hypertension, ischemic heart disease, heart failure, atrial fibrillation, chronic kidney disease, anemia, ischemic stroke, and dementia. Two or more of these disorders (multimorbidity) often coexist in the same elderly patient and the specific multimorbidity pattern depends on several factors including sex, ethnicity, common morbidity routes, morbidity interactions, and genomics. Regular exercise, salt restriction, statins in patients at high atherosclerotic risk, and stringent blood pressure control are interventions that delay progression of AoStiff and most likely decrease multimorbidity in the elderly.

Floppy mitral valve/mitral valve prolapse and sudden cardiac death.

It is well appreciated today that sudden cardiac death (SCD) occurs in patients with floppy mitral valve (FMV)/mitral valve prolapse (MVP) without significant mitral regurgitation . Data from studies most likely represent a heterogeneous population and probably underestimate the true incidence of SCD in this group of patients. SCD in patients with FMV/MVP occurs mostly in young individuals without comorbidities. Over the last decade, the phenotypic expression of patients with FMV/MVP at risk for SCD (bileaflet prolapse, redundant mitral leaflets, symptomatic young women) have been defined, possible pathophysiologic mechanisms leading to SCD have been proposed, and appropriate steps to prevent the catastrophic event, though in evolution, have been suggested. In this review, state-of-the-art knowledge related to SCD in patients with FMV/MVP is summarized.

The Interventricular Septum: Structure, Function, Dysfunction, and Diseases.

Vertebrates developed pulmonary circulation and septated the heart into venous and arterial compartments, as the adaptation from aquatic to terrestrial life requires more oxygen and energy. The interventricular septum (IVS) accommodates the ventricular portion of the conduction system and contributes to the mechanical function of both ventricles. Conditions or diseases that affect IVS structure and function (e.g., hypertrophy, defects, other) may lead to ventricular pump failure and/or ventricular arrhythmias with grave consequences. IVS structure and function can be evaluated today using current imaging techniques. Effective therapies can be provided in most cases, although definitions of underlying etiologies may not always be easy, particularly in the elderly due to overlap between genetic and acquired causes of IVS hypertrophy, the most common being IVS abnormality. In this review, state-of-the-art information regarding IVS morphology, physiology, physiopathology, and disease is presented.

Cardiovascular Disease, Cancer, and Multimorbidity Interactions: Clinical Implications.

BACKGROUND: With the aging population, the frequency of cardiovascular disease (CVD), cancer, and other morbid conditions is increasing dramatically. In addition, one disease may affect the other leading to a vicious cycle. SUMMARY: With aging, the function of organs and systems of the human body declines including the immune system resulting in a diminished response to various pathogens and a chronic inflammatory process; these changes, in addition to other risk factors, contribute to the development of multiple morbid conditions including CVD and cancer. Multimorbidity in the elderly has become the rule rather than the exception today. Further, this association between CVD and cancer, at least partially, is explained by both diseases sharing common risk factors and from accelerated vascular aging due to cancer and its associated therapies. Multiple studies have shown that the incidence of cancer is much higher in patients with CVD compared to the general population. These associations among CVD, cancer, and their connection to systems of the human body provide an opportunity for novel therapies. Development of new drugs should be addressed to focus on multiple systems and not just only to one disease. Further, collecting information from registries and processing large amounts of data using artificial intelligence may assist the clinician when treating an individual patient in the future. KEY MESSAGES: As the aging population increases, CVD, cancer, and multimorbidity will continue to constitute a major health problem in the years to come. The physician who is taking care of such a patient, in addition to knowledge, requires clinical wisdom, clinical experience, and common sense in order to apply the continuous evolving knowledge to the individual patient.

Totally endoscopic aortic valve replacement with concomitant trans-aortic mitral valve repair for mitral regurgitation.

BACKGROUND: Minimally invasive aortic valve procedures through a hemi-sternotomy or a right anterior mini-thoracotomy have gained popularity over the last several years. Totally endoscopic aortic valve replacement (TEAVR) is an innovative and a less invasive (incision-wise) surgical aortic valve replacement technique. The operative steps of TEAVR have been reported previously from our group. Mitral regurgitation (MR) frequently accompanies aortic valve disease that at times may also require repair. Totally endoscopic surgery in such cases has not been tested. PRESENTATION OF THE TECHNIQUE: We present a surgical technique for a totally endoscopic approach to aortic valve replacement and concomitant mitral valve repair for primary and secondary MR. An aortotomy incision was used avoiding an atriotomy, which results in an increase in cross-clamp (XC) and cardiopulmonary bypass (CPB) times that could be associated with higher mortality and morbidity. Neochords (artificial chordae tendineae) were used for primary MR and an edge-to-edge approach for secondary MR. CONCLUSION: TEAVR and concomitant mitral valve repair can be performed successfully with reasonable XC and CPB times with excellent short-term results.

