• News
  • Spirituality
    • Dream Interpretation
    • Angel Numbers
    • Tarot
    • Prayers
    • Spells
  • Medicine
  • Science
  • Celebs
  • Betting

Heart Failure - Analyzing New Drug Therapies

376Shares
46.9KViews

Even though the death rate from cardiovascular (CV) disease has gone down a lot in the last few decades, it is still the leading cause of death in some countries.

Even though CV medicines caused more people to have chronic CV problems like heart failure (HF), they also helped people with CV disease live longer.

The effectiveness of pharmacological therapy in HF patients has been evaluated in a number of clinical randomized studies. There is still a lot of CV death, but not as much as there used to be. This could be because new therapeutic options are often looked for using an "old" strategy that uses non-targeted, non-personalized treatments that aren't based on each person's pathophysiology.

Instead, each patient with HF may have unique etiologies, clinical traits, and comorbidities, all of which may potentially be taken into account.

The therapeutic benefits of drugs that work by regulating neurohumoral and hemodynamic processes reach a plateau quickly, and it is very rare to get more benefits from increasing doses or using other drugs that work in the same way.

COPYRIGHT_OAPL: Published on https://www.oapublishinglondon.com/hh/heart-failure/ by Alexander McCaslin on 2022-08-04T19:06:21.434Z

Recently, HF with intact ejection fraction (HFpEF) has been studied using a new paradigm. Some of the comorbidities that cause myocardial dysfunction in HFpEF are obesity, diabetes, and chronic obstructive pulmonary disease. They do this by inflaming the coronary microvascular endothelium.

What Exactly Is Heart Failure?

Congestive heart failure, often known as heart failure, is a condition where the heart muscle is unable to pump blood as efficiently as it should. Shortness of breath is frequently brought on by this because blood frequently backs up and fluid can accumulate in the lungs.

Some heart conditions, like coronary artery disease (CAD) or high blood pressure, eventually make the heart too weak or stiff to fill and pump blood properly.

With the right care, heart failure symptoms and signs can be reduced, and some people may even live longer. Your quality of life can be improved by making lifestyle changes, including losing weight, getting more exercise, cutting back on salt (sodium) in your diet, and managing stress.

Heart failure, however, poses a risk to life. Heart failure can cause severe symptoms, and some people may need a ventricular assist device (VAD) or a heart transplant. Preventing and managing problems like coronary artery disease, high blood pressure, diabetes, and obesity that can lead to heart failure is one way to do so.

Heart Failure Overview

What Are The Symptoms Of Heart Failure?

Signs and symptoms of heart failure can include:

  • Breathlessness when lying down or when exercising
  • Weakness and fatigue
  • Legs, ankles, and feet swell
  • Irregular or fast heartbeat
  • Reduced ability to exercise
  • Persistent cough or wheezing with blood-tinged mucus that is either white or pink
  • Swelling in the belly area (abdomen)
  • Very fast weight gain due to fluid accumulation
  • A lack of appetite and nausea
  • Having difficulty concentrating or being less alert
  • Chest pain if a heart attack leads to heart failure

Microcirculation

Myocardial activity and effectiveness depend on functional and "healthy" coronary microcirculation. It plays a pivotal role in the regulation of coronary blood flow in response to cardiac oxygen requirements. Impairment of this mechanism is defined as coronary microvascular dysfunction (CMD). HF patients often have problems with their microcirculation, and ischemic HF patients also tend to get worse over time.

CMD is associated with the development of HFpEF. In fact, decreased bio-accessibility of nitric oxide (NO) in endothelial dysfunction plays an important role in HF, mainly in HF with HFpEF. In HFpEF models, inflammation in the coronary microvascular endothelium lowers the amount of nitric oxide, the amount of cyclic guanosine monophosphate, and the activity of protein kinase G (PKG) in the cardiomyocytes next to it.

Recent reports suggest that microcirculation may have additional roles in supporting a healthy microenvironment. Experimental models have shown that restoring healthy microcirculation and endothelium could be a possible therapeutic approach to treat HF.

Coronary perivascular fibrosis and the resulting reduced coronary blood flow may represent a novel therapeutic target for improving coronary microcirculation.

Lastly, there are signs that new translational drugs, such as growth factors, non-coding RNA therapeutics, and drugs that target metabolites or metabolic signaling, have an effect on microcirculation.

Forthcoming trials will better assess coronary microcirculation by cardiac magnetic resonance imaging (cMRI).

Interstitium

Interstitium biology is critical for developing novel medications for HF, giving numerous possible therapeutic targets: fibroblasts, collagen, and collagen-regulating enzymes. Myocardial interstitium is a functioning micro-habitat, not an inert structure.

Extracellular matrix (ECM) enlargement and myofibroblast type I collagen secretion characterize HF interstitial and capillary fibrosis. When collagen type I is crosslinked, HF patients have higher filling pressures.

A novel cMRI approach, T1 mapping, analyzes the extracellular volume fraction, ECV, in human myocardium, allowing for a more exact characterization of myocardial fibrosis. ECV may be utilized in phase II studies to evaluate anti-myocardial fibrosis therapies.

Myocardial interstitial fibrosis (MIF) is frequent in HFpEF and HFrEF patients. It affects cardiac function and outcome. Changes in collagen fibers and ECM determine it.

New pathways may make safe pharmacological medications useful for treating MIF. Sacubitril/valsartan and empagliflozin reduced MIF in diabetic HF mice and enhanced LV function.

In individuals with HFpEF, sacubitril and valsartan demonstrated a modest decrease in hospitalizations for HF and CV deaths in a phase III clinical study. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are being tested to lower MIF in people.

Pirfenidone and tranilast reduce TGF-β signaling to prevent fibrosis. More research is needed to identify safe TGF-β pathway targets for MIF reduction.

Chymase is a chymotrypsin-like serine protease released by damaged mast cells and cardiomyocytes. Chymase is created after secretion and generates or activates locally profibrotic factors, such as angiotensin (Ang) II, transforming growth factor (TGF) β, and matrix metalloproteinases.

This makes it a possible post-MI therapeutic target. Oral chymase inhibitor Fulacimstat improves LV dysfunction after myocardial infarction.

What is heart failure?

Cardiomyocyte

Calcium Handling

Heart failure myocardial contractility is reduced by abnormal intracellular Ca2+ processing in cardiomyocytes. Ryanodine receptor and Ca-calmodulin kinase IIdelta (CaMKIIdelta) regulate Ca2+ homeostasis in cardiomyocytes, which is compromised in cardiac dysfunction.

Only translational medicine exists. Istaroxime may be a potential breakthrough medicine. Istaroxime has a luso-inotropic effect in HF by increasing SERCA2a ATPase activity and increasing Ca2+ absorption into the sarcoplasmic reticulum (SR) by reducing the effect of phospholamban on SERCAa. This is done without cAMP or PKA.

A 24-hour infusion of istaroxime improved the diastolic and systolic performance of the heart in AHF patients with HFrEF without causing any serious side effects.

SERCA2a sequesters cytosolic Ca2+, allowing actin-myosin uncoupling and ventricular relaxation. SERCA2a is downregulated in CHF, leading to systolic and diastolic function impairment.

Mitochondrial Function

HF patients have mitochondrial abnormalities. Researchers are looking into a lack of activity in the mitochondrial electron transport chain, an increase in reactive oxygen species (ROS) production, a change in how metabolic substrates are used, a change in mitochondrial dynamics, and a change in ion homeostasis.

Neladenoson and elamipretide influence mitochondrial activity. Neladenoson, a partial adenosine A1 agonist, had no atrioventricular conduction or neurological adverse effects in HFrEF patients. The therapy had a dose-dependent renal function decline and no significant change in exercise capacity in HFpEF patients.

Elamipretide may penetrate the inner mitochondrial membrane and combine with cardiolipin. This interaction stabilizes cytochrome c to facilitate electron transport and oxidative phosphorylation.

In animal models and people, elamipretide improved LVEF, LV end diastolic pressure, cardiac hypertrophy, myocardial fibrosis, and cardiac ATP production. In the PROGRESS-HF (phase 2) study, elamipretide did not improve LV end systolic volume compared to placebo after 4 weeks. More clinical investigations are needed to determine elamipretide's involvement in HF. HFrEF may also need longer-term studies.

Signaling Pathways

Reduced NO bioavailability reduces sGC and cGMP production, which are necessary for cardiac and vascular function. Cyclic GMP lowers heart fibrosis and improves endothelial function. HF's cGMP shortage may help treat HF's direct NO-independent sGC stimulation.