ACE2, the Counter-Regulatory Renin-Angiotensin System Axis and COVID-19 Severity.

Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin-angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1-7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin-angiotensin-aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1-7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed.

The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications.

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.

Renin-angiotensin-system inhibition in the context of corona virus disease-19: experimental evidence, observational studies, and clinical implications.

Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.

Fallacies in medical practice: Renin-angiotensin-aldosterone system inhibition and COVID-19 as a Paradigm.

In emergency situations, such as during the coronavirus disease 2019 (COVID-19) pandemic, medical community looks for quick answers and guidance. Under these circumstances, experts instead of admitting ignorance, feel obliged to give an answer, often pressurized by political or other authorities, even when such an answer is unavailable. Under these circumstances, publications based on fallacious reasoning are virtually unavoidable. In the present review, we summarize examples underlying fallacious reasoning recommendations regarding treatment with Renin-Angiotensin-Aldosterone inhibitors (RAASi) in the COVID-19 context. Most scientific societies emphasize that RAASi use is safe and that these agents should not be discontinued, based mainly on the results of observational studies (OSs) and occasionally preprints, as relevant randomized controlled trials (RCTs) are currently lacking. However, over the past 4 decades, results from successful RCTs have repeatedly proved that practices based on OSs were wrong. Lack of RCTs results in uncertainty. In this setting, the physician's wisdom and knowledge related to pathophysiologic mechanisms and effect of pharmacologic agents become even more important as they may limit fallacies. Based on these principles, in diseases (e.g., mild, or moderate arterial hypertension, etc.) where equally effective alternative therapies to RAASi are available, these therapies should be applied, whereas in diseases (e.g., heart failure, diabetic kidney disease, etc.), where equally effective alternative therapy compared to RAASi is not available, RAASi should be used. Admittedly this strategy, like all the other recommendations, is not based on solid evidence but is intended to be individualized and follows the Hippocratic "Primum non nocere".

Preoperative determination of artificial chordae tendineae length by transoesophageal echocardiography in totally endoscopic mitral valve repair.

OBJECTIVES: Artificial chordae tendineae are widely used for surgical repair in patients with mitral regurgitation due to floppy mitral valve/mitral valve prolapse. Expanded polytetrafluoroethylene has been used to construct these artificial chordae; however, the determination of the optimal length of the chordae prior to surgery has been an issue. For this reason, such a method was developed and the results of its use are presented. METHODS: Forty-seven consecutive patients with significant mitral regurgitation due to floppy mitral valve/mitral valve prolapse who underwent totally endoscopic mitral valve surgery were studied. The chordae length was predetermined using transoesophageal echocardiography. The length between the top of the fibrous body of the papillary muscle and the coaptation line of the 2 leaflets of the mitral valve was measured and used to define the length of the chordae to be used for repair. Then under stereoscopic vision, a total endoscopic mitral valve repair was performed. RESULTS: The predicted mean length of chordal loops was 19.76 ± 0.71 mm (median 20, range 16-28) and the actual mean length of chordal loops used was 19.68 ± 0.74 mm (median 20, range 16-26) demonstrating an excellent correlation between the two (r = 0.959). The mean number of chordae loops used per patient was 5.12 ± 0.62 (median 4, range 2-12). All patients at the time of discharge had no or trivial mitral regurgitation on transoesophageal echocardiography. CONCLUSIONS: The chordae length used for mitral valve repair can be determined prior to surgery using transoesophageal echocardiography with a high degree of accuracy. Further, total endoscopic repair in this group of patients provides excellent results. For these reasons, it is expected that this method will replace most traditional approaches to cardiac surgeries in the years to come.

Floppy mitral valve/mitral valve prolapse: A complex entity with multiple genotypes and phenotypes.

Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a common valvular abnormality affecting 2% to 3% of the general population. It occurs in a heterogeneous group of patients with varying and age dependent expressions. FMV/MVP can be familial or sporadic, isolated (called non-syndromic) or as a part of a well-defined syndrome of heritable connective tissue disorders or other diseases. A wide range of phenotypic expression exists ranging from asymptomatic to non-specific symptoms related to neuroendocrine or autonomic nervous system functional abnormalities, varying degrees of mitral regurgitation that may require interventional therapy, heart failure, infective endocarditis, cardiac arrhythmias and/or sudden cardiac death. FMV/MVP is predominantly considered a heritable disorder with clinical manifestations not present at birth, but appearing later in life. Though a variant gene may initiate the development of FMV/MVP, precise phenotypic expression may be related to multiple other molecular, genetic and epigenetic factors that modify the final expression of the disease. A better understanding of these mechanisms will help to better define the natural history of the disease, inhibit disease progression and even prevent the phenotypic expression of FMV/MVP.