Vericiguat is a soluble guanylate cyclase (sGC) stimulant studied in the SOCRATES PRESERVED, REDUCED, and VICTORIA trials. It bypasses nitric oxide and directly induces sGC. This potential medication boosts cGMP and benefits the CV system. The VICTORIA study found that compared to placebo, vericiguat cut the risk of CV death or hospitalization for HF by 10%.

HF may be caused by increased arginine vasopressin signaling in V1a or V2 receptors. V1a activation may produce vasoconstriction, cardiac hypertrophy, and fibrosis because intracellular signaling pathways are similar to angiotensin II. Water retention and hyponatremia may result from V2 activation.

Anti-inflammatory Effects Of Drugs

To the best of our knowledge, there is insufficiently reliable information on anti-inflammatory medications in HF (anti-TNF-α drugs have not shown advantages in CHF). According to earlier research, inflammatory mediators may have a role in CHF, leading to peripheral vascular abnormalities and unfavorable remodeling. Pro-inflammatory, pro-fibrotic, or immunological changes are some of the inflammatory pathways that are proposed in HFpEF.

Previous studies found elevated levels of TNF-α, IL-1β, and IL-6, three inflammatory cytokines, in HF. There is an inflammatory imbalance in the cytokine system in HF patients since this improvement in inflammatory mediators does not seem to be accompanied by a comparable rise in anti-inflammatory cytokines such as IL-10 and TGF-β.

Cardiac function is known to be suppressed by interleukin-1β (IL-1β). A possible therapeutic target in HF was identified by a small secondary study of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial. Anakinra (IL-1 receptor antagonist) medication was only related to an improvement in exercise capacity in individuals with LVEF <50% after 12 weeks of treatment.

Future Developments

Gliflozins provide the most promising outcomes for advances in the near future. Researchers looked at SGLT2i in people with HF, whether or not they had diabetes mellitus. They did this because the EMPAREG-HF study (empagliflozin), the CANVAS program (canagliflozin), and the DECLARE-TIMI 58 trial (dapagliflozin) all showed promising results in type 2 diabetic patients with prior CV events.

In both diabetics and non-diabetics, the DAPA-HF trial and the EMPEROR-Reduced trial results showed a significant decrease in CV mortality and HF hospitalization. Even though it is possible that these medications might have effects on cardiomyocytes, the exact way that gliflozins affect the heart is still not fully understood.

The effects and mechanisms of gliflozins in HFrEF and HFpEF patients with and without T2DM will be made clear by ongoing clinical studies. New information has come out of studies on endothelial function in CHF. The information about HFpEF patients taking empagliflozin is especially interesting.

The human heart in blue having arteries with a blue flatline in the background
The human heart in blue having arteries with a blue flatline in the background

People Also Ask

How Long Can You Survive With Heart Failure?

Although congestive heart failure treatment has recently advanced, researchers say the outlook for those who have the condition remains dire, with around 50% having an average life expectancy of fewer than five years. Nearly 90% of those with advanced heart failure pass away within a year.

What Is The Main Cause Of Heart Failure?

Most of the time, coronary artery disease, high blood pressure, and a previous heart attack are to blame for heart failure.

Does Heart Failure Mean Death?

Heart failure results when the heart cannot pump enough blood and oxygen to support the body's other organs. Although heart failure is a serious ailment, the heart is still beating when it occurs. Heart failure is not a death sentence, despite the fact that it can be a serious disease, and treatment is more effective than ever.

What Happens If You Get A Heart Failure?

Heart failure occurs when the weaker heart is unable to sufficiently pump blood to the cells. As a result, some people experience coughing, shortness of breath, and exhaustion. Daily tasks like carrying groceries, walking, and climbing stairs can become exceedingly challenging.

Concluding Remarks

Patients who are suffering from heart failure have a dismal outlook on life, notwithstanding recent developments in the treatment of chronic heart failure (whether through pharmacological or non-pharmacological means). This dismal outlook highlights the importance of establishing new avenues for testing new heart failure medications, in addition to neurohumoral and hemodynamic modulation approaches. Because of this, research and development of new medicines to treat HF must always focus on the use of new therapeutic approaches.

Myocytes, mitochondria, microvascular circulation, and the interstitium are some of the potential therapeutic targets for novel heart failure medications, particularly those intended for HFpEF. Further research is required to translate information generated from preclinical evidence into evidence that can be used in real-world settings, along with new possible therapy techniques focused on new therapeutic targets.

Share: Twitter | Facebook | Linkedin

About The Authors

Alexander McCaslin

Alexander McCaslin

Recent Articles

No articles found.